Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:21])([CH2:4][CH2:5][NH:6][C:7]1[N:8]=[N:9][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[CH3:3].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:3][C:2]1([CH3:1])[O:21][C:23](=[O:25])[N:6]([C:7]2[N:8]=[N:9][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH2:5][CH2:4]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(O)CCNc1ccc(C#Cc2ccccc2)nn1
Product: CC1(C)CCN(c2ccc(C#Cc3ccccc3)nn2)C(=O)O1

Procedure:
The title compound, a crystalline light yellow solid, MS: m/e=308.3 (M+H+), was prepared in accordance with the general method of Example 152, step 2 starting from 2-methyl-4-(6-phenylethynyl-pyridazin-3-ylamino)-butan-2-ol (Example 153, step 1) and triphosgene.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11].[N:17]1[N:18]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[N:19]=[CH:20][CH:21]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:5]1([F:7])[CH2:6][C@H:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:17]2)[C@@H:3]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:4]1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1N
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-methylpropane-2-sulfonamide (1.03 g, 4.02 mmol) in dry DCM (13.4 ml) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.91 g, 4.82 mmol), EDC (2.31 g, 12.06 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (1.64 g, 12.06 mmol) and DIPEA (2.11 ml, 12.06 mmol). The reaction was stirred at room temperature overnight then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 30-80% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=4)(=[O:35])=[O:34])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Yield: 57.7 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10 mg, 0.032 mmol) obtained in Example 1, (3), and 3-methoxybenzenesulfonyl chloride (13 mg, 0.063 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to obtain the title compound (9 mg, yield 59%) as slightly brown amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:9][Br:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Cc1nc(Cl)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-bromo-6-chloro-2-methylpyridine (105 g, 509 mmol) in CCl4 (2 L) was added N-bromosuccinimide (95 g, 534 mmol) followed by AIBN (8.35 g, 50.9 mmol). The reaction was brought to reflux for 24 hours and then cooled to r.t., filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 60% methylene chloride/heptanes afforded semi-pure product. Further purification by SFC on a Chiralpak AD-H column with 20% IPA/CO2 [the conditions of the preparative separation were as follows: column Chiralpak AD-H (2.1×25 cm, 5 μm particle size) (Chiral Technologies, West Chester, Pa., USA); mobile phase 20% 2-propanol/CO2; elution mode isocratic pump-mixed; flow rate 50 mL/min; pressure 100 bar.] gave 3-bromo-2-(bromomethyl)-6-chloropyridine. LCMS=285.7 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.81 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 4.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[C:18]([C:17]([F:22])([F:21])[F:16])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Product: COc1ccc(CCN(C)C)c2[nH]c(C(F)(F)F)nc12

Procedure:
600 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux for 3 hours with 10 ml of trifluoroacetic acid. After concentration, the residue is recrystallized from isopropanol, thus obtaining 908 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2-trifluoromethylbenzimidazole, trifluoroacetate, mp 182°-185° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][C@@H:20]1[CH:21]2[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]2)[CH2:19]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetic acid (710 mg, 2.76 mmol), (R)-quinuclidin-3-ol (421 mg, 3.31 mmol), DCC (683 mg, 3.31 mmol), HOBT (507 mg, 3.31 mmol) in THF (20 ml) was stirred at RT overnight. THF was evaporated, and the crude was portioned between EtOAc and 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetate (509 mg, 50.3% yield).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=C(O)C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.O(CC1S[CH:52]2[CH:49](C(=O)[N:51]2[C:54](=C(OS(C)(=O)=O)C)[C:55]([O:57][CH2:58][C:59]2C=CC([N+]([O-])=O)=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1>O1CCCC1.C(N(CC)CC)C>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:52]([N:51]2[CH2:54][CH2:55][O:57][CH2:58][CH2:59]2)[CH3:49])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 1.5 h

Procedure:
One dissolves p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (940 mg) in tetrahydrofuran (14 ml), adds triethylamine (0.61 ml) and methanesulfonyl chloride (0.172 ml), and stirs for 1 hour at -15° to -20° C. To the produced solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)-acetate, one adds morpholine (0.209 ml), stirs for 1.5 hours at -15° to -20° C., and for 2 hours at 0° C., to give a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -15° C., adds pyridine (0.174 ml) followed by after 5 minutes a solution of bromine in carbon tetrachloride (1 mole/liter: 2.1 ml), stirs for 15 minutes at the same temperature, pours into water (50 ml), and extracts with ethyl acetate (50 ml). The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give residue (1.7 g). Purification of the residue by chromatography over silica gel containing 10% water gives from the fractions eluted with a mixture of benzene and ethyl acetate (2:1) p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidene)acetate (1.109 g; Yield: 89.7%) and p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethyl)-α-methanesulfonylacetate (85 mg; Yield: 7.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH:19][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(NC(=O)c2cc(C(N)=O)ccc2OC)c(OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,4-dimethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1)(=[O:29])=[O:28]
Reactant: COC(=O)COc1cccc2c(CCO)coc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1cccc2c(CCOS(C)(=O)=O)coc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (4.12 g) was dissolved in dichloromethane (120 ml) and triethylamine (3 ml) and methanesulfonyl chloride (1.35 ml) were added to the solution, followed by stirring the resulting solution at 0° C. for 1.5 hours. The reaction mixture was then poured into 1N hydrochloric acid and the resultant was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and with saturated saline, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure. The residue was recrystallized from n-hexane/ethyl acetate to obtain the desired compound (5.25 g, yield: 97%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:13]([CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([O:10][CH2:11][CH3:12])=[O:9])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CCCC=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCCC(=O)C(CC(=O)OCC)C(=O)OCC
Yield: 85.6 %

