Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:45])[C@H:39]1[CH2:43][NH:42][CH2:41][C@@H:40]1[OH:44].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[CH3:37][N:38]([CH3:45])[C@@H:39]1[C@@H:40]([OH:44])[CH2:41][N:42]([C:2]2[C:21]([C:22]3[CH:27]=[N:26][CH:25]=[N:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:43]1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C[C@@H]1O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 60 mg, 0.149 mmol) and DIPEA (0.182 mL, 1.043 mmol) were added to a vial containing iPrOH (1 mL). (3S,4S)-4-(Dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added. The mixture was stirred at 110° C. for 16 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and was extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by preparative SFC (Column DEAP, from 13% to 18% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=5.62 min, UPLC-MS (Condition 3) tR=0.73 min, m/z=489.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 6H) 2.52-2.59 (m, 1H) 2.87 (dd, J=10.95, 5.08 Hz, 1H) 3.19 (dd, J=11.34, 5.90 Hz, 1H) 3.28 (m, J=11.30, 6.30 Hz, 1H) 3.45 (dd, J=11.34, 6.65 Hz, 1H) 4.08 (quin, J=5.08 Hz, 1H) 5.09 (d, J=5.08 Hz, 1H) 7.36 (d, J=8.60 Hz, 2H) 7.85 (m, J=9.00 Hz, 2H) 8.11 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.35 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1OC.[C:26]([O-])([O-])=[O:27].[K+].[K+].Cl>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([O:27][CH3:26])[CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A stirred solution of 1-benzylpiperazine (3.53 g, 20.0 mmol), 4-chloro-3-methoxy-nitrobenzene (3.75 g, 20.0 mmol), and K2CO3 (2.76 g, 20.0 mmol) in DMF is heated at 85° to 100° C. under nitrogen for 23 h, cooled to room temperature, treated with 2M aqueous hydrochloric acid, diluted with water and extracted with ether. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, 30:70 ethyl acetate:hexanes and 50:50 ethyl acetate:hexanes as eluent) to afford the title compound as a yellow-orange oil 2.64 g (57% yield), identified by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(-c2nc3n(c2Cl)CCCC3)c(Cl)c1
Product: O=[N+]([O-])c1cc(-c2nc3n(c2Cl)CCCC3)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 1.1 g (3.85 mmol) sample of 3-chloro-2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine was added to 8.0 ml of a 1:1 mixture of concentrated sulfuric/nitric acid at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes followed by warming to 20° C. After pouring the reaction mixture onto ice/water, the resulting aqueous mixture was extracted with 400 ml of ethyl acetate. The separated organic layer was washed with water, brine, and dried over magnesium sulfate. The yellow oily solid residue obtained after evaporating in vacuo was flash chromatographed on silica gel (1:1 hexane/ethyl acetate) to provide 0.8 g of the title compound as a yellow solid (m.p. 111°-112° C.). NMR (CDCl3, 200 MHz): δ1.95 (m, 2H), 2.05 (m, 2H), 2.91 (t, 2H), 3.92 (t, 2H), 7.66 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)(=[O:14])[CH3:13].CCOCC>C(O)C>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:12](=[O:14])/[CH:13]=[C:3](\[OH:5])/[C:2]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:17]=1)#[N:20]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
In a dry flask, under argon atmosphere, sodium (317 mg, 13.8 mmol, Eq: 1.00) was added portionwise to ethanol (9.0 ml). (The temperature increased to 60° C.). The reaction mixture was cooled at 0° C. Then Diethyl oxalate (2.01 g, 1.87 ml, 13.8 mmol, Eq: 1.00) was added dropwise followed by 4-acetylbenzonitrile (2 g, 13.8 mmol, Eq: 1.00) in Ethanol (3.00 ml). A white solid appeared. The reaction was stirred with mechanical stirrer overnight and monitored by TLC. Then the reaction mixture was concentrated in vacuo. The residue was cooled at 0° C. and water was added to the flask. 1M HCl was added to this solution (pH=3), then the solution was extracted two times with EtOAc. The organic layer was washed three times with 20 mL Brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid. This off-white solid was mixed with Ether at 0° C. The suspension was filtered to give a white solid (2.082 g, 61.6%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH2:14][C:15]#[N:16])=[C:9]([F:17])[CH:8]=1.[OH-:18].[NH4+]>C(O)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([F:17])[C:10]([CH2:14][C:15]([NH2:16])=[O:18])=[C:11]([F:13])[CH:12]=1
Reactant: [OH-]
Reactant: N#CCc1c(F)cc(Br)cc1F
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: NC(=O)Cc1c(F)cc(Br)cc1F
Temperature: 5 °C
Yield: 78 %

