Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[NH:15][CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:28](=[O:30])[CH3:29])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1cncc(-c2cnc3c(c2)CCCN3)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2cc(-c3cncc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
6-(5-Trifluoromethyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (200 mg, 0.72 mmol), whose synthesis is described in Step 1 of Example 4, is dissolved in DCM (25 mL). Triethylamine (220 mg, 2.1 mmol) is added followed by the addition of acetyl chloride (67 mg, 0.86 mmol) under N2 atmosphere at 0° C. The mixture is stirred at room temperature for 3 hrs. The solvent is removed and the residue is purified by preparative TLC to give 43 mg of the titled product.
Reaction SMILES: [CH:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])([CH3:11])[CH2:10]1)[CH:7](O)[CH2:6][CH2:5]2)([CH3:3])[CH3:2].OS([O-])(=O)=O.[K+].[C:21]1(C)C=CC=CC=1>>[CH:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])([CH3:11])[CH2:10]1)[C:7]([CH3:21])=[CH:6][CH2:5]2)([CH3:3])[CH3:2]
Reactant: CC(C)C12CCC(O)C(C1)C(C)(C)C2
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CC1=CCC2(C(C)C)CC1C(C)(C)C2
Yield: 81 %

Procedure:
A solution of 5-isopropyl-7,7-dimethyl-bicyclo[3.2.1]octan-2-ol (18.5 g, 88 mmol) and KHSO4 (100 mg) in toluene (250 ml) was heated 36 h in a Dean-Stark apparatus. The solution was cooled and washed once with water and brine, dried (MgSO4) and concentrated in vacuo to yield 5-isopropyl-2,7,7-trimethyl-bicyclo[3.2.1]oct-2-ene (13.77 g, 81%). 13H-NMR (100 MHz, CDCl3): 140.4 (s), 118.7 (d), 52.1 (d), 51.5 (t), 46.1 (s), 46.0 (s), 39.1 (t), 37.6 (d), 37.4 (t), 31.5 (q), 26.9 (q), 24.6 (q), 18.2 (q), 18.0 (q) ppm. GC/MS (EI): 192 (M+, 17), 177 (4), 149 (22), 136 (21), 121 (15), 107 (18), 93 (100), 77 (28), 57 (17), 41 (23). IR (ATR): 2957 s, 2933 s, 2869 m, 1468 m, 1452 m, 1366 m cm−1.
Reaction SMILES: [H-].[Na+].[ClH:3].[CH3:4][C:5]1([CH3:26])[C:14](=[O:15])[CH:13]2[C:8](=[C:9]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:10]3[C:11](=[O:16])[CH2:12]2)[CH:7]=[N:6]1.CS(C)=O.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36]Br)[CH3:32]>O>[ClH:3].[ClH:3].[CH3:4][C:5]1([CH3:26])[C:14](=[O:15])[CH:13]2[C:8](=[C:9]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:10]3[C:11](=[O:16])[CH:12]2[CH2:36][CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])[CH:7]=[N:6]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccccc4)N=C3C(=O)CC2C1=O
Reactant: CCN(CC)CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCCC1C(=O)C2=NC(c3ccccc3)=NC2=C2C=NC(C)(C)C(=O)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 gm of a 55% suspension of sodium hydride in oil were added in portions to a mixture of 5.1 gm of 7,7-dimethyl-2-phenyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione hydrochloride and 50 ml of dimethyl sulfoxide. After stirring the mixture at room temperature for one hour, 4.8 gm of 3-diethylamino propyl bromide hdyrobromide were added, and the mixture was heated at 50° C. for 3 hours. The reaction mixture was admixed with water and extracted several times with chloroform. The chloroform phases were evaporated and the residue was purified on a silicagel column. The dihydrochloride was precipitated from acetone with ethereal hydrochloric acid and recrystallized from methanol/acetone.
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[C:11]([O-:21])(=[O:20])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13]>C(C(C)=O)C>[CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[C:11]([O-:21])(=[O:20])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13]
Reactant: O=C([O-])[C@@H](O)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCC(C)=O
Product: O=C([O-])C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a boiling suspension of 160 ml. of methyl ethyl ketone containing 23.0 g. (0.165 mole) of methenamine is slowly added a hot suspension of 25 g. (0.16 mole) of l-mandelate acid in 60 ml. of methyl ethyl ketone. The heat source is removed. The solution is stirred to room temperature, then cooled in an ice-water bath. White crystals are collected by filtration, washed with a small amount of cold methyl ethyl ketone, followed by anhydrous ether, and dried at 50° C. in vacuum for 4.5 hours to obtain methenamine levo-mandelate. mp. 133.5°-135.5° C [α]D20 -63.3° (C = 3,H2O)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([NH2:15])=[NH:14])[CH2:2][CH2:3][CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.O>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[NH:15][C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1NC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
A mixture of N-(2-butoxyphenyl)guanidine (11.6 g) and diethyl ethoxymethylenemalonate (12.1 g) in DMF (70 ml) is heated at 100° C. for 9 hours. After cooling, water (50 ml) is added to the reaction mixture, and the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 2-(2-butoxyanilino)-1,6-dihydro-6-oxo-5-pyrimidinecarboxylate (16.1 g). M.p. 211°-213° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[N:11]1([CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1CCN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1CCN1CCNCC1

