Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH:21][OH:22])=[NH:20])[CH2:14]2)=[CH:9][CH:8]=1.[C:26](Cl)(=O)[CH3:27].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][C@H:15]([C:19]3[N:20]=[C:26]([CH3:27])[O:22][N:21]=3)[CH2:16][C:17]2=[O:18])=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: N=C(NO)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidine-3-carboxamidine (0.020 g, 0.58 mmol) was dissolved in a mixture of 0.4 ml pyridine and acetyl chloride (0.01 ml, 0.116 mmol) was slowly added at 0° C. The mixture was then stirred at 70° C. overnight. Iced water was added and the mixture was stirred for one hour. Extraction with a saturated solution of ammonium chloride and dichloromethane gave the crude product that was purified by column cromatography on silica gel using a 19:1-mixture of dichloromethane and methanol as the eluent to obtain the title compound as a light yellow solid (0.0197 g, 92% of theory). MS (m/e)=368.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(F)c([N+](=O)[O-])c2)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium (1 g) was added to a mixture of 5 g of 4-methoxyphenylboronic acid, 6.6 g of 5-bromo-2-fluoronitrobenzene and 30 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was heated to reflux for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried, and concentrated to give a brown oily solid. The solid was purified by column chromatography on silica gel in 5% ethyl acetate in hexane to give crude 4-fluoro-4′-methoxy-3-nitrobiphenyl as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28])[CH3:30]
Reactant: CCN(CC)CCCOc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCN(CC)CCCOc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Yield: 38.8 %

Procedure:
N,N-Diethyl-N-[3-({6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolyl}oxy)propyl]amine (525 mg), iron powder (330 mg), ammonium chloride (660 mg), ethanol (20 ml) and water (5 ml) were stirred together at 80° C. for 80 minutes. After filtration with celite, NH type silica gel was added to the filtrate, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate, followed by ethyl acetate:methanol=3:1) to obtain 190 mg of a brown oil.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:11][CH:12]=2)[O:7][CH2:6]1)[CH2:2][CH3:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:11][CH:12]=2)[O:7][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CCCNC1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN(Cc1ccccc1)C1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
Trifluoro-methanesulfonic acid 3-propylamino-chroman-7-yl ester (1.62 g, 4.78 mmol) and benzaldehyde (975 μl, 9.56 mmol) were dissolved in dichloromethane (60 ml). Acetic acid (710 μl, 12.37 mmol) and sodium trisacetoxyborohydride (3.04 g, 14.34 mmol) were sequentially added to the reaction mixture and stirred over the weekend at room temperature. Dichloromethane and water were added to the reaction mixture. The aqueous phase was adjusted to a pH=6 with a 1 molar solution of NaOH. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude product was purified by chromatography on silica gel using cyclohexane/ethyl acetate (100:0 to 95:5) as eluent, yielding the purified product (1.24 g, 50% purity, 30% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]2[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=2)=[CH:27][CH:26]=1>CCOCC>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:50])=[CH:52][CH:53]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from diethyl ether to yield 1-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}piperidine.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:9])[CH2:7][CH3:8].[OH2:10]>>[CH:1]([OH:9])([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:8][CH:7]([CH2:1][CH3:2])[CH:6]([OH:10])[OH:9]
Reactant: CCCO
Reactant: O
Reactant: CCCCO
Product: CCC(C)C(O)O
Product: CCCC(O)O

