Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH:32]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(C2c3ccccc3-c3ccccc32)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C[C@@H]2C[C@@H](NCc3ccnc4ccccc34)CCN2C2c3ccccc3-c3ccccc32)cc1

Procedure:
130 mg (0.219 mmol) (2R*,4S*)-2-benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 500 μl (0.500 mmol) of 1N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound ##STR77## is obtained (49 mg, 45%) as white foam. TLC: toluene/ethyl acetate (1:1) Rf =0.26; FD-MS: M+ =495.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2)(O)=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([NH:3][C:4]([C:7]1[C:8]2[CH2:9][C:10](=[O:16])[NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Reactant: CCN
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
Ethylamine (2.1 mL of 2.0 M solution in tetrahydrofuran, 4.2 mmol) was added dropwise to a suspension of 4-carboxy-2-oxindole (380 mg, 2.1 mmol) in dimethylformamide (8 mL), followed by 4-dimethylaminopyridine (385 mg, 3.15 mmol) and PyBOP (2.185 g, 4.2 mmol). The mixture was stirred at room temperature for 6 hrs. The reaction was concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and brine, dried, concentrated and recrystallized to give 280 mg (65%) of 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid ethylamide.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1)C>C1COCC1.CO>[C:9]1([CH2:8][CH2:7][C:6]([OH:15])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CCOC(=O)CCC1=CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC1=CCCCC1
Reaction time: 2 h

Procedure:
2N LiOH (3.5 mL) was added to a solution of 3-Cyclohex-1-enyl-propionic acid ethyl ester (0.6 g, 3.4 mmol, from Step 1) dissolved in THF (12 mL) and MeOH (3 mL). The mixture was stirred for 2 h under N2 and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a clear oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCc1ccccc1F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 2-fluoro-benzylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C43H49Cl2FN5O3 [(M+H)+] 772.3191, observed 772.3185.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.[CH2:14]([C:22]1[O:26][C:25]([C:27](ON2C(=O)CCC2=O)=[O:28])=[CH:24][CH:23]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH2:9][C:10]([O:12][CH3:13])=[O:11])([NH:1][C:27]([C:25]2[O:26][C:22]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:23][CH:24]=2)=[O:28])[CH2:3]1
Reactant: COC(=O)CC1(N)CCCN(C)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(CCc2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCCN(C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of methyl 2-(3-amino-1-methylpiperidin-3-yl)acetate (37 mg, 0.2 mmol) and 2,5-dioxopyrrolidin-1-yl 5-phenethylfuran-2-carboxylate (75 mg, 0.24 mmol) in DMF (1 mL) was treated with triethylamine (0.11 μL, 0.8 mmol) and stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and the resulting white precipitate was collected and purified by silica gel chromatography (elution 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to give the title compound as a white powder (69 mg, 87%). MS ESI 385.2 [M+H]+, calcd for [C22H28N2O4+H] 385.20.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].C([Sn]([N:26]=[N+:27]=[N-:28])(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOCC>[NH:26]1[C:1]([CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])=[N:2][N:28]=[N:27]1
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1nnn[nH]1)Nc1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of 2-cyano-acetanilide (0.801 g, 5.0 mmol) and tri-n-butyltin azide (2.05 mL, 7.5 mmol) in anhydrous toluene (10 mL) was heated at reflux for 48 hrs. The mixture was allowed to cool to room temperature and treated with 2.0 N HCl in Et2O (5.0 mL). The resulting precipate was collected by suction, washed with hexane and dried in vacuo to give 2-(1H-tetrazol-5-yl)acetanilide (0.917 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH:3]1[C@H:9]([OH:11])[CH3:10].[H][H]>[Cr].[Cu]>[CH3:10][C:9]([C@@H:3]1[C@@H:4]([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:1])[CH3:12])=[O:11]
Reactant: [H][H]
Reactant: C[C@@H](O)C1[C@@H](C)CCCC1(C)C
Agent: [Cr]
Agent: [Cu]
Product: CC(=O)[C@@H]1[C@@H](C)CCCC1(C)C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
The (1R,6S)-l-(2,2,6-trimethylcyclohexyl)-ethan-1-ol (15b) (250 g) synthesized in Reference Example 4 and a copper-chromium catalyst (12.5 g) pre-activated with hydrogen were placed in a 500 ml, 4-necked flask equipped with a thermometer, condenser and stirrer, followed by reacting at 200° C. for 6 hours. After cooling the reaction mixture and filtering out the catalyst, the reaction liquid was distilled with a Widmer distiller to obtain 224 g of (1R,6S)-2,2,6-trimethylcyclohexyl methyl ketone (1b) (b.p.: 76-78° C./1197 Pa (9 torr)).
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@:5]([CH3:42])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:21]([C:38]([F:41])([F:40])[F:39])[CH:20]=3)=[CH:17][N:18]=2)[CH2:4][O:3]1>C(#N)C.O>[NH2:6][C@@:5]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:21]([C:38]([F:40])([F:41])[F:39])[CH:20]=2)=[CH:17][N:18]=1)([CH3:42])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1ncc(-c2ccc(OCCCCCCc3ccccc3)c(C(F)(F)F)c2)s1
Solvent: O
Solvent: CC#N
Product: C[C@](N)(CO)c1ncc(-c2ccc(OCCCCCCc3ccccc3)c(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared from (R)-tert-butyl 2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.41 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=479.4; 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (d, 1H, J=2.0 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 7.28-7.23 (m, 2H), 7.18-7.15 (m, 3H), 6.96 (d, 1H, J=9.2 Hz), 4.06-3.99 (m, 4H), 2.62 (t, 2H, J=7.6 Hz), 1.85-1.78 (m, 5H), 1.69-1.62 (m, 2H), 1.56-1.50 (m, 2H), 1.44-1.38 (m, 2H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[F:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][N:23]=1.[I:29][CH3:30]>C1COCC1>[F:21][C:22]1[C:27]([CH3:26])=[C:30]([I:29])[CH:25]=[CH:24][N:23]=1
Reactant: CI
Reactant: Fc1ncccc1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(I)ccnc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78° C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78° C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78° C. The mixture is quenched with saturated sodium bicarbonate solution at -78° C. and then extracted with ether. Combined ether extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72%) of product as an off-white solid having amp of 90-91 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+]>C(O)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
5 g (14.5 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 70 mg of powdered potassium cyanide and 20 ml of benzyl alcohol are stirred at 110° for 1 hour, evaporated to dryness and the residue is taken up in chloroform. The solution is washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethanol and ether there is obtained benzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 141°-142°.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][S:5](OC1C=CC=CC=1)(=[O:7])=[O:6].[OH-].[K+].O.Cl>C1COCC1>[CH3:15][C:2]1([CH3:16])[CH2:3][CH2:4][S:5](=[O:7])(=[O:6])[NH:1]1
Reactant: CC(C)(N)CCS(=O)(=O)Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCS(=O)(=O)N1
Yield: 53.8 %

