Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.[ClH:24]>CO>[ClH:24].[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N[C@H](C)c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc2[nH]c3c(c2c1)CCC[C@@H]3N[C@H](C)c1ccccc1

Procedure:
(1S)-6-Methyl-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-methyl-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, 10% methanol, 1500 psi, 40° C., 2 mL/min, retention time: 10.0 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=−20.0 (c 0.20, MeOH); 1H-NMR (DMSO-d6): δ 7.58 (d, J=7.6 Hz, 2H), 7.55-7.46 (m, 3H), 7.26 (d, J=8.0 Hz, 1H), 7.26 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.74 (q, J=7.2 Hz, 1H), 4.43 (t, J=4.8 Hz, 1H), 2.82 (dt, J=16.4 Hz, J=4.0 Hz, 1H), 2.68 (dt, J=16.4 Hz, J=4.8 Hz, 1H), 2.40 (s, 3H), 2.32-2.20 (m, 1H), 2.18-2.00 (m, 2H), 1.98-1.88 (m, 1H), 1.75 (d, J=6.8 Hz, 3H); MS m/z 184 (M−121); Anal. Calcd. For C21H25BrN2Cl: C, 73.99; H, 7.39; N, 8.22. Found: C, 74.02; H, 7.30; N, 8.31.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:32][O:33][C:34](=[O:54])[CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38](OS(C(F)(F)F)(=O)=O)[CH:37]=1>>[CH3:32][O:33][C:34](=[O:54])[CH2:35][C:36]1[CH:37]=[C:38]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:20])[F:22])=[CH:18][C:13]=2[CH2:12][N:3]([C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:1][CH3:2])[CH:39]=[C:40]([C:42]([F:44])([F:43])[F:45])[CH:41]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)c1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-benzamide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [S:1](=[N:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])=[O:2].[OH-].[Na+].[CH3:19]N=C=S.Cl>CN(C=O)C>[S:1](=[N:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:19])(=[O:2])=[O:3]
Reactant: COc1ccc(CC(=O)O)cc1N=S(=O)=O
Reactant: CN=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)O)cc1N=S(=O)=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5 g of 3-sulfonylamino-4-methoxyphenylacetic acid were dissolved in 3 ml of DMF and stirred at 40° C. for 30 minutes with 245 mg of sodium hydroxide. 328 mg of methyl isothiocyanate were added thereto and the mixture was stirred for a further 2 h at 70° C. 2N hydrochloric acid was added to the cooled solution and the product was filtered off with suction. M.p. 1740° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([CH3:13])=[C:11](I)[CH:10]=[CH:9][N:8]=1.[O:15]=[C:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].O.C1COCC1>CCCCCC.C1COCC1>[F:6][C:7]1[C:12]([CH3:13])=[C:11]([C:16]([OH:15])([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(I)ccnc1F
Reactant: CCC(=O)C(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(C(=O)OC)c1ccnc(F)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
6.9 ml (11 mmol) of 1.6M butyllithium in hexane are added dropwise to a solution, stirred at −78° C. of 2.6 g (11 mmol) of 2-fluoro-4-iodo-3-methylpyridine (described in J.O.C., 1993, 58, pp. 7832) in 100 ml of THF. The reaction mixture is then stirred for 10 minutes at −78° C. before the addition of a solution of 1.5 g (12.9 mmol) of methyl 2-oxo-butyrate in 20 ml of THF. The reaction mixture is stirred for 10 minutes at −78° C., and then hydrolysed with a mixture of water/THF. The aqueous phase is decanted and then extracted 3 times with 50 ml of methyl acetate each time. The combined organic phases are dried, concentrated and purified by chromatography over silica (eluant dichloromethane/acetone 95/5) to yield the expected product.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([CH3:31])=[CH:19][C:20](=[O:30])[N:21]2[CH2:24][CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[CH:16][CH:15]=1>[Cu]=O.O.C(Cl)(Cl)Cl>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)[CH:23]=2)[C:18]([CH3:31])=[CH:19][C:20]1=[O:30]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(Br)ccc12
Agent: O=[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)n(CC2OCCO2)c2cc(-n3ccnc3)ccc12
Temperature: 142.5 °C
Reaction time: 0.17 h

