Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>C1COCC1>[N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][C:27]=2[NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:25])=[O:24])[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Isobutyryl chloride (42 mg, 0.40 mmol) and DIPEA (100 mg, 0.83 mmol) were added to a solution of 2-amino-N-quinolin-8-yl-benzenesulfonamide (Example Compound 8) (100 mg, 0.33 mmol) in THF (3 ml) at 0° C. The reaction was stirred at room temperature for 1 h. The reaction was quenched water and extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (49:1) as the eluent to give the title compound (43 mg, 36%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:23]=[CH:22][C:15]([O:16][C:17]([CH3:21])([CH3:20])[CH2:18]Br)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:24]([O-:27])(=[O:26])[CH3:25].[K+]>CN(C=O)C>[C:24]([O:27][CH2:18][C:17]([O:16][C:15]1[CH:22]=[CH:23][C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:14]=1)([CH3:21])[CH3:20])(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CN1CCC(c2ccc(OC(C)(C)CBr)cc2)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(C)(C)Oc1ccc(C2CCN(C)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3 g. of 2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-2-methyl-propyl bromide are dissolved in 20 ml. of DMF, 3 g. of anhydrous potassium acetate are added and the mixture is stirred for 3 hours at 60° C. Working up in the usual manner gives 2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-2-methyl-propyl acetate.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([F:20])[F:19])(=O)=O.[S:22]1[C:26]([C:27](O)=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.C(=O)([O-])O.[Na+]>O>[S:22]1[C:26]([C:27]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([F:19])[F:20])=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(CCCCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCCCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.29 g (1.1 mmol) of 8,8-difluoro-7-methyl-7-octenyl methanesulfonate and 0.26 g (1.5 mmol) of benzo[b]thiophene-2-carboxylic acid, followed by the addition of 0.28 g (3.3 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:8) to obtain 0.27 g (yield: 71%) of 8,8-difluoro-7-methyl-7-octenyl benzo[b]thiophene-2-carboxylate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([N:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[NH3:29]>C(OCC)C.C1COCC1>[CH:7]1([N:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH2:29])=[N:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(NN1CCCCC1)N(C1CCCCC1)C1CCCCC1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=NN1CCCCC1)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (4.0 mL, 20 mmol) and triethylamine (6 mL, 43 mmol) in diethyl ether (63 mL) was added dropwise to a stirred solution of triphosgene (2.0 g, 6.7 mmol) in diethyl ether (30 mL) at room temperature. The reaction mixture was stirred overnight under refluxing conditions. Then, a solution of piperidine (1.9 mL, 19 mmol) and triethylamine (5.8 mL, 42 mmol) in diethyl ether (37 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding N,N-dicyclohexylpiperidylurea as a yellow oil. Yield: 2.0 g (35%). Oxalyl chloride (1.0 mL, 12 mmol) was added to a stirred solution of the urea (2.0 g, 6.9 mmol) in diethyl ether (30 mL). The reaction mixture was evaporated to dryness after stirring at reflux temperature for 5 h. Ammonia (3 mL, 21 mmol, 7 M solution in methanol) was added to a solution of the resulting solid in diethyl ether (50 mL) and THF (5 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. The product mixture was treated with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over sodium sulfate. Filtration and evaporation to dryness yielded the desired guanidine as a yellow solid. Yield: 1.76 g (87%). 1H NMR (CDCl3, 300 MHz): δ 1.18-1.89 (m 20 H), 3.03 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 25.2, 26.1, 26.2, 32.4, 49.0, 57.8, 165.2 ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=O>C(O)C.C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:17][C:16]2[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[N:6]=1
Reactant: COCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: COCc1nc2c(C(=O)OC)cccc2[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
[step 2] methyl 2-(2-methoxyacetamido)-3-nitrobenzoate (1.9 g, 6.9 mmol) obtained in step 1 was dissolved in a mixed solvent of ethanol (14 mL) and acetic acid (14 mL), reduced iron (2.3 g, 41.4 mmol) was added, and the mixture was stirred at 120° C. for 3 hr. After completion of the reaction, the mixture was filtered through celite. Saturated aqueous sodium hydrogen carbonate was added to the solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-20/80 v/v) to give methyl 2-(methoxymethyl)-1H-benzo[d]imidazole-4-carboxylate (1.1 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[CH3:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19].C(=O)=O>O1CCOCC1.O>[CH3:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][C:18](=[O:19])[O:20][CH2:21][CH2:22][Cl:23]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(NC(=O)OCCCl)cccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
91 g of 2-nitro-6-aminotoluene and 31 g of calcium carbonate are initially introduced into the reaction vessel in 750 ml of dioxane, and are heated up to 70° C. 87 g of β-chloroethyl chloroformate are added dropwise to this mixture in the course of two hours such that the reaction mixture refluxes gently, carbon dioxide being evolved. The mixture is subsequently stirred under reflux for a further two hours and then cooled to 35° C., and water and ice are added. The product which has precipitated is filtered off with suction, washed with water, and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C([O:34]CCOCCO)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([NH2:29])=[O:34])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOCCOCCO
Reactant: COc1cccc(N2CCN(CCCCc3c[nH]c4ccc(C#N)cc34)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(N2CCN(CCCCc3c[nH]c4ccc(C(N)=O)cc34)CC2)c1
Reaction time: 3 h

