Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:7][CH:6]=1)#[N:4].CCN(CC)CC.[C:35]1([CH:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[BH3-]C#N.[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[CH2:42][CH:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:26][CH:27]=1)#[N:4]
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2CCCCN2)cc1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2CCCCN2CC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperidine-2(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide dihydrochloride (0.503 mmol) was dissolved in MeOH (3 mL) and the pH of the solution adjusted to 5 with Et3N. 2,2-Diphenylacetaldehyde (0.267 mL, 1.508 mmol) and NaCNBH3 (0.095 g, 1.508 mmol) were added, and the reaction mixture stirred for 18 hr at ambient temperature. The mixture was concentrated to remove the MeOH, then partitioned between CH2Cl2 and aq satd NaHCO3 solution. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound after SiO2 chromatography eluting with CH2Cl2 : MeOH, NH4OH, 98:1.8:0., and conversion to the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29][C:30]([O:32][CH2:33][CH:34]4[C:46]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]>CO.C(O)(=O)C.[Pd]>[NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29][C:30](=[O:31])[O:32][CH2:33][CH:34]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41]5[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCN(C(=O)OCc4ccccc4)CC3)nc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCNCC3)nc12
Yield: 65.8 %

Procedure:
A mixture of Example 49A (0.175 g, 0.3 mmol) and 10% Pd/C (0.015 g) in MeOH (5 ml) and acetic acid (0.2 ml), was stirred overnight under a H2 atmosphere at room temperature. The mixture was filtered through a a pad of silica then concentrated under vacuum. The residue was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide 0.095 g (69%) of the desired product. MS (ESI) m/e 482 (M+H)+. 1H NMR (DMSO-D6) δ ppm 8.55 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.82-7.91 (m, 3H), 7.65-7.78 (s, 3H) 7.42 (d, J=7.67 Hz 2H), 7.29-7.34 (m, 2H), 4.31 (d, J=7.06 Hz, 2H), 3.5-3.28 (m, 7H), 2.42 (s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=1)C.O.[NH2:15][NH2:16]>C(O)C>[CH3:12][N:7]1[C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]1
Reactant: CCOC(=O)Cc1cc(C)nn1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(CC(=O)NN)n(C)n1
Yield: 78 %

Procedure:
As described for example 112a, (2,5-dimethyl-2H-pyrazol-3-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) at reflux for 16 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 78%). MS: m/e=169.3 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([CH2:16]O)[NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:16][C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18])[CH:15]=2)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CO)[nH]c2c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CN=[N+]=[N-])[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-methanol (2.0 g, 7.21 mmol) is dissolved in DMF (950 ml), cooled to 0° C. TEA (2.01 ml, 14.42 mmol) and MsCl (0.83 g, 7.21 mmol) are added. The mixture is stirred at room temperature for 1 hour. NaN3 (2.34 g, 34 mmol) is added. The reaction is stirred at room temperature for 1 hour and then 80° C. overnight. The mixture is cooled to room temperature, concentrated. The residue is purified by column chromatography (10% ethyl acetate in hexanes) to give 2-Azidomethyl-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1.40 g, 64%). 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.38 (d, 1H), 6.80 (s, 1H), 6.58 (m, 1H), 6.40 (s, 1H), 4.53 (d, 2H), 0.96 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1>O1CCCC1.C(OCC)(=O)C>[I:25][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCI)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a stirred solution of triphenylphosphine (1.178 g, 4.49 mmol) and imidazole (0.611 g, 8.98 mmol) in tetrahydrofuran (10 mL) at 0° C. was added iodine (1.292 g, 5.09 mmol). The resulting dark mixture was stirred at 0° C. After 5 minutes, tert-butyl 4-(2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (1.19 g, 2.99 mmol) was added as a solution in tetrahydrofuran (5 mL). The mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate, saturated sodium thiosulfate, water, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:2 ethyl acetate:hexanes, giving the desired product (1.50 g, 99%) as an orange foam. 1H NMR (DMSO-d6) δ 7.59-7.54 (m, 1H), 7.45-7.38 (m, 2H), 5.45-5.37 (m, 1H), 3.98-3.85 (m, 2H), 3.73-3.61 (m, 1H), 3.35-3.27 (m, 5H), 3.19-3.03 (m, 1H), 3.02-2.82 (m, 2H), 1.92-1.84 (m, 2H), 1.45-1.34 (m, 11H); ESI-MS (m/z, %): 530 (M+Na, 6), 452 (25), 279 (100).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][CH:14]2[CH2:20][CH:19]3[N:21](C(OC(C)(C)C)=O)[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:16]12[NH:21][CH:19]([CH2:18][CH2:17]1)[CH2:20][CH:14]([O:13][NH:12][C:10]([C@@H:7]1[CH2:6][CH2:5][C@@H:4]3[CH2:9][N:8]1[C:2](=[O:1])[N:3]3[O:29][S:30]([OH:33])(=[O:32])=[O:31])=[O:11])[CH2:15]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OS(=O)(=O)O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOC1CC2CCC(C1)N2)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 48 (0.077 g, 0.17 mmol) in DCM (7 mL) was added trifluoroacetic acid (0.34 mL, 4.42 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-N-(8-azabicyclo[3.2.1]oct-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 27 (Table 1) (0.003 g, 7%) as a white solid.
Reaction SMILES: [O:1]=[C:2]([NH:6][C:7](=[O:16])[C:8]([NH:10][C:11](=[O:15])[CH2:12][CH2:13]Cl)=[O:9])[CH2:3][CH2:4]Cl.C(N(CC)CC)C>C(Cl)Cl>[O:15]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:2](=[O:1])[CH:3]=[CH2:4])=[O:16])[CH:12]=[CH2:13]
Reactant: O=C(CCCl)NC(=O)C(=O)NC(=O)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC(=O)C(=O)NC(=O)C=C
Yield: 4.6 %