Procedure:
To 0.7 mL of an N,N-dimethylformamide solution containing 74 mg of 60% sodium hydride, 0.14 g of imidazole was added at room temperature, and the mixture was stirred for 10 minutes. Thereto were added 0.20 g of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one and 17 mg of copper(II) oxide, and the mixture was heated to 140 to 145° C. and stirred for 40 minutes. Thereto was further added 2 mL of N,N-dimethylformamide, and the mixture was further stirred for 1 hour. The reaction mixture was cooled to room temperature, then chloroform and water were added thereto, and the insoluble material filtered off. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to obtain 77 mg of a brown oily substance, 1-(1,3-dioxolan-2-ylmethyl)-7-(1H-imidazol-1-yl)-4-methylquinolin-2(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1.CCN=C=NCCCN(C)C.[CH3:51][C:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:58][S:55]([C:52]5([CH3:51])[CH2:54][CH2:53]5)(=[O:57])=[O:56])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:4]=1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Reactant: CC1(S(N)(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
A solution of the acid 13e (250 mg, 0.46 mmol) and EDAC (150 mg, 0.6 mmol) in dry DCM (4 ml) was stirred overnight at room temperature. Methylcyclopropane sulphonamide (78 mg, 0.58 mmol) and DBU (182 mg, 1.2 mmol) were added and the mixture was stirred for additional 6 hours at room temperature. 5% Citric acid was added and the mixture was extracted with ethyl acetate. The organic phase was washed two times with 5% citric acid and water, dried with sodium sulphate and evaporated under reduced pressure. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the pure title compound, (130 mg, 44%), (M+H)+652.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12]C(N)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:31])[CH:29]=O>O>[CH3:21][O:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:29]([N:28]([CH3:31])[CH3:27])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(N)cc2)n1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(OC)cc(-c2ccc(N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-hydroxy-6-(4-aminophenyl)-2-pyridinecarboxylate (1.22 g), methyl iodide (3.82 g), potassium carbonate (2.76 g), dimethylformamide (20 ml) and water (1 ml) is agitated at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added water. The precipitated crystals are collected by filtration and dissolved in chloroform. The solution is passed through a column packed with silica gel (30 g). The solution passed through the column is concentrated to remove the solvent to give methyl 4-methoxy-6-(4-dimethylaminophenyl)-2-pyridinecarboxylate (0.74 g). M.P. 157°-158° C.
Reaction SMILES: Cl.Cl[C:3](Cl)([CH:5]([CH3:7])[CH3:6])[CH3:4].[C:9]([Cl:12])([Cl:11])=[CH2:10]>>[Cl:11][C:9]([Cl:12])=[CH:10][C:5]([CH3:7])([CH3:6])[CH:3]=[CH2:4]
Reactant: C=C(Cl)Cl
Reactant: CC(C)C(C)(Cl)Cl
Agent: Cl
Product: C=CC(C)(C)C=C(Cl)Cl

Procedure:
The addition of hydrogen chloride to isoprene leads to dichloroisopentane, which adds to vinylidene chloride and undergoes an elimination reaction with bases to give 1,1-dichloro-3,3-dimethyl-1,4-pentadiene. Reaction with sodium phenolate and hydrolysis yields the chloromethyl ketone of the formula (III): ##STR10##
Reaction SMILES: N1([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH2:13].[OH2:20]>COCCOCCOC>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:12][CH2:13][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1=[O:20]
Reactant: O
Reactant: C=Cc1ccccn1
Reactant: C1=C(N2CCCC2)CCCC1
Solvent: COCCOCCOC
Product: O=C1CCCCC1CCc1ccccn1
Reaction time: 2 h

Procedure:
Example 290 A) A sample of 1-Pyrrolidino-1-cyclohexene (7.1 mL, 44 mmol) and 2-vinylpyridine (4.3 mL, 40 mmol) were refluxed overnight in diglyme (100 mL). Water was then added and the mixture was stirred an additional 2 hours before extracting it with Et2O. The ether layer was dried over MgSO4 and concentrated in vacuo leaving an oil. The residue oil was distilled on a kugelrohr apparatus at 60-80° C. (0.1 mm) to give 2-(2-pyridyl) ethyl-2-cyclohexanone as a yellow oil (6.5 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16](=[O:31])[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=2)[O:21][C:22]=1[CH3:23]>>[CH3:14][O:15][C:16](=[O:31])[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:28][CH:29]=2)[O:21][C:22]=1[CH3:23]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Product: COC(=O)Cc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)oc1C