Procedure:
Before the reaction, the reaction system was charged in a similar way to Example 1 with 20 g of Raney Ni/Mo in 300 ml of water. At 30 bar and a reactor temperature of from 145 to 151° C., the product was obtained in an amount of 213 g/h and comprised 93.3% by weight of butanediol, 0.3% by weight of 2-methylbutanediol, 1.5% by weight of n-butanol, 4.2% by weight of n-propanol and a few further products in amounts of less than 0.08% by weight. The STY was about 0.25 kg of butanediol/l·h.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: OCc1ccccn1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
NaH (0.22 g, 5.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (15 mL), the suspension was cooled to 0° C. and 2-pyridylmethanol (0.55 g, 5.0 mmol) was added. The suspension was stirred at 0° C. for 1 h and added to a stirred solution of Intermediate 2 (0.66 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 2-pyridylmethanol in THF were added after 18 and 36 h, respectively. After 54 h the reaction mixture was quenched with water (10 mL), the solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 1%, 2% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 70% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyridin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (86.4 mg, 14.4%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])N(OC)C)[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]1)=[O:17].[CH3:42][Mg]Br.C1COCC1.[Cl-].[NH4+]>C1COCC1>[C:25]([C@H:23]1[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:20][C@@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:24]1)(=[O:30])[CH3:42]
Reactant: C[Mg]Br
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.06 g) in THF (20 ml) was added 1M-methyl magnesium bromide-THF solution (9.24 ml), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:2) was concentrated under reduced pressure to give the object product (0.59 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:30])[CH:10]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.[CH:42]1[CH:43]=[CH:44][C:45]2[N:50](O)N=[N:48][C:46]=2[CH:47]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:48][C:46]1[CH:47]=[CH:42][CH:43]=[CH:44][C:45]=1[NH:50][C:25]([C:24]1[CH:23]=[CH:22][C:21]([CH:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[O:12])[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:30])=[CH:29][CH:28]=1)=[O:27]
Reactant: O=C(O)c1ccc(C(C(=O)Nc2cccc(Cl)c2)C(=O)Nc2cccc(Cl)c2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2cccc(Cl)c2)C(=O)Nc2cccc(Cl)c2)cc1
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 4-(2-[(3-chlorophenyl)amino]-1-{[(3-chlorophenyl)amino]carbonyl}-2-oxoethyl)benzoic acid (61 mg, 0.14 mmol) in DMF (3 mL) at room temperature was added EDCI (31 mg, 0.16 mmol) and HOBT (22 mg, 0.16 mmol). The solution was stirred for 30 min and 1,2-phenylenediamine (45 mg, 0.42 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified directly by reverse phase HPLC (20% to 80% MeCN in water) to give 2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-N,N′-bis(3-chlorophenyl)malonamide (46 mg, TFA salt, 52%) as a white solid: 1H NMR (600 MHz, CD3OD) δ 8.06 (d, J=8.2 Hz, 2H), 7.79 (t, J=2.1 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.44 (dd, J=8.2, 1.2 Hz, 2H), 7.36 (d, J=7.9 Hz, 1H), 7.33-7.24 (m, 5H), 7.11 (dd, J=7.9, 0.8 Hz, 2H); ESIMS calcd 533.1 (M++H), found 533.0 (M++H).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (38 ml) was dissolved in hexane (300 ml), cooled in an ice-bath and n-butyllithium (100 ml of a 2.5M solution in hexane) added. The mixture was stirred at 0°C. for 15 minutes before adding 2,3-dihydrobenzo[b]furan (30 g) dropwise over 30 minutes. The mixture was allowed to warm to room temperature over 30 minutes, stirred at room temperature for a further 4 hours, poured onto an excess of solid carbon dioxide and left to stand for 3 days by which time the solvent had evaporated off. The residue was partitioned between ethyl acetate (1L) and 4N aqueous hydrochloric acid solution (240 ml), the layers separated and the aqueous layer extracted with ethyl acetate (500 ml). The organic extracts were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was then triturated with diethyl ether to give 2,3-dihydrobenzo[b]furan-7-oic acid as a white solid (21 g).
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][N:10]=[C:11]=[O:12]>>[CH3:9][NH:10][C:11]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:12]
Reactant: CN=C=O
Reactant: CSC(C)(C)C=NO
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
The process of this invention can be carried out by contacting 2-methyl-2-(methylthio) propionaldehyde oxime with methyl isocyanate in the presence of an aqueous medium for a period sufficient to form 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime as a solid in an aqueous slurry which is then filtered to give a water-wet cake.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].CO>C1COCC1.O.[Zn]>[C:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2)nc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of toluene (15 mL) and water (5 mL) was degassed with argon for 5 minutes. Sodium carbonate (0.802 g, 0.00454 mole) was then added and the mixture was degassed with argon for 5 minutes. Phenylboronic acid (0.587 g, 0.00454 mole) and 2-chloro-5-nitro-pyridine (0.6 g, 0.0037 8 mole) were then added and the resulting mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.878 g, 0.00076 mole) was added and the mixture was degassed with argon for 5 minutes. The resulting mixture was then heated to reflux for 3 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water followed by brine solution. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) afforded 0.5 g (66%) of 5-nitro-2-phenyl-pyridine. LCMS purity: 201 (M+1)+, 98.2%, 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 8.55 (dd, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.55 (m, 3H). To a stirred solution of 5-nitro-2-phenyl-pyridine (0.5 g, 0.0025 mole) in THF (10 mL) was added ammonium chloride (1.1 g, 0.020 mole) dissolved in water (15 mL). Methanol (5 mL) was then added, resulting in a clear solution. Zinc powder (1.3 g, 0.020 mole) was then added portionwise and the resulting mixture was stirred for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over Na2SO4, and evaporated under reduced pressure to afford 0.35 g (82%) of 6-phenyl-pyridin-3-ylamine. LCMS purity: 171.08 (M+1)+, 87.9%, 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 8.0 (d, 2H), 7.72 (d, 1H), 7.48 (t, 2H), 7.36 (t, 1H), 7.1 (dd, 1H), 5.6 (s, 2).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:24])[CH:13]1[CH:9]([CH2:10][CH:11]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=4)[N:29]=[C:28]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=3)[CH2:12]1)[C:8](=[O:44])[NH:7]2)=[O:5])C.CO.Cl>O1CCCC1.O>[CH3:37][O:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([O:25][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:24])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:44])[CH2:23]5)[CH2:12]3)=[CH:27][C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:29]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C12CC1C=CCCCCNC(=O)C1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NCCCCC=CC5CC5(C(=O)O)NC(=O)C4C3)cc(-c3ccccc3)nc2c1
Temperature: 65 °C
Yield: 71.8 %