Procedure:
A mixture of 30.6 g of 3-[4-(4-m-methoxyphenylpiperazino)butyl]-5-cyanoindole, 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred for 3 hours at a bath temperature of 140°. It is cooled and worked up in a conventional manner, and 3-[4-(4-m-methoxyphenylpiperazino)butyl]indole-5-carboxamide is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:35])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])CCC>O1CCCC1>[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][NH:6][C:26]1[C:25](=[O:35])[C:24](=[O:23])[C:27]=1[NH:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1ccc(C)c(CN)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2cc(C)ccc2C)c(=O)c1=O
Yield: 87.2 %

Procedure:
Tetrahydrofuran (10 mL), 2,5-dimethylbenzylamine hydrochloride (0.858 g, 5.0 mmol, Example 94, Step 2), triethylamine (0.51 g, 5.0 mmol), and 3-butoxy-4-(1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol, Example 3) were stirred together at room temperature for approximately 18 hours. After removal of solvent the residue was triturated with water, with diethyl ether, and dried to give 1.31 g of a light yellow solid. Three recrystallizations of the crude product from acetonitrile provided 0.812 g of the title compound as a fluffy, white solid: mp 199°-200° C. (softens 195° C.). MS (m/z) 301 ([M+H]+). HPLC indicates a major component (>99%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][S:33]([CH3:35])=[O:34])[CH:25]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:36][C:37]#[N:38].[Na+]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][S:33]([CH3:35])=[O:34])[CH:25]=3)[C:37](=[O:36])[N:38]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cccc(OCCS(C)=O)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCS(C)=O)c1

Procedure:
The title compound (yellow oil) is prepared from (4-isopropyl-phenyl)-{2-[3-(2-methanesulphinyl-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-methanone and sodium cyanate as described for the preparation of example 3.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Si:8]([O:15][CH2:16][CH2:17]Br)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CN(C=O)C>[Si:8]([O:15][CH2:16][CH2:17][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To 86.4 mg (2.2 mmoles) of 61.1% sodium hydride mineral oil dispersion in 5 mL sieve dried DMF at 0° C. was added 136 mg (2.0 mmoles) of imidazole. The mixture was stirred at 0° C. under nitrogen for 15 minutes and 476 mg (2.0 mmoles) of neat t-butyldimethylsilyloxyethyl bromide was added. The ice-water bath was removed and the mixture stirred overnight and it was then partitioned between ether and ice-water. The organic phase was separated, washed thrice with ice-water, dried over sodium sulfate, filtered, and evaporated to give 282.3 mg (63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(COc2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a solution of 2-chloro-5-nitrophenol (10 g, 57.6 mmol) in acetonitrile (100 mL) was added potassium carbonate (11.7 g, 86 mmol) followed by 4-methoxy benzyl bromide (13.9 g, 69.1 mmol), at room temperature. The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. It was then filtered and the solid mass was washed with ethyl acetate (100 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica gel) using 2% MeOH in CHCl3 to give 1-chloro-2-(4-methoxybenzyloxy)-4-nitrobenzene (15 g, 89%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, s), 7.79 (1H, d, J=8.8 Hz), 7.53-7.51 (1H, d, J=8.4 Hz), 7.41-7.39 (2H, m), 6.95-6.87 (2H, m), 5.17 (2H, s), 3.82 (3H, s).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[CH3:15][C:16]1([CH3:28])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[O:17]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([CH2:3][C:4]1([N:26]2[CH:27]=[C:23]([B:18]3[O:17][C:16]([CH3:28])([CH3:15])[C:20]([CH3:22])([CH3:21])[O:19]3)[CH:24]=[N:25]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.2 %

