Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:42])[O:11][CH2:12][C:13]2([C:30](=[O:41])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[CH3:40])[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][NH:21]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)[CH3:2].Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:42])[O:11][CH2:12][C:13]2([C:30](=[O:41])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[CH3:40])[CH2:14][CH2:15][N:16]([C:19](=[O:29])[CH2:20][NH2:21])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(NC(=O)OCC2(C(=O)NCc3cccc(F)c3C)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3cccc(F)c3C)CCN(C(=O)CN)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of give (1-(2-(tert-butoxycarbonylamino)acetyl)-4-(3-fluoro-2-methylbenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (12 mg, 0.021 mmol, 1.0 equiv.) in CH2Cl2 (1 mL) was added 4N HCl (1 mL). The mixture was stirred at rt for about 1 h and concentrated to dryness. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-aminoacetyl)-4-(3-fluoro-2-methylbenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (8 mg, 79%). LRMS (M+H+) m/z 485.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3(O)[CH2:21][CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1

Procedure:
Prepared in analogy to Example A65(a) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-tetrahydro-furan-3-ol (Example A66(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown solid. MS (m/e): 278.0 ([M+H]+, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(c2ccccc2)CC1

Procedure:
This compound, m.p. 277°-279° C., obtained as a dimethylformamide solvate was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and 4-phenylpiperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:43][C:44]([N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[C:53](=[O:62])[NH:54][C:55]4[C:60]([CH:61]=3)=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH2:48][CH2:47]2)=[O:45])[C:13]([NH:15][C@H:16]([C:29](=[O:42])[N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:15][C:13](=[O:14])[C@H:12]([NH:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[C:53](=[O:62])[NH:54][C:55]3[C:60]([CH:61]=2)=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:48][CH2:47]1)=[O:45])[CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)[C:29](=[O:42])[N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[CH2:34][CH2:35]1
Reactant: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCN)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Reaction time: 1 h
Yield: 72 %

Procedure:
To a suspension of tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate (230 mg, 0.27 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at 0° C. After 1 h at room temperature, the solvent was removed under high vacuum and then dissolved in methanol. The free base of title compound was liberated by passing the methanolic solution over Strata-X—C-33μ cation polymeric sorbent followed by elution with 3.0 M ammonia solution in methanol to give N-((R)-1-((S)-6-amino-1-oxo-1-(4-(pyridin-4-yl)piperazin-1-yl)hexan-2-ylamino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide as a white solid in 72% yield. 1H-NMR (CD3OD) δ 8.08-8.07 (m, J=2, 2H), 7.95 (s, 1H), 7.61 (d, J=10 Hz, 1H), 7.51-7.44 (m, 3H), 7.29 (d, J=10 Hz, 1H), 7.23-7.19 (m, 1H), 7.11 (s, 1H), 6.79-6.78 (m, 2H), 4.80-4.77 (m, 2H), 4.60-4.55 (m, 1H), 4.11-4.04 (m, 2H), 3.82-3.80 (m, 2H), 3.66-2.78 (m, 11H), 2.51 (s, 3H), 1.87-1.11 (m, 11H; MS (ESI) 747 (M+H); Rf=1.64.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[N:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[N:40]1[CH:44]=[CH:43][N:42]=[CH:41]1)=[O:23]
Reactant: Cc1c(-n2ccnc2)n(CCCCCCO)c2ccccc12
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(-n2ccnc2)n(CCCCCC=O)c2ccccc12
Reaction time: 0.42 h

Procedure:
To a solution of Collins Reagent prepared with chromium trioxide (5.6 g) and pyridine (8.86 g) in dichloromethane (150 ml) at 0°-5° under a nitrogen atmosphere is added all at once 1.8 g of 1-(6-hydroxyhexyl)-3-methyl-2-(1-imidazolyl)-indole in dichloromethane (15 ml). The mixture is stirred for an additional 25 minutes, then filtered through celite. The filtrate is then passed through a silica gel column. The product is eluted from the silica gel with a 1:1 mixture of ethyl acetate:dichloromethane (500 ml). Concentration in vacuo yields 1-(5-formylpentyl)-2-(1-imidazolyl)-3-methylindole.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[C:9]1(O)[CH2:10][CH2:11][CH2:12]2.[CH3:19][O:20]C(CC)CCCCC1CCC2C1CC(O)C2.[I-].[Na+].CI>O1CCCC1>[CH3:19][O:20][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Reactant: CCC(CCCCC1CCC2CCCC12O)OC
Agent: [I-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC(CCCCC1CCC2CC(OC)CC12)OC
Temperature: 50 °C