Procedure:
Compound 92 (95 mg, 0.159 mmol) was dissolved in tetrahydrofuran (10 ml), methanol (5 ml) and water (4 ml) Lithium hydroxide (40 mg, 1.67 mmol) was dissolved in water (1 ml) and added. The reaction mixture was heated to 65° C. After 3 h the reaction mixture was cooled, acidified with aqueous HCl (pH=5), evaporated on silica and purified by silica gel chromatography (10% MeOH in dichloromethane→15% MeOH in dichloromethane) to give the pure title product (65 mg, 72%). MS (M+H+): 569.8
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 88.4 %

Procedure:
The general method described in Part A of Example 28 was used to react 4-chloro-3-nitroquinoline (49.6 g, 238 mmol), ethyl 4-aminobutyrate hydrochloride (43.8 g, 262 mmol), and triethylamine (36.1 g, 357 mmol) in dichloromethane for 15 hours to provide ethyl 4-(3-nitroquinolin-4-ylamino)butyrate (63.8 g) as a yellow solid that was used directly in the next step without further purification.
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)(C)(C)C.N1CCCCC1.[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH2:53][C:54]([OH:56])=O)=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:44]1[C:45]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH2:53][C:54]([NH:8][C@H:7]([C:26]([OH:28])=[O:27])[CH2:6][OH:5])=[O:56])=[O:51])[C:47]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)N[C@@H](CO)C(=O)O
Reaction time: 0.5 h

Procedure:
1 g (0.62 mmol) of a Wang resin (Merck Biosciences; loading: 0.62 mmol/g) preloaded with O-tert.-butyl-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-serine is treated twice in succession with piperidine as follows: the resin is mixed with 10 ml of a 20% piperidine solution in dimethylformamide, shaken for 30 min and collected by suction filtration. The resin obtained in this way is provided in 10 ml of dimethylformamide, and 369 mg (1.24 mmol) of N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycine, 398 mg (1.24 mmol) of N-[(1H-benzotriazol-1-yloxy)(dimethyl-amino)methylene]-N-methylmethanaminium tetrafluoroborate (TBTU) and 240 mg (1.86 mmol) of N-ethyl-N-isopropylpropan-2-amine (DIEA) are added. The mixture is shaken at RT overnight. The solid is collected by suction filtration, washed three times each with 10 ml of dimethylformamide, methanol and dichloromethane and collected by suction filtration. 20 ml of a 50% trifluoroacetic acid solution in dichloromethane are added and left to act for 60 min, the resin is removed by filtration on a frit and the resin is washed three times with 10 ml of dichloromethane. The filtrate is concentrated and the target compound is obtained as crude product.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#N.[OH-:20].[K+].C(O)C[OH:24]>O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([OH:24])=[O:20]
Reactant: OCCO
Reactant: [OH-]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Agent: [K+]
Solvent: O
Product: COc1ccc(C2(C(=O)O)CCC(=O)CC2)cc1OC
Yield: 99 %

Procedure:
A mixture of 17.54 g. (0.058 mole) of 4-cyano-4-(3,4-dimethoxy)cyclohexanone, ethylene ketal (prepared as in Example 22) and 17.5 g. of potassium hydroxide in 175 ml. of ethylene glycol is heated at reflux for about 16 hours. The resulting solution is allowed to cool, diluted with water and washed with ether. The aqueous layer is covered with ether and then cautiously acidified. The aqueous layer is extracted with two additional portions of ether and the extracts combined. The extracts are evaporated to dryness to give 19 g. (99% yield) of 4-carboxy-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal, as an amorphous gum.