Procedure:
A mixture of 79 parts of 1,3-dihydro-1-{2-[4-(phenylmethyl)-1-piperazinyl]ethyl}-2H-benzimidazol-2-one and 320 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is alkalized with ammonium hydroxide and a small amount of water is added. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue solidifies on triturating in 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1,3-dihydro-1-[2-(1-piperazinyl)ethyl}-2H-benzimidazol-2-one; mp. 122.6° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)=[N:2]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCNc1nsc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-(Benzo [d]isothiazol-3-yl)ethane-1,2-diamine (50 mg, 0.26 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (50 μL, 0.28 mmol). The solution was cooled on an ice-water bath and then a solution of 4-chlorobenzoyl chloride (36 μL, 0.28 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2 h while warming to room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes, and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chlorobenzamide as a white solid, (50 mg). 1H NMR (300 MHz, DMSO-d6): 8.7 (broad s, 1H), 8.1 (d, 1H), 7.9 (m, 3H), 7.5 (m, 4H), 7.4 (m, 1H), 3.6 ppm (m, 4H). MW=332 confirmed by LC-MS, tr=3.89 min (Method B) MH+=333.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>O1CCCC1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:17][CH:16]=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To 29 g of benzophenone in 150 mL of tetrahydrofuran (THF) at 0° C. was added 88 mL of 2M allyl magnesium chloride. After 16 hrs, the starting material was completely consumed as indicated by thin layer chromatography (TLC). To the reaction mixture was added 1 mL of methanol to quench the excess Grinard reagent. The THF was distilled in vacuo and the residue was shaken with dilute aqueous hydrochloric acid and chloroform. The layers were separated and the aqueous phase was extracted with chloroform. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give 37 g of 1,1-diphenyl-3-buten-1-ol which is characterized by:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(N)c1N

Procedure:
Commercially available 2-amino-4-methyl-3nitropyridine (10.0 g, 65.3 mmol) was suspended in ethanol (450 mL) and the flask was filled with argon. 10% palladium carbon (13.9 g, 50% water-containing) was added to the mixture and stirred at room temperature overnight under the flow of hydrogen. Solids were filtered through Celite and this was washed with ethanol. The filtrate was concentrated under reduced pressure to obtain Compound P12 (7.81 g, 63.3 mmol, 97%).
Reaction SMILES: [CH3:1][C:2]1([O:12][C:13](=[O:20])[CH2:14][O:15][C:16](=[O:19])[CH2:17][OH:18])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.COC1C=CC(O)=CC=1.[C:37](Cl)(=[O:41])[C:38]([CH3:40])=[CH2:39]>C(OCC)C.C1COCC1>[C:37]([O:18][CH2:17][C:16]([O:15][CH2:14][C:13]([O:12][C:2]1([CH3:1])[CH:9]2[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]1[CH2:11]3)[CH2:10]2)=[O:20])=[O:19])(=[O:41])[C:38]([CH3:40])=[CH2:39]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Agent: COc1ccc(O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(=O)OCC(=O)OC1(C)C2CC3CC(C2)CC1C3
Yield: 97 %