Procedure:
In a 5 L flask, tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (Preparation F, Step A; 94.2 g, 485 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (85.6 g, 441 mmol) were dissolved in acetonitrile (882 mL). To this was then added DBU (33.0 mL, 220 mmol). The resulting clear orange brown mixture was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated down to remove solvents and afforded a dark reddish-orange oil. Solid crystals formed within a few hours at ambient temperature. This was isolated by washing with cold Et2O and cold EtOAc (carefully to prevent dissolution) to afford 110 g (64% yield) of the title compound. The recrystallization was repeated to give another 13.7 g (8% yield). Additional compound was isolated by purification of the filtrate from the above recrystallization. This was purified by silica chromatography eluting with a 20-50% EtOAc/Hexanes gradient to afford an additional 22.7 g (13%) of the title compound. MS (apci) m/z=289.2 (M+H-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>CN(C=O)C>[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:21]=1
Reactant: BrC1C=CCCC1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1OC1C=CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K2CO3 and 20 g of 3-bromo-cyclohexene in 200 ml of DMF is stirred at 90° C. overnight. The mixture is then poured onto water, extracted with ethylacetate., washed with water, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([O:4][CH2:3][CH:2]3[CH2:5][CH2:6][CH2:7][NH:1]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3CCCN3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of prolinol (0.0243 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH-CHCl3) to afford the title compound E22 as an off-white solid (0.35 g, quantitative). mp 84-86° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/%B=0/60, 10/60,25/80, 40/80, 45/60, 50/60; 268 nm, Rt 24.67 min, 99.59% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [C:1]1([C:7](=[O:15])[C:8]([O:10][Si](C)(C)C)=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][C:18](=C)[CH3:19]>>[C:7]([C:8]1([OH:10])[CH2:19][CH2:18][CH:17]=[CH:16][CH2:9]1)(=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=C)C
Reactant: C=C(O[Si](C)(C)C)C(=O)c1ccccc1
Product: O=C(c1ccccc1)C1(O)CC=CCC1

Procedure:
If the 1-phenyl-2-trimethylsiloxyprop-2-en-1-one is reacted with isoprene instead of butadiene, an analogous procedure gives an oily product which, after bulb tube distillation (150°/0.06 mm Hg), gave the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.CN([CH:24]=[O:25])C>C(OCC)C>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH:24]=[O:25])=[N:13]1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2=NC(C)(C)CO2)c(C=O)c1
Reaction time: 4 h
Yield: 84 %

Procedure:
In dry environment under N2, 2-(4-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (20 g, 0.097 mole), prepared as described in example 1, was dissolved in ethyl ether (200 ml) and added at −2° C. with n-butyl lithium (44 ml, 0.11 mole), keeping the temperature below 5° C. The mixture was stirred and after 4 hours added with DMF (15.4 g, 16.3 ml, 0.21 mole). After stirring overnight at room temperature, the mixture was cooled and extracted with water/ice. The aqueous phase was extracted again with ethyl ether. The organic phase was washed with water/NaCl, discoloured with charcoal, anhydrified and concentrated under vacuum to give 19 g of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[C:48]([N:51]3[C:56](=[O:57])[CH2:55][C:54]([CH3:59])([CH3:58])[CH2:53][C:52]3=[O:60])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[C:48]([N:51]3[C:52](=[O:60])[CH2:53][C:54]([CH3:59])([CH3:58])[CH2:55][C:56]3=[O:57])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 400 mg (0.5 mMol) of 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl in 10 ml of methanol is mixed with 1.5 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with 15 ml of water and made alkaline with concentrated ammonia, whereupon the product goes into solution. By acidification with glacial acetic acid, the crude product is precipitated and then purified by column chromatography (150 g of silica gel; eluant:methylene chloride+5% ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: NCc1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 111.4 %

Procedure:
A solution of 4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.57 g, 10 mmol), benzylamine (1.20 mL, 11 mmol) and p-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) in toluene (40 mL) was heated at reflux under a Dean-Stark trap for 22.75 hours. The mixture was cooled to room temperature and concentrated under vacuum to provide a yellow gummy solid (3.86 g), used without further purification. 1H NMR (300 MHz, CDCl3) δ9.25 (bt, J=6 Hz, 1H), 7.4-7.1 (m, 5H), 4.42 (d, J=6 Hz, 2H), 4.11 (s, 2H), 3.71 (s, 3H), 3.49 (t, 2H), 2.38 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: I[CH:2]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:22]([CH:2]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C2Cc3ccccc3NC(=O)C2I)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2N=[N+]=[N-])cc1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
A solution of 2,3,4,5-tetrahydro-3-iodo-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one (270 mg, 0.687 mmol) in 2mL of dimethylformamide was treated with sodium azide (65 mg, 1.0 mmol, 1.5eq) and the mixture was heated at 60° C. in an oil bath for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and filtered. Removal of the solvent under vacuum followed by column chromatography on silica gel (eluant 2:1; hexane/ethyl acetate) gave 148 mg (70%) of the product as a single isomer. 1H NMR (400 MHz, CDCl3): 295 (dd; 7,14 Hz; 1H), 3.15 (dd; 13, 14 Hz; 1H), 3.75 (m, 1H), 3.80 (s, 3H), 4.11 (d, 7Hz, 1H), 6.89 (d, 8Hz, 2H), 7.04 (d, 8Hz, 1 H), 7.20-7.30 (m, 5H), 7.88 (br s, 1H). FAB-MS: calculated for C17H16N4O2 308; found 309 (40%).