Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:18][CH2:19][N:20]([C:27]([NH2:26])=[O:28])[CH2:21][CH2:22]3)=[N:7][N:8]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)nn(-c3ccccc3)c2c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Yield: 67.9 %

Procedure:
A mixture of 4.5 g of 6-fluoro-1-phenyl-3-(1-piperazinyl)-1H-indazole, 4.3 g of nitrourea, and 75 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized twice from toluene (one charcoal treatment) to yield 3.5 g (73%) of 4-(6-fluoro-1-phenyl-1H-indazol-3-yl)-1-piperazine carboxamide, m.p. 168°-170°.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH:10]([CH3:14])C(O)=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:21]([O:23][C:24](=[O:28])CNC)[CH3:22].C(N(C(C)C)CC)(C)C.[CH3:38][N:39]([CH3:42])[CH:40]=[O:41]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][CH2:10][CH2:14][C:40](=[O:41])[N:39]([CH2:42][C:24]([O:23][CH2:21][CH3:22])=[O:28])[CH3:38])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OC(C)C(=O)O
Reactant: CCOC(=O)CNC
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(=O)CCOC(=O)/C=C/C(=O)OC
Yield: 39 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]propanoic acid (24) (0.50 g, 2.47 mmol) was activated with oxalyl chloride (0.25 mL, 0.35 g, 2.71 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with sarcosine ethyl ester (H-Sar-OEt) (0.43 g, 2.90 mmol) and diisopropylethylamine (DIEA) (0.506 mL, 0.376 g, 2.90 mmol) in DCM and in the presence of a catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.30 g (39% yield) of the title compound (38) as a white solid. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.88-6.81 (m, 2H), 5.47 (q, 0.75H, J=6.8 Hz), 5.32 (q, 0.25H, J=6.8 Hz), 4.40-4.33 (m, 1H), 4.16-4.11 (m, 2H), 3.94-3.75 (m, 4H), 3.10 (s, 2.25H), 2.96 (s, 0.75H), 1.50-1.44 (dd, 3H), 1.26-1.20 (m, 3H). MS (ESI): m/z 302.09 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[F:11].O.C(=O)([O-])[O-:14].[Ca+2].Cl>O1CCOCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)c(F)c1CBr
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1c(F)ccc(Br)c1F
Yield: 114.3 %

Procedure:
1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene (45.2 g, 0.158 M) was dissolved in dioxane (800 mL), water (800 mL) and calcium carbonate (80 g, 0.80 M) were added and the mixture was refluxed for 16 h. The mixture was cooled, acidified with 2N HCl and extracted with dichloromethane. Organic phases were pooled, dried with Na2SO4 and and evaporated to yield a brownish oil (40.3 g). The residue was purified by column chromatography (silica gel; n-hexane/ethyl acetate 9:1) to yield 31.2 g (88%) of the title compound as a colorless solid. MS (EI): 224.0 (M)+.
Reaction SMILES: [C:1]([CH2:5][S:6](Cl)(=[O:8])=[O:7])([F:4])([F:3])[F:2].[NH4+:10].[OH-]>C(Cl)Cl.O>[C:1]([CH2:5][S:6]([NH2:10])(=[O:8])=[O:7])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)CC(F)(F)F
Temperature: 25 °C

Procedure:
The CF3CH2SO2NH2 was prepared by cooling a solution of commercially available CF3CH2SO2Cl (0.6 ml, 1 eq) in CH2Cl2 to 0° C. NH4OH (0.75 ml, 14.8 N, 2 eq) was then added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted three times with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The sulfonamide was used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>>[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C:33]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9]2)=[O:34])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(F)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCOCC2)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound, MS: m/e=505.3 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(4-fluoro-phenyl)-piperidin-4-one, morpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[S:6]1C=CC=C1.O1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:3]12[S:6][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: c1ccsc1
Reactant: C1CCOC1
Reactant: C=CC(=O)O
Product: O=C(O)C1CC2C=CC1S2
Temperature: 700 °C
Reaction time: 24 h