Procedure:
To a solution of sulfuric acid (0.96 mL, 18.1 mmol) in acetic acid (20 mL) was slowly added 2-(4-bromo-2,6-difluorophenyl)acetonitrile (0.84 g, 3.6 mmol) portion-wise while stirring, and the reaction mixture was then stirred for 1 h at 100° C. After cooling to 5° C., the mixture was carefully adjusted to pH 9 with 28-30% aq ammonium hydroxide and then was extracted with chloroform (3×40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% ethyl acetate/hexanes) provided the title product (0.71 g, 78%). MS(ES+) m/e 250 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 3.60 (s, 2 H) 5.54 (br. s., 2 H) 7.10-7.21 (m, 2 H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[N:17]=[C:16]([O:22][CH3:23])[CH:15]=[CH:14]2)(=O)[CH3:8].[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[C:16]([O:22][CH3:23])[CH:15]=[CH:14]3)[C:24]([CH3:25])=[N:27][N:28]=1
Reactant: CC(=O)NN
Reactant: COc1ccc2cc(NC(C)=O)cc(C)c2n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2cc(-n3c(C)nnc3C)cc(C)c2n1
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
Phosphorus pentachloride (1.0 g) was added to a stirred solution of 6-acetamido-2-methoxy-8-methylquinoline (1.0 g) in toluene (50 cm3) and the mixture was stirred at 50° for 15 minutes. Acetyl hydrazine (1.35 g) was then added and the mixture was stirred for 3 hours at 60°. The toluene was removed in vacuo the residue dissolved in ethanol, and aqueous ammonia solution (S.G. 0.88) (25 cm3) was added. Dichloromethane (100 cm3) was added and the organic phase was separated. The aqueous phase was further extracted with dichloromethane (2×25 cm3), and the combined organic phases were dried (MgSO4) and evaporated to give a solution which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of appropriate fractions afforded 6-[3,5-dimethyl-1,2,4-triazol-4-yl]-2-methoxy-8-methylquinoline (0.306 g), which was recrystallised from toluene to give microcrystals, m.p. 211°-213° (0.066 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:28]([O:30][CH3:31])=[O:29])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:9].[C:33]1([O:39][CH2:40][CH:41]2[O:43][CH2:42]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:28]([O:30][CH3:31])=[O:29])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:42][CH:41]([OH:43])[CH2:40][O:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN)C1c1cccc(C(F)(F)F)c1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCNCC(O)COc2ccccc2)C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 32.9 %

Procedure:
In 45 ml of methanol were dissolved 2.51 g of 6-aminohexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.83 g of glycidyl phenyl ether, and the mixture was stirred for 45 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The produce was eluted with chloroform-methanol (95:5 v/v), and 1.10 g of 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridin-3,5-dicarboxylate was obtained. This product was treated with an ethanol solution of hydrogen chloride to obtain amorphous powder of 1.16 g of hydrochloric acid salt.
Reaction SMILES: COCCOC.[CH2:7]([O:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[N:22]([S:30]([C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:19][CH:18]=[C:17]([C:40]([F:43])([F:42])[F:41])[CH:16]=2)=[O:11])[CH3:8].[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=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>[CH2:7]([O:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[N:22]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:19][CH:18]=[C:17]([C:40]([F:43])([F:42])[F:41])[CH:16]=2)=[O:11])[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(Br)cc1
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: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To 8.5 mL of degassed ethylene glycol dimethyl ether, was added 500 mg (0.85 mmol) of the ester, 110 mg (0.93 mmol) of phenylboronic acid, 80 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium and 1.1 ml (2.2 mmol) of 2M aqueous Na2CO3 and the mixture ws heated to reflux under nitrogen for 36 hr. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give 4-[(biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:41][CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: COCCN
Product: COCCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methoxyethylamine according to conditions described in general procedure C. Mp: 87-88° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.63 (m, 6 H), 3.00-3.38 (m, 1 H), 6.20-6.40 (m, 1 H), 6.99 (d, J=12.4 Hz, 1 H), 7.09-7.18 (m, 2 H), 7.40 (d, J=7.7 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.62 (m, 3 H), 7.82 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:27][C:28](Cl)=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:28](=[O:29])([O:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.90 g. of chloroformic acid n-pentyl ester as in Example 1. The 1.5 g. of yellow, partially crystallized oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.479 g. of colorless crystrals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-pentyl carbonate obtained melts at 50.1°-51.0° and has a clearing point of 61.1°. UV (EtOH): ε 270 = 26800.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][C:10]([CH3:12])=O.C(OC(=O)C)(=O)C>C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[C:3]([C:2](=[C:10]([CH3:12])[CH3:9])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C(C)=O)=C(C)C
Temperature: 50 °C

