Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C1COCC1>[Si:35]([C:27]1[S:28][CH:29]=[C:25]([CH2:24][C@H:11]2[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[O:14][C:13]([CH3:15])([CH3:16])[N:12]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[N:26]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2csc([Si](C)(C)C(C)(C)C)n2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Temperature: -50 °C

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.148 g, 0.334 mmol) in THF (3 mL) was cooled to −78° C. when n-butyllithium (2.5 M in hexanes)(0.160 ml, 0.401 mmol) was added dropwise. The solution was warmed to −50° C. for 40 minutes and then cooled to −78° C. TBS-Cl (0.0605 g, 0.401 mmol) in THF (2 mL) was added dropwise and the solution was allowed to slowly warm to 0° C. when it was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].C(=O)(O)O.[NH2:14][NH:15][C:16]([NH2:18])=[NH:17].C(=O)=O>O>[C:1]([O-:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].[NH2:14][NH:15][C:16]([NH2:18])=[NH2+:17]
Reactant: N=C(N)NN
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NNC(N)=[NH2+]
Product: O=C/C(Br)=C(/Br)C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Mucobromic acid (2.0 g, 7.76 mmol) was dissolved in 10 ml of distilled water. Aminoguanidine bicarbonate (1.06 g, 7.76 mmol) was added in portions at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 18 hours. The water was removed in vacuo with heating to approximately 90° C. The product was isolated as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20](OC(=O)C)(=[O:22])[CH3:21].O1CCOCC1>O>[C:20]([NH:1][C:2]1[C:11]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[CH3:21]
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate (5.54 g, 20.9 mmol), acetic anhydride (21.0 mL, 222 mmol), and dioxane (35 mL) was heated at 40° C. under N2 for 17 h and then allowed to cool to rt. Water (10 mL) was added, and after 15 min of stifling, the reaction was concentrated to give methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 307.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:30]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:30])[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc(N3CCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (18 mg, 0.044 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (12 mg, 0.032 mmol, 72.1% yield). 1H NMR (300 MHz, CDCl3) δ 12.03 (s, 1H); 9.30 (s, 1H); 8.48 (s, 1H); 8.15 (dd, J=8.92, 2.48 Hz, 1H); 6.76 (d, J=9.06 Hz, 1H); 5.24 (s, 2H); 3.95 (s, 3H); 3.66 (dd, J=5.85, 4.09 Hz, 4H); 2.49 (s, 3H); 2.00 (t, J=6.43 Hz, 4H). m/z (ESI, +ve ion) 380.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.[H-].[Na+].[H][H].[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[C:39]([N:8]([C:5]1[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:9](=[O:34])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:20][C:19]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=2)=[CH:12][C:11]=1[CH3:33])(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Temperature: 0 °C
Yield: 46.3 %

Procedure:
In a solution of 0.20 g of N-(5-chloro-2-pyrimidinyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide in 3 mL of tetrahydrofuran, 0.025 g of 55% oily sodium hydride was added under cooling with ice and with stirring and stirred at room temperature for 10 minutes. After ceasing the generation of hydrogen gas, 0.045 g of acetyl chloride was added under cooling with ice and with stirring, and continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of ice water, extracted with ethyl acetate (10 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:9 to 3:7) to obtain 0.10 g of the aimed product as white crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1
Reactant: Fc1ccc(F)nc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Temperature: 110 °C
Yield: 21.7 %

Procedure:
Potassium carbonate (16.75 g, 128.1 mmol) was added to a solution of 2,5-difluoropyridine (4.91 g, 42.7 mmol) and 2,4-dimethoxybenzylamine (6.85 g, 42.7 mmol) in DMSO (30 mL). The mixture was heated to 110° C. for 16 hours, cooled to room temperature and poured into water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with two further portions of ethyl acetate (25 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10 to 30% ethyl acetate in heptanes to afford the title compound as a white solid (2.43 g, 22%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([N:7]1[C:13]2[CH:14]=[C:15]([C:18](=[O:22])[CH2:19][CH2:20]Cl)[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5]>ClCCl>[C:4]([N:7]1[C:13]2[CH:14]=[C:15]([C:18](=[O:22])[CH2:19][CH2:20][N:2]([CH3:3])[CH3:1])[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5]
Reactant: CNC
Reactant: CC(=O)N1CCCCc2ccc(C(=O)CCCl)cc21
Solvent: ClCCl
Product: CC(=O)N1CCCCc2ccc(C(=O)CCN(C)C)cc21
Reaction time: 4 h

Procedure:
50% aqueous dimethylamine (27 ml) was added to a solution of 1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-3-chloro-1-propanone (7.10 g, 25.4 mmol) obtained in Reference Example 7 in dichloromethane at room temperature, and then stirred for 4 hours. After the reaction solution was separated, the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=1:1) and crystallized from hexane, whereby the title compound (5.38 g) was obtained as colorless powder with a mp. of 68 to 70° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C(=O)C(F)(F)F)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].O.O.O.C([O-])(=O)C.[Na+]>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1csc(N)n1
Reaction time: 72 h
Yield: 66.8 %

