Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1COCC1.Br[C:24]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32].[OH-].[Na+]>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.O>[Br:30][C:28]1[CH:27]=[CH:26][C:25]([N+:31]([O-:33])=[O:32])=[C:24]([C:2]2[C:15]3[C:10]([C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH:3]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:29]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Br)cc1-c1cc2ccccc2c2ccccc12
Yield: 61.6 %

Procedure:
A 2 L round bottom flask was charged with phenanthracene-9-boronic acid (76.61 g, 345 mmol), THF (700 mL), and H2O (350 mL), and the mixture was dissolved. To the resultant mixture, 2,4-dibromo-1-nitrobenzene (146 g, 518 mmol), NaOH (42 g, 1035 mmol), and Pd(PPh3)4 (20 g, 17.3 mmol) were sequentially added, followed by reaction at 80° C. for 24 hours. After the reaction was completed, the resultant product was extracted with methylene chloride, water, and brine, and the organic layer was dried with MgSO4. The obtained organic layer was purified by silica gel column (methylene chloride:hexane=1:3) so as to give 80.4 g of a product (62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[C:7]1=[O:17])[CH3:2].[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Reactant: OC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)c2ccc(OC3CCCCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a mixture of (5-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (8.0 g) in anhydrous tetrahydrofuran (160 ml) was added cyclohexanol (3.2 g), diethylazadicarboxylate (6.9 g) and then triphenyl phosphine (12.6 g). Resulting mixture was stirred at room temperature overnight and concentrated. Residue was partitioned between water and ethyl acetate. Aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over magnesium sulfate and filtered. Filtrate was concentrated and purified by silica gel chromatography (eluting with 5% ethyl acetate in methylene chloride) to give the title compound (6.2 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (dd, J=8.2, 0.8 Hz, 1H), 7.30 (br s, 1H), 7.12 (m, 1H), 4.38 (m, 3H), 4.21 (q, J=7.1 Hz, 2H), 2.02 (m, 2H), 1.82-1.25 (m, 13H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:3]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[C:8]([C:6]1[CH:7]=[C:2]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=2)[N:3]=[C:4]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:5]=1)#[N:9]
Reactant: N#Cc1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
2-Chloro-4-cyano-6-(3-thienylmethyloxy)pyridine (0.79 g, 0.00315 mol) and meta-trifluoromethylphenol (0.57 g, 0.00315×1.1 mol) were dissolved in 20 ml of N-methyl-2-pyrrolidinone, and anhydrous potassium carbonate (0.48 g, 0.00315×1.1 mol) was added thereto, and the resultant solution was stirred for about 4 hours at about 100° C.
Reaction SMILES: N[C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.N([O-])=O.[Na+].[S:24](=[O:26])=[O:25].[ClH:27]>O.C(O)(=O)C.[Cu](Cl)Cl>[Cl:18][C:5]1[CH:4]=[C:3]([Cl:19])[C:2]([S:24]([Cl:27])(=[O:26])=[O:25])=[CH:7][C:6]=1[N:8]1[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]1
Reactant: O=S=O
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2cc(S(=O)(=O)Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A stirred mixture of 12.0 g (0.0388 mole) of 1-(5-amino-2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 50 mL of hydrochloric acid was cooled to 0° C. A solution of 2.79 g (0.0405 mole) of sodium nitrite in 20 mL of water was added while maintaining a reaction temperature of approximately 0° C. After complete addition, the reaction mixture was allowed to warm to room temperature and stir for 1.5 hours. This mixture was added slowly to a solution of 5.44 g (0.0405 mole) of copper (II) chloride in 15 mL of water and 50 mL of acetic acid which was saturated with sulfur dioxide. The resultant mixture was stirred at room temperature for one hour, forming a precipitate. The reaction mixture was poured into ice water and was stirred for a brief period of time. This mixture was filtered to collect approximately 16 grams of 1-(2,4-dichloro-5-chlorosulfonylphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl -1,2,4-triazol-5(1H)-one as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[NH3:20].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:27][CH2:28][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)CC1
Product: N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[4-(dimethylamino)-1-piperidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 25) (652 mg, 1.37 mmol) in dichloromethane (15 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred for 2 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped from toluene. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:1) gradually changing to dichloromethane:methanol:0.88 ammonia (70:30:2) to afford the title compound as a colourless oil (702 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:19]2[N:27]=[C:26](Cl)[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[C:1]([C:3]1[C:4]([S:9][C:26]2[CH:25]=[CH:24][C:20]3[N:21]=[CH:22][N:23]=[C:18]([NH:10][C:11]4[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=4)[C:19]=3[N:27]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1ccc(N)n1
Reactant: N#Cc1cccnc1S
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cn1ccc(Nc2ncnc3ccc(Sc4ncccc4C#N)nc23)n1

Procedure:
The compound of Example 60 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-cyano-2-mercapto-pyridine, 3-amino-1-methyl-1H-pyrazole and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20](I)=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][C:19]=3[C:20]([C:30]#[N:31])=[CH:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(I)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Agent: [Fe+2]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Yield: 28.7 %

Procedure:
4-(4-benzyloxy-3-isopropylphenoxy)-7-iodo-5-methylindane (214 mg), potassium cyanide (60 mg), bis(dibenzylidenacetone)palladium (4 mg), 1,1′-bis(diphenylphosphino) ferrocene (8 mg), and 1-methyl-2-pyrrolidone (2 mL) were stirred under an argon atmosphere at 80° C. overnight. Adding water, the reaction mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate) to give the title compound (49 mg).