Procedure:
A mixture of 86 g of diethyl maleate, 144 g of butyraldehyde and 4 g of dibenzoyl peroxide was boiled at reflux for 20 hours. After completion of the reaction, the excess butyraldehyde was firstly distilled off over a Vigreux column and then the yellow coloured crude product was taken up in 250 ml of hexane and washed with 200 ml of 5% (wt./vol.) sodium hydrogen carbonate solution and 200 ml of water. The aqueous phases were back-extracted with a small amount of hexane. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting crude product in a high vacuum over a Vigreux column gave 104.5 g (85.6%) of diethyl 2-butyrylsuccinate as a slightly yellow coloured liquid; b.p. 84°-90° C./0.08 Torr.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)c1cccnc1

Procedure:
According to the general method of Example 61, 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and nicotinoyl chloride hydrochloride were combined to provide N3-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide as a white crystalline solid, m.p. 84.5-86.1° C. 1H NMR (300 MHz, DMSO-d6) δ8.91 (s, 1H), 8.69 (m, 1H), 8.56 (m, 1H), 8.07 (m, 2H), 7.75-7.41 (m, 8H), 7.21 (m, 1H), 6.72 (broad s, 2H), 4.60 (m, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.86 (m, 2H), 1.40 (m, 2H); MS (CI) m/e 437 (M+H).
Reaction SMILES: COC1[C@@H](C(C)C)N=[C:6]([O:17][CH3:18])[C@H:7]([CH2:9][C:10]2[C:11]([CH3:16])=[N:12][O:13][C:14]=2[CH3:15])[N:8]=1.Cl.[O:23]1CCOCC1>>[NH2:8][C@@H:7]([CH2:9][C:10]1[C:11]([CH3:16])=[N:12][O:13][C:14]=1[CH3:15])[C:6]([O:17][CH3:18])=[O:23]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1c(C)noc1C
Reactant: C1COCCO1
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1c(C)noc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(3,5-dimethyl-4-isoxazolylmethyl)pyrazine (2 g, 6.8 mmol), 1.0M HCl (13.6 ml, 13.6 mmol) and dioxane (13.6 ml) was stirred at ambient temperature overnight under N2. Dioxane was removed under reduced pressure and the water phase extracted with diethyl ether (20 ml). Aqueous ammonia was added to the water phase until pH 9, extracted with CHCl3 (3×30 ml), dried (MgSO4) and the solvent removed under reduced pressure. The valine methyl ester was removed by bulb-to-bulb distillation at 40°-50° C. (0.05 mbar). The undistilled title compound was used without further purification.
Reaction SMILES: [I:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:23]1[O:24][C:11]2([CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([CH2:3][C@@H:2]([I:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)[O:21][CH2:22]1
Reactant: OCCO
Reactant: C[C@]12CC[C@H](I)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C[C@]12CC[C@H](I)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Yield: 87.3 %

Procedure:
More specifically, 3β-iodoandrost-5-en-17-one (11) (11.83 g, 29.7 mmol), ethylene glycol (20 ml) and p-toluene sulfonic acid (200 mg) in benzene (250 ml) were refluxed under a Dean-Stark trap for 72 hrs. The solution was washed with saturated sodium bicarbonate, water, then dried over magnesium sulfate. Evaporation and recrystallization from ether afforded 11.5 g (87.3%) of 3β-iodoandrost-5-en-17-one-17-ethyleneketal (12): mp 140°-141° C., IR (KBr): 3010, 2940, 1470, 1425, 1375 cm-1 ; 1H NMR (CDCl3): δ5.44 (brd J=6 Hz, 1H, H-6), 3.91 (s, 4H, ketal), 1.07 (s, 3H, C-19 Me), 0.88 (s, 3H, C-18 Me); MS (m/e): 442 (M+, 1), 380 (35), 315 (57), 253 (67), 227 (11), 105 (24), 99 (100), 91 (35), 55 (27), 41 (33).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[NH2:16])(=O)[CH3:2].C([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[C:23]([Cl:29])[CH:22]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.C(OCC)(=O)C>[Cl:29][C:23]1[CH:22]=[C:21]([OH:20])[CH:28]=[CH:27][C:24]=1[CH2:25][N:16]1[C:6]2[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=[CH:15][C:5]=2[N:4]=[C:1]1[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(N)c1
Reactant: CC(=O)Oc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 15.6 %