Procedure:
Tetrahydrofuran solvent (500 g), acrylic acid (1.2 mole) and thiophene (1.0 mole) are introduced into a 2-liter flask. After stirring at 700° C. for 24 hours, the solvent and excessive acrylic acid are removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylic acid of Chemical Formula 142 (yield: 80%).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:11][CH2:10][CH2:9]O1.[I:20](O)(=O)=O>>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[CH:11][CH2:10][CH2:9][I:20]
Reactant: Cc1ccccc1C1(c2ccccc2C)CCCO1
Reactant: [O-][I+2]([O-])O
Product: Cc1ccccc1C(=CCCI)c1ccccc1C

Procedure:
A solution of 2,2-di-(2-tolyl)-tetrahydrofuran 33a (40 g) in 57% aqueous iodic acid (250 mL) was boiled under reflux for 30 min. The cooled solution was extracted wiyh diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo. The residue was subjected to CC (n-heptane/ethyl acetate 15:1) to give the title compound 36a as an oil (44 g). 1H NMR (CDCl3) δ2.10 (s,3H), 2.30 (s,3H), 2.65 (q,2H), 3.19 (t,2H), 5.73 (t,1H), 7.05-7.22 (m,8H)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CCC(N)CC
Product: CCC(CC)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (750 mg, 1.48 mmol) and 3-aminopentane (520 μl, 4.44 mmol) as starting materials.
Reaction SMILES: [C:1]1([CH2:17]P(=O)(OCC)OCC)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C[O-].[Na+].C(O)(=O)C>CN(C)C=O.O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[CH:17][C:1]2[C:14]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=3)[CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5][C:4]4=[CH:3][CH:2]=2)=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc2ccc3cccc4ccc1c2c34)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(C=Cc2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.47 g (7 mmol) of diethyl 1-pyrenylmethylphosphonate and 0.99 g (7 mmol) of 4-chlorobenzaldehyde were dissolved with stirring in 25 ml of N,N-dimethylformamide. To this reaction mixture, 1.62 g (7×1.2 mmol) of sodium methylate (28 wt. % methanol solution of sodium methylate) was gradually added in such a manner that the temperature of the reaction mixture did not exceed 30° C. The reaction mixture was then stirred at room temperature for 1 hour, neutralized with acetic acid, and diluted with about 300 ml of water. Crystals separated out. The crystals were separated by filtration, washed with water, dried and then purified by column chromatography two times. In the first time, the purification was carried out on a column of silica gel, using a mixed solvent of toluene/n-hexane (1/1) as the developing solvent, and in the second time, the purification was carried out on a column of silica gel, using a mixed solvent of toluene/n-hexane (1/2) as the developing solvent, whereby yellow 1-(4-chlorostyryl)pyrene was obtained with a yield of 2.21 g (93.5%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+]=[N-])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>>[CH3:11][C:12]12[N:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=3)[CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: CC1=CCCCC1
Product: Cc1ccc(N2C3CCCCC32C)cc1

Procedure:
p-Tolyl azide (0.100 g, 0.751 mmol), 1-methyl-cyclohexene (4.055 g, 42.2 mol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0104 g, 0.0075 mmol) were used in the General Catalytic Reaction described above yielding 0.059 g, 39%. 1H NMR (CDCl3, 499.74 MHz): δ 7.02 (d, J=7.5 Hz, 2H), 6.75 (d, J=6.5 Hz, 2H), 2.28 (s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.99 (m, 2H), 1.64 (m, 1H), 1.55 (m, 2H), 1.35 (m, 1H), 1.25 (m, 1H), 0.99 (s, 3H) 13C NMR (CDCl3, 125.66 MHz): δ 148.74, 130.52, 129.27, 120.49, 44.17, 41.60, 32.41, 24.62, 21.16, 20.85, 20.81, 20.65. GC/MS (m/z): 201.1. DART HR MS (m/z): [M+H]+202.1594 (found). C15H22N, 202.1596 (calcd).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C@H:10]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl>[ClH:21].[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([Cl:21])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[O:23]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Product: Cl
Reaction time: 5.5 h
Yield: 217.4 %