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 4 using 4-(methanesulfonyl)benzene boronic acid and [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester [CAS 478540-95-3].
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:34][C@@H:33]([CH3:35])[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:36])=[O:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc2c(=O)[nH]cnc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc2c(=O)[nH]cnc2c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 4-oxo-3,4-dihydro-quinazoline-7-carboxylic acid in tetrahydrofuran, 1.2 equivalents of 1,1′-carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, the (S)-L-Alanine tert-butyl ester is added and the mixture is stirred for 24 hours until disappearance of starting material. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired compound.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br)[CH3:3].[SH:13][C:14]1[NH:15][C:16]2[C:17](=[CH:19][S:20][CH:21]=2)[N:18]=1>CC(C)=O>[CH2:2]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][S:13][C:14]1[NH:18][C:17]2=[CH:19][S:20][CH:21]=[C:16]2[N:15]=1)[CH3:3]
Reactant: Sc1nc2cscc2[nH]1
Reactant: CCNc1ccccc1CBr
Agent: Br
Solvent: CC(C)=O
Product: CCNc1ccccc1CSc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.12 g of 2-ethylaminobenzyl bromide hydrobromide are added to a solution of 0.60 g of 2-mercaptothieno-[3,4-d]imidazole in 100 ml of acetone. After the mixture has been stirred at room temperature for 24 hours, the solvent is removed by distillation in vacuo, and the crystalline residue is washed with acetone. Then 1N NH4OH solution is added to the product, the mixture is stirred for 2 hours, and the solid is filtered off with suction and washed wit water. The residue which has been dried in air is dissolved in methylene chloride, active charcoal is added, and the mixture is filtered. Concentration in vacuo results in the clorless crystalline product.
Reaction SMILES: C([O:5][C:6](=[O:30])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:29])=[CH:20][N:21]=[C:22]2[NH:25][C:26]([NH2:28])=[NH:27])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(C)(C)C>CCOC(C)=O.Cl>[ClH:29].[Cl:29][C:19]1[C:18]2[C:23](=[CH:24][C:15]([S:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:7]3[C:6]([OH:30])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=2)[C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@H]3C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.2 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-proline t-butyl ester (60 mg, 0.13 mmol) was dissolved in a solution of EtOAc saturated with HCl (5.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo , azeotroping with EtOAc, and the residue triturated with CH2Cl2 to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-proline hydrochloride (44 mg, 0.095 mmol) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4.C(N(CC)CC)C.Br.[Br:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.Br>C1COCC1>[BrH:29].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4
Reactant: BrCc1cccnc1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1cccnc1)CC3

Procedure:
Similarly to the preparation of Example 4, the title compound was prepared from the reaction of (+)-3-methoxy-morphinan hydrochloride (1 g, 3.4 mmol) in THF (20 ml), triethylamine (1.43 ml, 10.3 mmol), and 3-(bromomethyl)pyridine hydrobromide (0.95 g, 3.75 mmol) gave a solid which was treated with 45% HBr to afford 1 g of a tan solid (68% yield); ms (ESI+): m/z 349 (M+1).
Reaction SMILES: [CH2:1]1[CH:8]2[CH:2]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](=O)[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH2:1]1[CH:8]2[CH:2]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](=[N:19][OH:20])[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12
Reactant: O=C1c2ccccc2C2CC2c2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2ccccc2C2CC2c2ccccc21

Procedure:
A solution of 6.6 g (0.03 mole) of 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one, 8.4 g (0.12 mole) of hydroxylamine hydrochloride in 120 ml of pyridine was held at reflux for 18.5 hrs. The solvent was evaporated under reduced pressure and the residue was dissolved with a mixture of water and methylene chloride. The layers were separated and the organic layer was in turn washed with 10% hydrochloric acid, and saturated brine, dried and solvent evaporated to give 7.4 g of crude 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime, mp 201° (ex. MeOH, dried at 110°/0.1 mm). The NMR spectrum in CDCl3 -DMSO-d6 : a singlet at δ10.9 (1H), multiplet at 6.9-7.6 (8H), multiplet at 2.1-2.6 (2H) and multiplet at 1.3-1.8 (2H). Anal. Calcd. for C16H13NO: C, 81.46; H, 5.57; N, 5.95. Found: C, 81.48; H, 5.68; N, 6.08. Mass spec.: Calcd. for C16H13NO: 235.0996. Found: 235.0997.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[C:7](=[O:20])[C:6]=3[C:2]=1[CH3:1])/[C:34](=[O:40])[NH:35]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 29 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 as starting materials to obtain (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 12 (20 mg, yield 29%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:16]([CH:28]=O)=[CH:15][C:14]=1[O:30][CH3:31].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33]1.[O-]S(C(F)(F)F)(=O)=O.[In+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[OH:12][C:13]1[C:14]([O:30][CH3:31])=[CH:15][C:16]([CH:28]2[CH:33]3[CH2:34][C:35]4[C:40]([CH:32]3[C:11]3[C:3](=[CH:4][CH:5]=[C:6]([C:7]([NH2:9])=[NH:8])[CH:10]=3)[NH:2]2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=2)[CH:18]=1
Reactant: COc1cc(C=O)c(-c2ccc(C(C)C)cc2)cc1O
Reactant: N=C(N)c1ccc(N)cc1
Reactant: C1=Cc2ccccc2C1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: CC#N
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(C)C)cc2)cc1O
Temperature: 70 °C