Procedure:
The starting material, 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 3.9 mmoles) is added to a reaction vessel containing sodium iodide (0.12 g, 4.9 mmoles) and tetrahydrofuran (12 ml). The solution is stirred while methyl iodide (0.84 g, 5.9 mmoles) is rapidly added. The reaction is heated in a 50° C. water bath for 4 hours. The water bath is removed and the reaction neutralized with the addition of water (5 ml). The organic phase is separated and the aqueous phase extracted with ether (2×50 ml). The ether extracts are combined and washed with brine (50 ml). The solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear yellow oil. The product is then kugelrohred under reduced pressure leaving a pale yellow oil (0.8 g, 3.1 mmoles).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].O>CO>[C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH:2]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2oc(C(=O)C=Cc3ccccc3)c(N)c2c1Cl
Temperature: 45 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
A mixture of 7G (1.5 g, 6.26 mmol), benzaldehyde (0.863 g, 8.14 mmol, 1.3 eq) and NaOH (1.0 g, 25.04 mmol, 4 eq) in MeOH (20 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids precipitated out were collected by filtration and dried to give product 8A (1.9 g, 92.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14](OC)=[O:15])[C:11]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cn(-c2ccc(OC)cc2)nc1CN1CCOCC1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C=O)c(CN3CCOCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A solution (20 mL) of methyl 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazole-4-carboxylate (11.3 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added to an ice-cooled solution (80 mL) of lithium aluminum hydride (1.4 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (3.7 mL), 1N aqueous sodium hydroxide solution (18.5 mL) and water (3.7 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (8.5 g) of 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (150 mL), manganese dioxide (15 g) was added, and the mixture was heated for 30 min with a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (7.2 g, 70%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24].N1CCCCC1.Cl>CN(C)C=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[C:17]1[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][C:16]1=[O:24])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=C1C(=O)Nc3ccccc31)CC2
Temperature: 130 °C
Yield: 20.8 %

Procedure:
A mixture of 0.6 g 5,6-dimethoxy-1-indanone, 1.04 g oxindole and 2.3 ml piperidine in 4 ml dimethylformamide was heated in a sealed tube at 130° C. for 12 hours to yield an orange suspension. The mixture was added to 1N hydrochloric acid in ethanol and the solids which formed were filtered and rinsed with water and ethanol. The solid was slurried in ethanol and filtered to yield 200 mg of 3-(5,6-dimethoxyindan-1-ylidene)-1,3-dihydroindol-2-one.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])[N:3]=[CH:2]1.[CH2:20]([Mg]Br)[CH3:21].CCOCC>C1COCC1>[OH:7][C:6]([C:8]1[CH:9]=[C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[CH2:20][CH3:21]
Reactant: CCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]cn2)c1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1cccc(NS(=O)(=O)CC)c1)c1c[nH]cn1
Temperature: 25 °C

Procedure:
To a solution of Example 55E (84 mg, 0.3 mmol) in THF (10 mL) at 0° C. was added dropwise a 2M solution of ethyl magnesium bromide in ether (0.6 mL, 1.2 mmol) and the resulting mixture was allowed to warm to room temperature for 6 hours. The mixture was quenched with saturated NH4Cl and concentrated under vacuum. The residue was passed through a Dowex® 50×8-400 ion exchange resin with 5% NH4OH as eluent. The ammonia solution was concentrated under vacuum and purified again by chromatography (silica gel, 9:1 CH2Cl2:ethanol) to provide 20 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[CH:9]=2)=[CH:4][C:3]=1[CH3:18].[CH:19](O)=[O:20].O1COCOC1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2[CH:19]=[O:20])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2)ccc1F
Reactant: O=CO
Agent: C1OCOCO1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(C2=C(C=O)C(C)(C)CC(C)(C)C2)ccc1F
Temperature: 25 °C

Procedure:
To a mixture of 20 kg of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene, 72 kg of 96% formic acid and 3.6 kg of 1,3,5-trioxane, 96 g of 70% benzoyl peroxide catalyst was added and the bath was heated to reflux for about 3 hours. The mixture was then cooled to room temperature and 48 kg of heptane was added with stirring. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with water, then 48 kg of methanol and 7.2 kg of 50% aqueous sodium hydroxide were added. The mixture was stirred for about 10 minutes, washed with water and dried with 10 kg of anhydrous sodium sulfate. The sodium sulfate was filtered off and the filter cake was washed with 10 kg of heptane. To the combined filtrates, 96 kg of dimethyl sulfoxide and 28 kg of triethylamine were added. Sulfur trioxide/pyridine complex (36 kg) was then charged portionwise at 30°-35° C. The batch was agitated for 15 minutes and the reaction was quenched with 96 kg of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with dilute hydrochloric acid and with brine. Methanol (48 kg) and 50% sodium hydroxide (4.8 kg) were added and the batch was stirred at 21°-25° C. for one hour. Ice (0.6 kg) was added and the mixture was stirred for 15 minutes. The phases were allowed to separate and the bottom layer was discarded. The top solution was washed with brine and concentrated in vacuo to remove the volatiles. The residue was dissolved in 22 kg of isopropanol and 2.8 kg of water. The mixture was then cooled to about -10° C., seeded and stirred for 16 hours. The crystallized product was filtered off, washed with cold aqueous isopropanol and dried to constant weight. Yield: 8.5 kg of 2-(4-fluoro-3-methylphenyl)- 4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](Cl)=[N:8]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: COc1ccccc1CN
Reactant: COc1cccc2nc(Cl)ccc12
Product: COc1ccccc1CNc1ccc2c(OC)cccc2n1