Procedure:
11.58 g of phenyl 3-amino-3-methylbutane-1-sulfonate and 5.34 g of KOH were boiled under reflux in 240 ml of THF/95 ml of water for 7 hours. Then a further 2.7 g of KOH, 50 ml of water and 120 ml of THF were added, and the mixture was again boiled under reflux for 7 hour. Then a further 5.34 g of KOH were added, and the mixture was again boiled under reflux for 3 hours. It was allowed to cool and then 300 ml of a 2N aqueous HCl solution were added, and the mixture was extracted 5 times with 250 ml of EA each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP 1:1 afforded 3.82 g of white crystals, mp 72° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[CH3:15].[B:16](OC)([O:19]C)[O:17]C>O1CCCC1>[F:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([B:16]([OH:19])[OH:17])=[C:8]([CH3:15])[CH:9]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(F)c(F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)c(F)cc1B(O)O
Reaction time: 1 h

Procedure:
n-Butyl lithium (4.6 mL, 11.5 mmol) is added to the mixture of 1-bromo-4,5-difluoro-2-methylbenzene (2.0 g, 9.6 mmol) and trimethyl borate (1.5 g, 14.5 mmol) in anhydrous tetrahydrofuran (30 mL), drop wise, at −78° C. over one hour, under an atmosphere of argon. The reaction mixture is stirred for another hour at the same temperature, quenched and acidified with 1 N HCl. The resulting mixture is extracted with ethyl acetate(3×). The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH3:9].N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>C(Cl)(Cl)Cl.O>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:10][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH3:9])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC/C=C\C/C=C\CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC/C=C\C/C=C\CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
(3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate can be prepared from 2-Pentyn-1-ol by dissolving 2-Pentyn-1-ol (1.03 g, 12 mmol) in chloroform (10 ml) and adding pyridine (1.90 g, 24 mmol) followed by p-toluenesulfonyl chloride (3.43 g, 18 mmol) in small portions with constant stirring. After about 4 hrs, ether (30 ml) and water (7 ml) can be added and the organic layer can be washed successively with HCl (7 ml), 5% NaHCO3, water (7 ml) to produce pent-2-ynyl p-toluenesolfonate. Pent-2-ynyl p-toluenesolfonate (1.37 g, 5.78 mmol, 1.1 eq) can be added at low temperature under nitrogen to a well-stirred suspension in DMF (15 ml) of but-3-yn-1-ol (368 mg, 5.25 mmol), sodium carbonate (834 mg, 7.87 mmol), tetrabutylammonium chloride (1.46 g, 5.25 mmol) and copper(I) iodide (1.00 g, 5.25 mmol). The mixture can then be stirred at room temperature for about 48 hrs, and ether (30 ml) and 1M HCl (30 ml) can be added, the organic phase can be collected and washed with brine, and dried over sodium sulfate to produce nona-3,6-diyn-1-ol. Nona-3,6-diyn-1-ol (198 mg, 1.45 mmol) can be hydrogenated at atmospheric pressure, in the presence of a mixture of quinoline (44 mg) and palladium (5%) on calcium carbonate (100 mg), poisoned with lead in methanol (25 ml). After several hours, the methanol can be evaporated in vacuo, quinoline can be removed by silica gel column chromatography using ether-hexane (35:65) as the eluent to produce (3Z,6Z)-nona-3,6-dien-1-ol. (3Z,6Z)-Nona-3,6-dien-1-ol (167 mg, 1.19 mmol) can be dissolved in chloroform (5 ml) and the solution can be cooled in an ice bath. Pyridine (376 mg, 4.76 mmol) can be added, followed by p-toluenesulfonyl chloride (340 mg, 1.78 mmol) in small portions with constant stirring. The mixture can be stirred for about 24 hrs at low temperature, and ether (15 ml) and water (5 ml) can be added, the organic layer can be collected and washed successively with 1 N HCl (10 ml), 5% NaHCO3, water (10 ml), and brine (10 ml), and then dried over Na2SO4 to produce (3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2([CH2:23][OH:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1
Reactant: CCCCCN1C(=O)C(CO)(c2cc(Br)ccc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21
Yield: 4 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 4% yield: 1H NMR (300 MHz, CDCl3) δ 7.38-7.23 (m, 2H), 7.17-7.01 (m, 2H), 6.93 (d, 1H), 6.84 (d, 1H), 6.79 (d, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.64 (m, 2H), 1.81-1.65 (m, 2H), 1.48-1.28 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.7, 160.1, 142.6, 132.7, 132.1, 131.4, 129.3, 126.5, 124.1, 123.5, 113.1, 112.2, 108.9, 80.3, 58.0, 40.6, 29.2, 27.3, 22.5, 14.2; MS (ES+) m/z 386 (M+1), 388 (M+23).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nccc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)nccc3c21
Yield: 59.2 %