Reaction SMILES: N[C:2]1[C:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][NH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].[C:18]([NH:22][C:23](=[N:26][C:27]([O:29][CH3:30])=[O:28])SC)([O:20][CH3:21])=[O:19].C([N:33](CC)CC)C>C(#N)C>[C:18]([N:22]([C:2]1[C:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][NH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15])[C:23]([NH:26][C:27]([O:29][CH3:30])=[O:28])=[NH:33])([O:20][CH3:21])=[O:19]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: COC(=O)c1[nH]cc(Cc2cccnc2)c1N
Reactant: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)NC(=N)N(C(=O)OC)c1c(Cc2cccnc2)c[nH]c1C(=O)OC
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Methyl 3-amino-4-(3-pyridylmethyl)-1H-pyrrole-2-carboxylate, obtained from Example 16 (2.31 g, 0.01 mol), N,N′-bis-carbomethoxy-S-methylisothiourea (2.27 g, 0.011 mol) and triethylamine (3.6 g, 0.35 mol) were stirred together in acetonitrile (50 mL) and cooled to 5° C. Mercuric chloride (2.98 g, 0.011 mol) was added and an immediate precipitate was observed. The mixture was stirred at room temperature overnight.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CN(C=O)C.[Br:23][C:24]1[CH:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>CCOCC>[Br:23][C:24]1[CH:29]=[C:28]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(Br)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
N-Boc-4-piperidinemethanol (860 mg, 4.0 mmol) was added to a suspension of 60% sodium hydride (160 mg, 4.0 mmol) in DMF (40 mmol) at room temperature. After 20 minutes, 2-bromo-4-chloro-5-nitropyridine (949 mg, 4.0 mmol) was added in one portion, and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ether and washed with water. The aqueous phase was extracted with ether. The combined organic phases were washed with water and brine, then dried (Na2SO4) and concentrated. Silica column chromatography, eluting with 20% ethyl acetate-hexane, gave tert-butyl 4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (789 mg, 62%) as a viscous, pale yellow oil which solidified on standing.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]1([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[C:11]1([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][C:22]3[CH:21]=[CH:20][C:19]([N:18]=[N:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:24][CH:23]=3)=[O:9])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Reactant: O=C(O)CCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CCCCC(=O)Oc1ccc(N=Nc2ccccc2)cc1)Oc1ccc(N=Nc2ccccc2)cc1
Reaction time: 4 h

Procedure:
164 g. of polyphosphoric acid ethyl ester is dissolved in 60 ml. of chloroform. A suspension of 14.86 g. of adipic acid and 40.0 g. of p-(phenylazo)-phenol in 340 ml. of chloroform is added to this solution. The reaction mixture is agitated for 4 hours. Then, 35 g. of adipic acid bis(4-phenylazophenyl)ester is obtained by vacuum-filtering the reaction mixture; this product is recrystallized from ethyl acetate. In this way, 30 g. of a pure compound is obtained, m.p. 176°-177° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:23]1([CH2:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:25][N:26]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:27][CH2:28]1)=[O:30])[CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)NC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of tert-butylisocyanate (0.097 ml, 0.85 mmol) in 8.0 mL of CH2Cl2, was added 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (prepared from example 36, step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 ml, 0.97 mmol) and stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether:hexanes (1:1) to provide 0.284 g (73%) of the desired product as a white solid. Electrospray Mass Spec: 479.2 (M+H)+
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[N:21][OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:12][C@H:11]2[C@H:10]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)=[N:21][O:22]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccc(Cl)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To N-Boc pyrroline (480 mg; 2.83 mmol) and chloro oxime 2a (557 mg; 2.93 mmol) in ethyl acetate (15 mL), was added dropwise triethylamine (0.4 mL) in ethyl acetate (15 mL). The reaction mixture was stirred at room temperature for 24 hours. An additional portion of chloro oxime 2a (234 mg; 1.23 mmol) and triethylamine were added. After stirring overnight, the reaction mixture was poured into water (50 mL) and extracted. The organic layer was dried (MgSO4), filtered and evaporated. Chromatography with 30% ethyl acetate/hexanes yielded 3a as a white solid.