Procedure:
A solution of 7-[2-methoxyimino-2-{-2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in acetone (4 ml) was added at ambient temperature to a solution of sodium acetate trihydrate (2.4 g) in water (10 ml), and the mixture was allowed to stand for 3 days at ambient temperature. Acetone was distilled off under reduced pressure and water (10 ml) was added thereto. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.62 g).
Reaction SMILES: [C:1]([C:5]1C=C(O)C(=C[CH:11]=1)O)(C)([CH3:3])[CH3:2].CN(CCN(C)C)C>>[CH2:11]=[CH:5][C:1](=[CH2:2])[CH3:3].[CH2:2]=[CH:1][CH:5]=[CH2:11]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: CN(C)CCN(C)C
Product: C=CC(=C)C
Product: C=CC=C
Reaction time: 3 h

Procedure:
In this example, a coupled isoprene-butadiene rubber (IBR) was prepared in a one-gallon (3.8 liters) batch reactor at 70° C. In the procedure used, 2,000 grams of a silica/molecular sieve/aluminum dried premix containing 19.0 weight percent of a mixture of isoprene and 1,3-butadiene in hexanes at the ratio of 10:90 was charged into a one-gallon (3.8 liters) reactor. After the amount of impurity in the premix was determined, 4.0 ml of a 1.0 M solution of n-butyl lithium (in hexane) was added to the reactor. The target Mn (number averaged molecular weight) was 100,000. The polymerization was allowed to proceed at 70° C. for three hours. An analysis of the residual monomer indicated that monomers was all consumed. Then, 1.0 ml of a 1 M solution of tin tetrachloride (in hexane) was added to the reactor and the coupling reaction was carried out at the same temperature for 30 minutes. At this time, 1.5 phr (parts per 100 parts by weight of rubber) of 4-t-butylcatechol and 0.5 phr of TMEDA was added to the reactor to shortstop the polymerization and to stabilize the polymer.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[CH2:23][CH2:22]3)=[CH:18][CH:19]=[CH:20][C:13]1=2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:1].[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][O:30][C:4]4[CH:3]=[CH:2][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[N:5]=4)[CH2:25][CH2:26]3)=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: c1ccc2nc(OCCCN3CCN(c4cccc5sccc45)CC3)ccc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
4-Chloroquinoline (230 mg, 1.58 mmol), 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol (310 mg, 1.05 mmol), and potassium carbonate (220 mg, 1.6 mmol) were added to dimethylformamide (10 ml), followed by stirring at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, then water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure after filtration. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=4:1), and concentrated under reduced pressure. The resulting residue was dissolved in ethanol (3 ml), and 1N—HCl-ethanol solution (1 ml) was added thereto. Insoluble matters produced were filtered out and dried to obtain 4-[(3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinoline hydrochloride (360 mg, yield: 78%) as light yellow powder.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13](Cl)=[CH:14][CH:15]=2)[C:10]2([C:23]3[NH:24][C:25]4[C:30]([C:22]=3[CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:9]1=[O:31])C1C=CC=CC=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:41](=O)(O)[O-].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:41][CH:19]1[NH:18][C:10]2([C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:12]=3)[NH:8][C:9]2=[O:31])[C:23]2[NH:24][C:25]3[C:30]([C:22]=2[CH2:21][CH2:20]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: O=C([O-])O
Reactant: O=C1N(Cc2ccccc2)c2ccc(Cl)cc2C12NCCCc1c2[nH]c2ccccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCc2c([nH]c3ccccc23)C2(N1)C(=O)Nc1ccc(-c3ccccc3)cc12
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
A mixture of compound 1 (7 mg, 0.018 mmol), benzeneboronic acid (2.6 mg, 0.021 mmol) and tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) in DMF (2 mL)/aqueous 2 N sodium bicarbonate solution (0.5 mL) is stirred for 20 minutes in a microwave reactor at 130° C. After being cooled to room temperature, the reaction mixture is extracted with ethyl acetate (3×10 mL). The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The residue is subjected to flash column chromatography (silica gel, 30% EtOAc in hexanes) to afford compound 29 (2.3 mg, 33%) as white solid.
Reaction SMILES: [C:1]([C:11]1[C:12]([OH:23])=[C:13](CN)[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:24]([NH2:27])CN.[I:28]I.[I-].[K+]>C(O)C.O>[I:28][C:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:20]([CH2:24][NH2:27])=[C:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[C:12]=1[OH:23]
Reactant: II
Reactant: NCCN
Reactant: NCc1c(O)c(C(=O)OCc2ccccc2)cc2c1CCCC2
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NCc1c2c(c(I)c(O)c1C(=O)OCc1ccccc1)CCCC2
Temperature: 30 °C
Yield: 108.1 %