Procedure:
A 2 liter 3-neck flask fitted with a thermometer, a cooling tube and a stirrer was charged with 165 g (584 mmol) of 2-(2-(2-methyl-2-adamantyloxy)-2-oxoethoxy)-2-oxoethanol, 2,000 ml of THF, 105 ml (754 mmol) of triethylamine and 0.165 g (1,000 ppm) of p-methoxyphenol, and the mixture was stirred to form a solution. Following dissolution, the solution was cooled in an ice bath and 62.7 ml (648 mmol) of methacryloyl chloride was added gradually to the solution. The reaction mixture was then returned to room temperature, and stirred for 3 hours. Following completion of the reaction, 1,000 ml of diethyl ether was added, and the filtrate was washed 5 times with 200 ml samples of distilled water. The washed extract was then concentrated, yielding 198 g (yield: 97%, GC purity: 99%) of the targeted colorless liquid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[C:43]2[CH3:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([C:2]1[N:3]=[C:4]3[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]3=[N:6][CH:7]=1)[N:44]=[C:43]2[CH3:49]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1n[nH]c2ccc(Cl)cc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nn(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc12
Temperature: 110 °C
Reaction time: 15 h

Procedure:
2-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 248 μmol) was dissolved in toluene (1.4 mL), and copper (I) iodide (2.49 mg, 27.8 μmol), sodium iodide (74.4 mg, 496 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (9.00 mg, 63.3 μmol) added. The mixture was sealed under nitrogen and the mixture heated at 110° C. After 15 h, 5-chloro-3-methyl-1H-indazole (41.3 mg, 248 μmol) and potassium phosphate tribasic (111 mg 521 μmol) were added, the mixture degassed under vacuum, backfilled with nitrogen, and the mixture heated at in sealed tube at 110° C. for 24 h. The mixture was cooled, filtered, and the cake washed with ethyl acetate. The combined filtrates were concentrated and purified by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) to give 2-(5-Chloro-3-methyl-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:13]3[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:12]=3[O:11][N:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO>[N:1]1([C:7]([C:9]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:12]=3[O:11][N:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)N3CCCCC3)c2C1
Agent: Cl
Solvent: CO
Product: O=C(c1noc2c1CNCC2)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-(piperidine-1-carbonyl)-6,7-dihydroisoxazolo[4,5-c]pyridine-5(4H)-carboxylate (0.3 g, 0.89 mmol) (product of stage 6) was dissolved in 7 ml of methanol, concentrated HCl (0.56 ml, 17.8 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was then distilled off in vacuo, the residue was taken up in NaHCO3 solution and the mixture was extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and concentrated in vacuo. The crude product was employed in the next stage without further purification.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:13]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[N:12][N:11]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CCCCCC.CO.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:27][C:22]([C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:10]([CH2:9][OH:8])=[N:11][N:12]=2)=[CH:23][CH:24]=1
Reactant: Fc1ccccc1-n1c(COCc2ccccc2)nnc1-c1ccc(-c2ccccc2)cc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OCc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
3-Benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole (6.00 g) was dissolved in chloroform (200 ml), followed by dropwise addition of 1 mol/liter boron trichloride-hexane solution (30 ml) at −44° C. and stirred at the same temperature for 30 minutes and at ambient temperature for one hour. To the reaction solution were added methanol (5 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml), followed by concentration under reduced pressure. To the resulting residue were added tetrahydrofuran (100 ml), aqueous 2 mol/liter sodium hydroxide solution (100 ml) and tetrabutylammoniumhydrogensulfate (0.10 g), and stirred at ambient temperature for 12 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=96/4) and recrystallized from a mixture solution of n-hexane-ethyl acetate-ethanol, to afford the entitled compound as white crystal (2.09 g, 44%). The physico-chemical values are as follows.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:14][O:15][C:16]([C:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].ON1C2C=CC=CC=2N=N1.[O:35]1[CH:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1([NH:24][C:40]([C:37]2[CH:38]=[CH:39][O:35][CH:36]=2)=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:17]
Reactant: O=C(O)c1ccoc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccoc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to obtain 114 g (91%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:15]=23)[CH2:3][CH2:2]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c5) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][NH:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH:23]3[CH:21]([CH:22]3[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])[CH2:20]2)=[N:17][CH:18]=1)=[O:12].S(OC)(O[CH3:43])(=O)=O.[Cl-].[NH4+]>CCCCCCC.C1COCC1.C(Cl)Cl>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][NH:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:20][CH:21]3[CH:23]([CH:22]3[N:25]([CH3:43])[S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:27])=[O:28])[CH2:24]2)=[N:17][CH:18]=1)=[O:12]
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CC3C(C2)C3NS(=O)(=O)c2ccc3ccccc3c2)nc1
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C1C2CN(c3ncc(C(=O)NOC4CCCCO4)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 48 h