Procedure:
To a mixture of 9.54 g (70 mmol) of anhydrous ZnCl2, 53.9 mL (500 mmol) of methyl acetoacetate and 55 mL (750 mmol) of acetone are added 64 mL of acetic anhydride. The reaction medium is then heated for 3 days at 50° C., and then diluted with 1 L of DCM and washed with water (3×100 mL). The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. After concentrating under reduced pressure, 51.5 g of methyl 2-acetyl-3-methylbut-2-enoate are obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:60][CH3:61])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[CH:41]([CH3:40])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A solution containing the product from Example 2C (0.01 g, 0.019 mmol) in THF (0.2 mL) was treated with the product from Example 7B (0.009 g, 0.021 mmol), DEPBT (0.009 g, 0.030 mmol), and N,N-diisopropylethylamine (0.016 mL, 0.092 mmol), stirred at 25° C. for 16 hours and partitioned between a mixture of dichloromethane, ethyl acetate (2:1, respectively) and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between a mixture of dichloromethane and ethyl acetate (2:1, respectively) and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (0.0076 g, 51% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (m, 18 H), 1.31 (m, 3 H), 1.52 (m, 2 H), 1.80 (m, 1 H), 2.45 (s, 3 H), 2.67 (m, 4 H), 3.09 (m, 4 H), 3.50 (s, 1 H), 3.66 (m, 1 H), 3.84 (d, J=9.93 Hz, 1 H), 3.93 (d, J=11.03 Hz, 1 H), 4.14 (m, 1 H), 4.35 (s, 1 H), 4.67 (d, J=7.35 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.21 (m, 12 H), 7.66 (t, J=7.72 Hz, 1 H), 7.86 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:15]([N:17]([CH:22]([CH3:26])C(O)=O)[CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:40]([O:44]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:70]([NH2:75])[C:71]([CH3:74])([CH3:73])[CH3:72]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:17]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH2:22][CH2:26][C:40](=[O:44])[NH:75][CH2:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)CN
Reactant: CC(C(=O)O)N(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CNC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of ({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-cyclobutyl-amino)-propionic acid (0.025 g) and HATU® (0.038 g) in DMF (1 ml) was added DIPEA (0.017 ml) followed by neopentylamine (0.053 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.016 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:14](Cl)=[N:13][CH:12]=[CH:11][N:10]=1.C[O-].[Na+]>C(O)C>[Cl:8][C:9]1[C:14]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nccnc1Cl
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1nccnc1Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
22 g (0.2 mol) of thiophenol and 29.8 g (0.2 mol) of 2,3-dichloropyrazine are successively added dropwise to a solution of 10.8 g (0.2 mol) of sodium methylate in 200 ml of ethanol and the mixture is stirred for 1 hour. The reaction mixture is then cooled to 0° C. and the reaction product which has precipitated is filtered off and washed with ethanol and water. After drying, 2-chloro-3-phenylthiopyrazine, melting point 100°-111° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.C(O[B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]1)(C)C.O>C1COCC1>[CH3:21][C:16]1([CH3:22])[C:17]([CH3:20])([CH3:19])[O:18][B:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[O:15]1
Reactant: Cc1ccccc1[Mg]Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.25 h

Procedure:
To 200 ml (0.21 mol) of 1.07 M solution of 2-methyl phenylmagnesiumbromide in THF, 49.3 g (0.27 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added at room temperature. The resulting solution was stirred for 15 min at the same temperature, and then 50 ml of water was added. The formed mixture was poured into 500 ml of water, and crude product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Fractional distillation of the residue in vacuum gave colorless oil, b.p. 81-84° C./3 mmm Hg. Yield 33.1 g (57%). Anal. calc. for C13H19BO2: C, 71.59; H, 8.78. Found: C, 71.78; H, 8.65. 1H NMR (CDCl3): 7.78 (m, 1H, 6-H), 7.33 (m, 1H, 5-H), 7.16-7.19 (m, 2H, 3, 4-H), 2.56 (s, 3H, Me in 2-MeC6H4), 1.36 (s, 12H, Bpin).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([O-])=O>>[NH2:5][C:8]1[C:17]2[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Solvent: O=[N+]([O-])O
Product: Nc1cccc2c(N)cccc12

Procedure:
The invention also provides a process for the production of 1,5-diaminonaphthalene in which naphthalene and/or 1-nitronaphthalene is reacted with nitric acid in the presence of a zeolite and then the resulting 1,5-dinitronaphthalene is hydrogenated to form 1,5-diaminonaphthalene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:7][CH:6]=2)=[O:9])[CH:15]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(O)cc2)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(OCCN3CCCCC3)cc2)c1
Yield: 83.5 %

Procedure:
Synthesized from (4-hydroxyphenyl)[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]methanone (1.3 g) and 1-(2-chloroethyl)piperidine hydrochloride (970 mg) according to an analogous synthetic method to Example 383 described below, the title compound (yellow viscous oil) (1.4 g) was obtained.