Reaction SMILES: C(SCCCCCC[NH2:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].CCN(C(C)C)C(C)C.C(O)(=O)C>C1COCC1>[C:29](=[O:30])([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)[NH2:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
6-(Tritylthio)hexane-1-amine (1.21 g, 3.22 mmol) and p-nitrophenyl chloroformate (0.78 g, 3.86 mmol) were suspended in dry THF (15 mL). DIEA (841 μL, 4.83 mmol) was added, and the resulting solution was stirred at room temperature for 2 h. After acidification by addition of acetic acid the solvent was evaporated under reduced pressure, and the residue was purified by RP-HPLC. 1.21 g (2.25 mmol) p-nitrophenyl carbamate were obtained after lyophilisation.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1>>[CH:15]1([CH2:18][C@H:19]([NH:23][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=3[N:6]=2)[C:20]([NH:34][CH2:33][CH2:32][NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:22])[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]1
Reactant: Fc1ccc2oc(Cl)nc2c1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: NCCNc1ccc(F)cc1
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2cc(F)ccc2o1

Procedure:
The title compound was prepared from 2-chloro-5-fluorobenzoxazole, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=8.0 Hz), 8.16 (t, 1H, J=5.6 Hz), 7.27 (dd, 1H, J=4.4 Hz, J=8.4 Hz), 6.97 (dd, 1H, J=2.6 Hz, J=9.4 Hz), 6.80 (m, 2H), 6.72(m, 1H), 6.46(m, 2H), 5.42(m, 1H), 4.20 (m, 1H), 3.15(m, 2H), 2.95(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28F2N4O2(M+H+) 443.22. found 443.5.
Reaction SMILES: B(Br)(Br)Br.CN1CCC2C(CCCC2)C1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[OH-:25].[NH4+].Cl[CH2:28][Cl:29]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:28]([Cl:29])=[O:25])=[CH:18][CH:19]=1
Reactant: COc1ccc(CC2C3CCCCC3CCN2C)cc1
Reactant: [OH-]
Reactant: ClCCl
Agent: BrB(Br)Br
Agent: [NH4+]
Product: COc1ccc(CC(=O)Cl)cc1
Temperature: -75 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
8-Ethano-1-(p-hydroxybenzyl)-2-methyl- 1,2,3,4,5,6,7,8-octahydroisoquinoline (10). A 100 mL three-necked flask was dried for 24 h at 210° C. While cooling under a stream of dry nitrogen, the flask was immersed in an ethanol/dry ice bath and cooled to -75° C. Boron tribromide (300 μl, 3.16 mmole) was introduced, followed by 10 ml of dry dichloromethane. Purified 9 (224 mg, 0.754 mmole), as the base, in 30 ml of dry dichloromethane was added in a dropwise fashion. Thirty minutes after the addition of 9, the stirring was stopped, the nitrogen was replaced by a calcium sulfate drying tube, and the mixture was left in the cold for 12 h. After refluxing for 1 h, the reaction mixture was recooled in an ice bath and 3.5 ml of 10% ammonium hydroxide was slowly added and a flocculent precipitate formed. After stirring for 15 min, the cold bath was removed and 50 ml of water was added. The subsequent isolation of the product was conducted in the dark to minimize photooxidation. The phases were separated, the dichloromethane was removed in vacuo and the residue was dissolved in ethyl ether. The aqueous phase (pH 8.4) was adjusted to pH 9.1 with 10% ammonium hydroxide and extracted eight times with 20 ml portions of ether. All ether phases were combined, dried (Na2SO4), and concentrated to give a yellow oil. An attempt was made to purify this base by methansulfonate salt formation, but this salt form resisted crystallization. The hydrochloride salt was made and recrystallized from acetone/ethanol/ethyl ether in 29% yield. There