Procedure:
4-amino-benzamidine mono HCl salt (34.5 mg, 0.2 mmole) was suspended in acetonitrile (1 mL). The suspension was treated with 5-Hydroxy-4′-isopropyl-4-methoxy-biphenyl-2-carbaldehyde (27.0 mg, 0.1 mmole) and indene(23.2 mg, 0.2 mmole). Indium triflate (11.2 mg, 0.02 mmole) was added and the reaction was heated at 70° C. for 24 hours. The desired product was purified using reverse phase HPLC. Mass spectrum: 504 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([O:18][CH3:19])[C:14]([O:16]C)=[O:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([O:18][CH3:19])[C:14]([OH:16])=[O:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)C(NC(=O)Cc1cc(F)cc(F)c1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O

Procedure:
Methyl 2-[(3,5-difluorophenyl)acetylamino]-2-methoxyacetate 2A (0.4 g) was dissolved in 10 mL of dioxane and treated with 2.8 mL of a 1.0 N aqueous sodium hydroxide solution. After 1.5 h most of the solvent was removed by evaporation at reduced pressure. The mixture was acidified with an aqueous solution of sodium bisulfate and washed with two successive portions of ether. The combined organic extracts were washed with brine and then dried with magnesium sulfate. The solution was filtered and the solvent was evaporated at reduced pressure to yield 2-[(3,5-Difluorophenyl)acetylamino]-2-methoxyacetic acid 3 as 0.35 g of a white powder. 1H-NMR (DMSO-d6): δ 9.06 (d, J=8.7 Hz, 1H), 7.15-6.85 (m, 3H), 5.23 (d, J=8.7 Hz, 1H), 3.57 (s, 3H), 3.21 (s, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[O:13][C:12](=[O:14])[C:11]([C:15](O)=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C1C=CC=CC=1>CN(C)C=O.CCCCCC>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[O:13][C:12](=[O:14])[C:11]([C:15]([Cl:25])=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)oc2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)oc2cc1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 6,7-diacetoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (306 mg), thionyl chloride (80 μL), dimethyl formamide (one drop), and benzene (15 mL) was refluxed for 1 hour. After cooling to room temperature, hexane (10 mL) was added. Solids were filtered off to give 6,7-diacetoxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride (286 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>C(Cl)Cl>[Br:18][C:10]1[C:9]([CH3:12])=[C:8]2[C:3]([CH2:4][CH2:5][CH2:6][C:7]2=[O:13])=[C:2]([CH3:1])[CH:11]=1
Reactant: BrBr
Reactant: Cc1ccc(C)c2c1CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1CCCC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 15.0 g of 5,8-dimethyltetralone (purchased from Wiley Organics) in 250 mL of methylene chloride was added 28.7 g of aluminum chloride (purchased from Aldrich Chemical Co.). The mixture was cooled to 0° C. and then a solution of 15.2 g bromine in 90 mL of methylene chloride was added dropwise. After the mixture was stirred at room temperature for 2 h, it was cooled to 0° C. and then approximately 200 g of ice was added. The resulting mixture was filtered. The organic layer was separated and was washed with 1N aqueous sodium hydroxide, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from 1-chlorobutane to give 21.8 g of the title compound of Step A as a solid melting at 64°-68° C. 1H NMR (CDCl3): δ 2.11 (m, 2H), 2.25 (s, 3H), 2.64 (t, 2H), 2.66 (s, 3H), 2.77 (t, 2H), 7.53 (s, 1H).