Procedure:
To a solution of (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine (5.03 g) in dichloromethane (50 ml) was added 1-chloroethyl chloroformate (1.51 ml) slowly at 0° C., and then the mixture was heated at reflux under stirring. After 5.5 hours, the solvent was removed in vacuo and then the resulting residue was dissolved in methanol (20 ml) and refluxed for 0.5 hour. After removal of the solvent, the resulting residue was triturated with isopropyl ether to afford (2R)-1(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine hydrochloride (4.84 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:19][S-:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[N:4][CH:5]=[C:6]([CH2:8][S:20][CH3:19])[CH:7]=1
Reactant: C[S-]
Reactant: Fc1ccc(Oc2ncc(CBr)cc2Br)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Reaction time: 4 h
Yield: 96.3 %

Procedure:
The product from Example 60C (0.75 g, 1.979 mmol) and sodium thiomethoxide (0.139 g, 1.979 mmol) were combined in dimethylformamide (3.96 mL), stirred for 4 hours and partitioned into ethyl acetate and cold water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.66 g, 96%).
Reaction SMILES: BrC1N=C([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])C=CC=1.COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:52]1[CH:53]=[CH:54][C:55]([Cl:58])=[N:56][CH:57]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[Cl:58][C:55]1[N:56]=[CH:57][C:52]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[CH:53][CH:54]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: Clc1ccc(Br)cn1
Agent: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(Cl)nc1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (100 mg, 0.29 mmol) was reacted with 5-bromo-2-chloropyridine (55 mg, 0.29 mmol) and Na2CO3 (90 mg, 0.86 mmol) in DME (2 mL), and H2O (2 mL) to afford the desired 2-[4-(6-chloropyridin-3-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.59 (d, 1H), 7.85–7.66 (m, 3H), 7.44–7.78 (m, 1H), 7.56–7.60 (m, 1H), 7.48–7.45 (d, 1H), 7.42–7.38 (m, 3H), 3.98 (s, 3H). MS (ESI) 337 (M+H)+.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=3)[N:14]([CH2:26][CH3:27])[C:13]2=[O:28])[CH2:8][CH2:7]1)=O)C.Br.C(N1C2C(=CC([N+]([O-])=O)=CC=2)C(=O)N(C2CCNCC2)C1=O)C.[Cl:53][C:54]1[N:63]=[C:62](Cl)[C:61]2[C:56](=[CH:57][C:58]([O:67][CH3:68])=[C:59]([O:65][CH3:66])[CH:60]=2)[N:55]=1>>[Cl:53][C:54]1[N:63]=[C:62]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=4)[N:14]([CH2:26][CH3:27])[C:13]3=[O:28])[CH2:8][CH2:7]2)[C:61]2[C:56](=[CH:57][C:58]([O:67][CH3:68])=[C:59]([O:65][CH3:66])[CH:60]=2)[N:55]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CCOC(=O)N1CCC(n2c(=O)c3cc([N+](=O)[O-])ccc3n(CC)c2=O)CC1
Agent: Br
Agent: CCn1c(=O)n(C2CCNCC2)c(=O)c2cc([N+](=O)[O-])ccc21
Product: CCn1c(=O)n(C2CCN(c3nc(Cl)nc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 78 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 3.62 g (9.4 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound ii) was used in place of Compound a, whereby 3.20 g of crude 1-ethyl -1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound jj) was obtained. The product (198.0 mg) was treated in the similar manner as in Example 40, except for the use of 2,4-dichloro-6,7-dimethoxy-quinazoline in place of 4-chloro-6,7-dimethoxy-quinazoline, to give 220.7 mg (yield: 78%) of Compound 79 as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH2:44])=[O:36])=[CH:33][CH:32]=1>>[NH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:46][CH:45]=1)=[O:36]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccccc6N)cc5)cccc4c3)c2cc1OC
Yield: 71.9 %