Procedure:
In 750 ml of ethanol was dissolved 50 g of the compound (4) under heating, and 7.5 g (8.35 L ml) of ethylenediamine was added to the solution. A mixture of 50.8 g of iodine and 41.5 g of potassium iodide was dissolved in 500 ml of water, and the resulting aqueous solution was added dropwise to the previously prepared solution over about 30 minutes under stirring at 30° C. After additional 1 hour`s stirring, the precipitating solid was filtered off, which was washed with 50% ethanol, and dried to provide 59 g of the title compound (5) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]S(C)(=O)=O)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][N:32]=[N+:33]=[N-:34])=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30]
Reactant: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CC(CN=[N+]=[N-])=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of {6-[(methane-sulfonyl)methyl]-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 23, (1.62 g, 3.52 mmol) in DMF(10 mL) is added sodium azide at room temperature. The reaction is then heated to 50° C. and stirred 18 hours after which time the solution is diluted with water. The resulting solution is extracted three times with CH2Cl2 (70 mL), the organic layers combined and washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the resulting residue is purified by HPLC to afford 0.46 g (59% yield) of the desired product. 1H NMR (CDCl3) δ 9.49–9.46 (m, 1H), 9.21–9.19 (d, J=6.9 Hz, 1H), 8.48–8.46 (m, 1H), 7.81–7.74 (m, 2H), 7.69–7.60 (m, 2H), 5.83–5.81 (m, 1H), 5.51–5.43 (m, 1H), 4.76–4.69 d, d, J=17.4, 2.4 Hz, 1H), 4.46–4.40 (d, J=17.4 Hz, 1H), 4.20–4.14 (d, J=17.7 Hz, 1H), 3.84–3.76 (d, J=13.2 Hz, 1H), 3.74–3.70 (m, 3H), 3.68–3.64 (d, J=13.2 Hz, 1H), 3.44–3.39 d, J=17.7 Hz, 1H), 2.99–2.92 (d, d, J=18.3, 3.9 Hz, 1H), 2.50–2.40 (d, d, J=15.6, 14.7 Hz, 1H); MS 409 (M+H)+.
Reaction SMILES: C(S([CH2:8][CH2:9][CH2:10][CH:11]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O)(=O)=O)CCC.[OH-].[K+].CS(C)=O>C1(C)C=CC=CC=1>[C:11]12[CH2:10][CH2:9][CH:8]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=2
Reactant: CCCCS(=O)(=O)CCCC1CCCCCCCCCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 84 %

Procedure:
10 g (0.029 mole) of 2-(3-n-butylsulfonyl-prop-1-yl)-cyclododecanone in 40 ml of toluene were heated to reflux for 30 min. in the presence of powdered KOH, in accordance with the process of Example 1, letter (b). After addition of 6 ml of DMSO, heating to reflux for 12 further hours and usual treatments of extraction and distillation as previously described, the desired title compound was isolated in a 84% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([CH:13]3[C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH:12]3[CH:14]([CH:13]3[C:16]3[CH:17]=[C:18]([NH:22][S:30]([CH3:29])(=[O:32])=[O:31])[CH:19]=[CH:20][CH:21]=3)[CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of 3-[3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 25, 34 mg, 0.11 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then methanesulfonylchloride (13 mg, 10 μl, 0.11 mmol). The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (29 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]4[O:30][CH:29]=[N:28][C:27]=4[C:31]([OH:33])=O)[CH2:15][N:14]3[C:34]=2[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:36]1([C:12]2[C:11]3[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:35][C:34]=3[N:14]3[CH2:15][C:16]([C:26]4[O:30][CH:29]=[N:28][C:27]=4[C:31]([N:64]4[CH2:69][CH2:68][O:67][CH2:66][CH2:65]4)=[O:33])=[CH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=4[C:13]=23)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COc1ccc2c(c1)C=C(c1ocnc1C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Yield: 109 %

Procedure:
5-(10-(tert-Butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylic acid (185 mg, 0.334 mmol) was dissolved in DMF (3.2 ml), and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (193 mg, 0.600 mmol) was added. The reaction was stirred capped at room temperature for 25 minutes and DMAP (163 mg, 1.334 mmol) was dissolved in the reaction then morpholine (0.058 ml, 0.667 mmol) was added. The reaction was capped and stirred at room temperature overnight. The reaction was poured into 30 ml of water and extracted with dichloromethane. The organic layer was washed sequentially with 0.1M aqueous citric acid, 0.1M aqueous NaH2PO4, then dried over anhydrous sodium sulfate. The sample was filtered, volatiles removed and the sample dried in vacuuo to obtain 227 mg of an amorphous orange solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16-1.50 (m, 7H) 1.53-1.61 (m, 6H) 1.62 (s, 10H) 1.76 (d, J=10.38 Hz, 2H) 1.83-2.15 (m, 5H) 3.40-3.84 (m, 7H) 3.83-3.95 (m, 5H) 4.40 (d, J=11.60 Hz, 1H) 5.64 (d, J=12.21 Hz, 1H) 6.97 (d, J=2.75 Hz, 1H) 7.05 (dd, J=8.39, 2.59 Hz, 1H) 7.50 (d, J=8.55 Hz, 1H) 7.53 (s, 1H) 7.65 (d, J=8.24 Hz, 1H) 7.77-7.86 (m, 2H) 7.97-8.04 (m, 1H) 8.10 (s, 1H). LC-MS retention time 2.64 min m/z 624 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.