Procedure:
NaH (147 mg, 3.75 mmol) was washed with heptane, and suspended in THF (10 ml). N-(Tetrahydro-2H-pyran-2-yloxy) 2-[6-(naphthalene-2-sulfonylamino)-3-azabicyclo[3.1.0]hex-3-yl]pyrimidine-5-carboxamide (1.113 g, 2.2 mmol) was then added, followed by addition of dimethyl sulfate (0.22 ml, 2.3 mmol). The mixture was stirred for 48 h, then poured into DCM (150 ml). 2.4M ammonium chloride (50 ml) was added. The aqueous layer was further extracted with DCM (150 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give an orange oil. This was carried forward without any further purification.
Reaction SMILES: [CH2:1]([C:5]1([CH2:23][CH3:24])[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].Cl>O>[CH2:1]([C:5]([CH2:23][CH3:24])([CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:7])[CH:6]=[N:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CCCCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Yield: 100 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 283.4 g (0.875 mol) of 3-n-butyl-3-ethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene, 60.8 g (0.87 mol) of hydroxylamine hydrochloride, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 310 g (0.87 mol) of 2-n-butyl-2-ethyl-11-phenyl-11-amino-undeca-4,8-dienal oxime; yield 99.5% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)[CH:22]=2)(=[O:29])=[O:28])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Br)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
2-Amino-5-bromobenzenesulfonamide (0.60 g, 2.39 mmol) was dissolved in pyridine (6 ml) and 3-(3,4-dichlorophenyl)-phenylsulfonyl chloride (0.82 g, 2.51 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (0.70 g, 55% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:33]=[CH:32][C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15]([CH2:17][O:18]CC3C=CC=CC=3)=[N:16][C:12]=2[CH:11]=1.Cl>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:33]=[CH:32][C:13]2[N:14]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:15]([CH2:17][OH:18])=[N:16][C:12]=2[CH:11]=1
Reactant: c1ccc(COCc2nc3cc(-c4nc5ccccc5s4)ccc3n2-c2ccccc2)cc1
Agent: Cl
Product: OCc1nc2cc(-c3nc4ccccc4s3)ccc2n1-c1ccccc1
Yield: 94.3 %

Procedure:
An eggplant flask (50 mL) equipped with a reflux condenser was charged with 5-(benzothiazol-2-yl)-1-phenyl-2-(phenylmethoxy)methylbenzimidazole (see Working Example 1-2) (0.40 g, 0.89 mmol) and dilute hydrochloric acid (6 M, 5 mL), and this was refluxed for 2 hours. When the pale yellow clear solution obtained was cooled in ice, it became a milky white suspension. The precipitated crystals were filtered off, washed successively with distilled water, and then t-butyl methyl ether, and dried under reduced pressure to yield the title compound (0.30 g, 94% yield) as a white powder.