Procedure:
A mixture of 6.34 g of ethyl 4-(acetylamino)-3-amino-benzoate, 14.0 g of 4-acetoxy-2-chlorobenzyl bromide, 5.12 g of potassium carbonate, 1.28 g of sodium iodide, 35 ml of ethyl acetate, and 13 ml of water was stirred at 70° C. for 15 hours. After the reaction was completed, the solution was separated. After washed with water, the organic layer was concentrated under reduced pressure. To the oily residue, 30 ml of ethanol and 3.2 g of 35% hydrochloric acid was added and the solution was stirred at 70° C. for 3 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was concentrated, and, for crystallization, ethanol was added to the residue obtained. The crystals obtained through filtration were dried to give 1.53 g of 1-(2-chloro-4-hydroxybenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole. The filtrate was concentrated, and, for crystallization, ethanol was added to the residue obtained. The crystals obtained through filtration were dried to give 4.72 g of 1-(2-chloro-4-hydroxybenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C:27]1([CH2:31][CH2:32][OH:33])[CH2:30][O:29][CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C:27]3([CH2:31][CH2:32][OH:33])[CH2:30][O:29][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1(CCO)COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3(CCO)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-aminooxetan-3-ethanol. MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (d, 1 H), 7.89 (d, 1 H), 7.64 (t, 1 H), 7.55 (s, 1 H), 7.49-7.42 (m, 2 H), 7.35-7.32 (m, 1 H), 6.63 (s, 1 H), 5.15 (s, 2 H), 4.50 (d, 2 H), 4.41 (brs, 2 H), 4.39 (d, 4 H), 3.66 (d, 2 H), 2.33 (s, 3 H), 2.27 (t, 2 H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:21][CH:20]=3)[CH2:16][CH2:15][CH2:14][C:13](=O)[C:12]=2[CH:37]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:21][CH:20]=3)[CH2:16][CH2:15][CH2:14][C:13](=[CH2:1])[C:12]=2[CH:37]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.86 g) in tetrahydrofuran (20 ml) is added with stirring potassium t-butoxide (0.23 g) at -5° C., and the mixture is stirred at -5° C. for one hour. To the mixture is added 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) at the same temperature, and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-methylidene-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as yellow amorphous.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: COCOCCc1ccc(OCc2ccccc2)c(C#N)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOCCc1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 2-benzyloxy-5-(2-methoxymethoxyethyl)benzonitrile (711 mg) in ethyl acetate (10 ml) was added 10% palladium carbon (100 mg), and the mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. After removal of the catalyst by filtration, removal of the solvent under reduced pressure gave 2-hydroxy-5-(2-methoxymethoxyethyl)benzonitrile (496 mg).
Reaction SMILES: [CH3:1][C@:2]([C:14]([NH:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].[C:27]12([CH2:37][C:38](Cl)=[O:39])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C1COCC1>[OH:26][CH2:25][CH:17]([NH:16][C:14](=[O:15])[C:2]([CH3:1])([NH:3][C:38](=[O:39])[CH2:37][C:27]12[CH2:36][CH:31]3[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]3)[CH2:34]1)[CH2:28]2)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@](N)(Cc1c[nH]c2ccccc12)C(=O)N[C@H](CO)Cc1ccccc1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)CC12CC3CC(CC(C3)C1)C2)C(=O)NC(CO)Cc1ccccc1
Yield: 113 %

Procedure:
A solution of α-methyl-D-tryptophyl-L-phenylalaninol (1 g, 2.85 mmol) and 4-N,N-dimethylaminopyridine (0.35 g, 2.87 mmol ) in dry THF (50 mL ) at 0° C. was treated dropwise, with stirring, with a solution of 1-adamantylacetyl chloride (0.605 g, 2.85 mmol). A precipitate formed immediately. The reaction mixture was left until all starting materials were consumed as assayed by TLC and IR spectroscopy. The final TLC showed three spots (10% MeOH:90% CH2Cl2). The reaction mixture was washed with 1M citric acid solution and extracted into ethyl acetate. The organic phase was then washed with water and dried over MgSO4. Concentration in vacuo gave a syrup (1.7 g) which was chromatographed over silica using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.35 g, 90%) as a white solid crystallized from ethyl acetate-hexane, mp 91°-94° C. (EtOAc-hexane); IR (KBr) 3304 and 1652 cm-1 ; NMR (CDCl3) δ1.48 (9H, m), 1.59 (6H, m), 1.76 (2H, q, J 13 Hz), 1.9 (3H, m), 2.74 (2H, d, J 7Hz), 3.21 (1H, half ABq J 14.5Hz), 3.30 (1H, 6, J 6Hz), 3.40 (1H, half Abq J 14.5Hz), 3.45 (1H, m), 3.70 (1H, m), 4.16 (1H, m), 5.91 (1H, s), 6.38 (1H, d, J 8Hz), 6.92 (1H, d, J 3Hz), 7.07-7.27 (7 H, m), 7.35 (1H, d, J 8Hz), 7.56 (1H, d, J 8Hz) and 8.54 (1H, s); Anal. (C33H41N3O3.0.25 H2O), C, H, N.