was evidence of additional product in the mother liquor but it resisted crystallization: mp (sealed tube) 218°-220° C. sublime; 1H NMR (base in CDCl3) δ 6.67 (AA'BB', 4 H aromatic), 4.58 (s, 1 H, OH), 2.87-3.30 (m, 1 H, 1-H), 2.43-2.87 (m, 4 H, 1-CH2, 3-H2), 2.33 (s, 3 H, NCH3), 1.90-2.27 (m, 4 H, 4-H2, 5-H, 8-H), 0.93-1.72 (m, 8 H, remaining protons); IR (base, neat) 3300 (OH stretch) cm -1 ; mass spectrum, m/z 283 (M+), 176 (M+ -p-hydroxybenzyl, base), 148 (retro-Diels-Alder), 107 (p-hydroxybenzyl+), 106 (p-hydroxybenzyl-1+), 42 (CH2 =N=CH2+).
Reaction SMILES: [CH:1]1([N:13]2[CH2:30][CH2:29][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19](=O)[CH2:18][C:17]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.O>[CH:1]1([N:13]2[CH2:30][CH2:29][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][CH2:18][CH2:17]3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[CH:1]1([N:13]2[CH2:30][CH2:29][C:16]3([N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH:17]3[OH:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C1CC(=O)C2(CCN(C3Cc4cccc5cccc3c45)CC2)N1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC1CCN(c2ccccc2)C12CCN(C1Cc3cccc4cccc1c34)CC2
Product: c1ccc(N2CCCC23CCN(C2Cc4cccc5cccc2c45)CC3)cc1

Procedure:
To a stirred solution of (RS)-8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decane-2,4-dione (0.67 g, 1.7 mmol) in THF (35 ml) was added at RT lithium aluminiumhydride (128 mg, 3.4 mmol) and the reaction mixture was boiled under reflux for 7 h. Water (20 drops) was added slowly at RT to the stirred solution and afterwards the reaction mixture was dried (Na2SO4) and filtered. The filtrate was evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/hexane 9:1) to yield (RS)-8-acenaphthen-1-yl-1-phenyl-1,8-diaza-spiro[4.5]decane (50 mg/see example 20) as a pale yellow oil and 8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (127 mg) as a pale brown foam, which while stirring was dissolved in 3N MeOH—HCl (0.5 ml) and treated with diethyl ether (15 ml). After 1 h the solid was filtered off to yield the desired product (128 mg, 55%) as a pale brown solid, m.p. 196° and MS: m/e=385.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:36]([O-])([OH:38])=[O:37]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:23]([N+:36]([O-:38])=[O:37])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
Benzyl 4-(benzyloxy)-3-methoxybenzoate (135 g) was dissolved in dichloromethane (339 ml). Glacial acetic acid (175.5 g) was added and the mixture cooled to 10° C. Concentrated sulfuric acid (151.6 g) was added in a controlled manner maintaining the temperature of the reaction mixture below 25° C. Concentrated nitric acid (61.6 g) was then added in 15 minutes keeping the temperature of the reaction mixture below 25° C. The reaction mixture was then heated to 40° C. and stirred for 3 hours. The lower aqueous layer was removed and the organic layer was washed twice with water (2×168 ml). The organic layer was distilled to at atmospheric pressure to remove dichloromethane (186 ml). Isopropanol (339 ml) was added to the reaction mixture at 40° C. The reaction mixture was held at 40° C. for 15 minutes. The resulting suspension was then cooled to 20° C. within 30 minutes, then to 5° C. and held at this temperature for one hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (336 ml) and dried at less than 25° C. Yield: 135.7 g, 89.6%; NMR Spectrum (CDCl3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1H), 7.3-7.4 (m, 10H), 7.5 (s, 1H); Mass Spectrum (M+H)+=394.1.