Procedure:
The title compound (43.1 mg, 72% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 600 (M+1).
Reaction SMILES: C(C(C(C([O-])=O)O)O)([O-])=O.[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N=C=S)C1C=CC=CC=1.[CH:31]1([CH2:34][N:35]2[CH2:53][CH2:52][C@:42]34[C:43]5[C:44]6[O:51][C@H:41]3[C@H:40]([NH:54][CH3:55])[CH2:39][CH2:38][C@@:37]4([OH:56])[C@H:36]2[CH2:49][C:48]=5[CH:47]=[CH:46][C:45]=6[OH:50])[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][N:35]2[CH2:53][CH2:52][C@:42]34[C:43]5[C:44]6[O:51][C@H:41]3[C@@H:40]([N:54]([CH3:55])[C:19]([NH:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:20])[CH2:39][CH2:38][C@@:37]4([OH:56])[C@H:36]2[CH2:49][C:48]=5[CH:47]=[CH:46][C:45]=6[OH:50])[CH2:32][CH2:33]1
Reactant: O=C=NCc1ccccc1
Reactant: CN[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: S=C=NCc1ccccc1
Product: CN(C(=O)NCc1ccccc1)[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5

Procedure:
tartrate 132 (yield: 65%), 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(N-methyl-N′-benzylthioureido)morphinan.tartrate 133 (yield: 88%) and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-N′-benzylthioureido)morphinan.tartrate 134 (yield: 74%) were obtained by following the procedure of example 121 but using benzylisocyanate and benzylisothiocyanate instead of 3,4-dichlorophenylisocyanate, and using 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-methylaminomorphinan 10 instead of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-methylaminomorphinan 4.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O.C(OCC)(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(SCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
79.7 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 303.1 mg of 4-acetamidothiophenol in 6 ml of dimethylformamide at room temperature, followed by the addition of a solution of 454.8 mg of 2-bromomethyl-benzothiazole in 1 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 462.7 mg (yield 81%) of the title compound as a solid having a melting point of 147° to 149° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH2:47][CH3:48])=[CH:45][N:44]=[C:43]([CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH2:47][CH3:48])=[CH:45][N:44]=[C:43]([CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (300 mg, 63%).
Reaction SMILES: [OH-].[Li+].O.[CH:4]([C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:5]>O1CCCC1.CO>[CH:4]([C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([OH:13])=[O:12])=[O:5]
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
Lithium hydroxide (207 mg, 8.66 mmol) and water (2.5 ml) were added to a solution of phenylmethyl 5-formyl-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in description 96) (1 g, 2.89 mmol) in tetrahydrofuran (10 ml) and methanol (2.5 ml). The mixture was stirred overnight. The tetrahydrofuran/methanol was removed in vacuo and the remaining aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×20 ml). The solvent was removed in vacuo to yield the title compound as a white solid. 1.1 g.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>CN(C)C=O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)n1

Procedure:
2.9 ml benzyl alcohol was dissolved in 10 ml N,N-dimethylformamide and 0.7 g sodium hydride (purity 95%) was slowly added. After gas evolution has ceased, 6 g 2,6-dibromopyridine was added and the mixture heated to reflux for 3 hours. After cooling, the reaction mixture was filtered through a silica gel column using hexane/ethyl acetate 1/1. The solvent was removed in vacuo and the crude product purified by flash silica gel column chromatography. The title compound was obtained as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cc(CC2CCCC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F
Reaction time: 18 h

Procedure:
A mixture of 4-cyclopentylmethyl-1H-pyrrole-2-carboxylic acid ethyl ester (A1-II) and cesium carbonate were stirred in dry DMF for 10 minutes at 40-50° C. To it 1-bromomethyl-2,4-difluorobenzene was added and the reaction was stirred for 18 hrs. at 50° C. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4-cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid ethyl ester (A1-III).