Procedure:
The title compound, MS: m/e=295.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-methoxy-2-chloroquinoline (CAS-RN: 160893-07-2) and 2-methoxybenzylamine.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6])C.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6]
Reactant: CCOC(=N)c1ccc(C(=O)OCC)cc1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1 g (3.9 mmol) of ethyl 4-ethoxycarbonimidoylbenzoate hydrochloride was stirred in a mixture of 3 ml of ethanol and 10 ml of 50% aqueous dimethylamine solution overnight. Then the solvent was evaporated, and 10 ml of dioxane containing 4 N hydrogen chloride and 1 ml of ethanol were added to the residue. After stirring at room temperature for 5 days, the solvent was evaporated. 1 N sodium hydroxide was added to the residue. After the extraction with dichloromethane, the organic layer was washed with saturated Aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CI.[CH3:16]C(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)NS(=O)(=O)c1cc[nH]c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of N-(1,1-dimethylethyl)-1H-pyrrole-3-sulfonamide 9 g (0.044 mol) in 90 mL N,N-dimethylforamide was cooled to 15° C. under a nitrogen atmosphere. To this was added 3.2 mL (0.053 mol) of methyl iodide followed by 5.43 g (0.048 mol) of potassium t-butoxide. The mixture was warmed at ca. 60° C. for 2 hours then allowed to cool to room temperature and stirred for ca. 2 hours. The reaction mixture was diluted with ethyl acetate, washed three times with 1N HCl, once with brine, dried (MgSO4) and evaporated to an oily solid which was triturated with 5% diethyl ether/95% hexanes affording 6 g of the title compound as a beige solid, m.p. 134°-135° C. 1H NMR (CDCl3, 200 MHz.) δ: 7.11(s,1H), 6.59(d,1H), 6.41(d,1H), 4.32(bs,1H), 3.67(s,3H), 1.26(s,9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a suspension of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (500 mg, 1.20 mmol) in anhydrous DCE (8 mL) were added hexanal (0.25 mL, 2.07 mmol) and sodium triacetoxyborohydride (825 mg, 3.89 mmol). The reaction mixture was stirred at 70° C. for 3.5 hrs. Then the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc) gave 460 mg (77%) of the title compound as a pale yellow oil. HPLC, Rt: 6.3 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.47 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.18 (m, 5H), 6.95 (dd, J=10.1, 9.0 Hz, 1H), 6.74 (m, 1H), 4.52 (s, 2H), 3.91 (s, 3H), 3.38 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.60 (m, 4H), 1.42-1.25 (m, 8H), 0.92 (m, 6H).
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:4]([O:3][C:1]([NH:11][C:12]([CH3:13])([CH3:17])[C:14]([NH:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30])=[O:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (200 MHz, CDCl3): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H), 8.65 (s, 1H). FAB-MS: calculated for C22H25N3O4 395; found 396 (M+H,100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:25][CH3:26])=[CH:13][C:14]2[O:19][C:18](=[O:20])[C:17]3[CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:24]=1)(=O)=O.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:26][O:25][C:12]1[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)=[CH:24][C:15]2[C:16]3[CH2:23][CH2:22][CH2:21][C:17]=3[C:18](=[O:20])[O:19][C:14]=2[CH:13]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 55 %

Procedure:
Method B (16 h at 80° C.); starting materials: 2,3-dihydro-8-[4-(methanesulfonyloxy)butyloxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 84) and 1-phenylpiperazine; yield 55%; fusion point 162°-165° C. (from ethanol). Fumarate: method E; yield 95%; fusion point 179°-183° C. (from acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4.C=O.[C:24]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:24])[C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1Cl)CCN[C@@H]1Cc3ccccc3[C@@H]21
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCN(C)[C@@H]1Cc3ccccc3[C@@H]21
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 300 mg (1.00 mmol) of Compound P from step E was dissolved in 20 mL acetonitrile and 0.40 mL (5.3 mmol) 37% aqueous formaldehyde was added followed by 0.10 grams (1.59 mmol) sodium cyanoborohydride. After 30 minutes, the solution was brought to pH 7 by dropwise addition of glacial acetic acid then stirred an additional 1 hour and 45 minutes. The solvent was removed under reduced pressure, and the residue was taken up into 125 mL ethyl acetate. This was washed with 50 mL 10% sodium bicarbonate, dried (MgSO4) and evaporated to give an oil, which was purified by flash chromatography over silica gel, eluting with ethyl acetate to give 150 mg of trans-5,6,7,7a,8,12b-hexahydro-2-methoxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine (Compound Q) as an oil, 200 MHz NMR (CDCl3) d 2.17(dd,1H,J=12,Hz), 2.69(m,2H) 2.37(s,3H), 2.90-3.40(m,4H), 3.77(s,3H), 4.67(d,1H,J=9 Hz), 7.03(s,1H), 7.17(s,1H), 7.20-7.35(m,4H).