Procedure:
An activated manganese dioxide (108 mg, 1.25 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c][1,7]naphthyridine (93 mg, 0.25 mmol) in toluene (9.0 mL) and methylene chloride (3.0 mL) and the mixture was heated under reflux for three days. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (55 mg) as pale brown crystals.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[Cl:27])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:27].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:43])[NH2:26])=[CH:21][C:20]=4[Cl:27])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1Cl)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1Cl)n2C)c1ccccc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([N:24]=[C:25]([NH2:28])[NH:26][CH3:27])=[O:23])=[CH:18]2)=O)(C)(C)C>Cl.CO>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([N:24]=[C:25]([NH2:28])[NH:26][CH3:27])=[O:23])=[CH:18]2
Reactant: CNC(N)=NC(=O)c1cc2cccc(NCCCNC(=O)OC(C)(C)C)c2[nH]1
Agent: Cl
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2cccc(NCCCN)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
After 0.04 g (0.10 mmol) of 7-[(3-tert-butoxycarbonylaminopropyl)amino]-1-methyl-2-indoloylguanidine was dissolved in 2 ml of hydrochloric acid/methanol, the solution was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. After 2N sodium hydroxide aqueous solution was added to the residue thus obtained, the mixture was extracted three times with chloroform. The combined extracts were dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography to give 0.023 g (80.0%) of 7-[(3-aminopropyl)amino]-1-methyl-2-indoloylguanidine. The guanidine derivative was converted into the hydrochloride with hydrochloric acid/methanol. Recrystallization from methanol gave 7-[(3-aminopropyl)amino]-1-methyl-2-indoloylguanidine dihydrochloride.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:16][C:15]3[N:17]=[CH:18][CH:19]=[N:20][C:14]=3[N:13](COC)[C:12]=2[CH:24]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH:33]([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:26]1.CC(CC)C([O-])=O>>[N:20]1[C:14]2[NH:13][C:12]3[CH:24]=[C:8]([CH2:7][CH2:6][N:25]4[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH:33]([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:26]4)[CH:9]=[CH:10][C:11]=3[S:16][C:15]=2[N:17]=[CH:18][CH:19]=1
Reactant: COCN1c2cc(CCOS(C)(=O)=O)ccc2Sc2nccnc21
Reactant: CCOC(=O)C(C)CCC1CCNCC1
Agent: CCC(C)C(=O)[O-]
Product: CCOC(=O)C(C)CCC1CCN(CCc2ccc3c(c2)Nc2nccnc2S3)CC1

Procedure:
Starting with 2-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl methanesulfonate and ethyl 4-(piperidin-4-yl)-2-methylbutanoate, ethyl 4-[1-[2-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-ethyl]piperidin-4-yl]-2-methylbutanoate was obtained by the same method as the one of Example 63. Next, this product was treated by the same method as the one of Example 8 to thereby give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:34]5[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 17.8 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (282 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 233 (87.2 mg, yield: 17%). 1HNMR (DMSO-d6, 400 MHz): δ8.81 (s, 1H), 8.31 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.85-7.78 (m, 2H), 7.49 (d, J=2.4 Hz, 2H), 7.21 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 4.27 (s, 2H), 3.93 (s, 3H), 3.17 (s, 2H). ESI-MS: m/z=490 [M+H+]