Procedure:
To a suspension of N,N'-bis(1-oxo-3-chloropropyl) ethanediamide (3.0 g; 11 mmol) in methylene chloride (40 ml), triethylamine (2.82 g; 28 mmol) was added, and the resultant mixture was stirred at room temperature for 2 hours. The precipitated solid was collectd and washed with water to give N,N'-bis(1-oxo-2-propenyl)ethanediamide (0.1 g). Yield, 4.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Br[CH2:35][CH2:36][O:37][C:38](=[O:40])[CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:35][CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CC(=O)OCCBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)OCCN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (24 mg, 0.06 mmol, 1.0 equiv; Example 122) in anhydrous DMF (1 mL) was added lithium aluminum hydride (2.3 mg, 0.06 mmol, 1.0 equiv; [CAS RN 16853-85-3]) and the reaction mixture stirred at rt. After 30 min, acetic acid 2-bromo-ethyl ester (12.0 mg, 8 μL, 0.072 mmol, 1.2 equiv; [CAS RN 927-68-4]) was added and the reaction mixture heated by microwave irradiation to 180° C. for 60 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 8.9 mg (31%) of the title compound as a light yellow powder. MS (ISP): 486.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[O:5][C:6]1[N:11]=[C:10]([NH2:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[O:5][C:6]1[N:11]=[C:10]([NH:12][C:32](=[O:34])[CH3:33])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
To a round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 2-(3,4-difluorophenoxy)-4-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 32) (20 mg, 0.04 mmol), 500 μL acetic anhydride and 10 mg of 4-(N,N-dimethylamino)pyridine (DMAP). The mixture was heated at reflux for 10 minutes and then worked up by removing the solvent/reagent under high vacuum. Flash chromatography on silica gel (70/30 hexanes/ethyl acetate) afforded the desired product. 1H-NMR 500 MHz (CDCl3): δ 2.41 (s, 3H), 7.06-7.67(m, 10H), 8.03 (bs, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Oc1ccccc1F
Product: CCCCOC(=O)c1nc(Oc2ccccc2F)c2ccccc2c1O

Procedure:
Synthesized from 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 2-fluorophenol in analogy to Example D-20 d); MS-(+)-ion: M+1=356.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]=[CH:3]1>CCO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[C:6]2[C:5]([CH2:4][CH2:3][C:2]([CH3:14])([CH3:1])[O:7]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)OC(C)(C)C=C2
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)OC(C)(C)CC2
Yield: 90 %

Procedure:
A solution of precocene I (5.0 g, 26.3 mmol) in EtOH (200 mL) was hydrogenated by using 10% Pd/C (0.5 g ) as catalyst. The catalyst was filtered of and EtOH was removed under reduced pressure. The crude material was then washed with dichloromethane (2×50 mL) to afford the desired product as white solid (4.55 g, 90%). 1H-NMR (CD3CN) δ 6.97 (d, J=8.0 Hz,1H), 6.42 (d, J=8.0 Hz, 1H), 6.27 (s,1H), 3.74 (s, 3 H), 2.72 (t, 2 H), 1.80 (t, 2 H), 1.32 (s, 6 H); MS LC-MS (MH+=193).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH3:16])[CH:12]=[CH:11][C:10]=1[N:26]1[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH3:16])[CH:12]=[CH:11][C:10]=1[N:26]1[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]1
Reactant: Cc1cc(C)c(C(C)c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(C)c2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c(C)c1

Procedure:
A solution of 5-{2-benzyloxy-4-[1-(2,4,6-trimethylphenyl)-ethyl]-phenyl}-1,1-dioxo-1,2,5-thiadiazolidin-3-one and K2CO3 (60 mg) in EtOH (5 mL)/water (7 mL) is hydrogenated at 1 atm over 10% Pd/C (50 mg) for 10 days. The catalyst is filtered and the solvent evaporated to give the title compound as a pale-yellow solid: (M−1)−=373. HPLC retention time: 1.45 min (Method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 90 °C

Procedure:
A solution of Example 87C (2.35 g, 4.17 mmol) in ethanol (40 mL) was added to 20% palladium hydroxide on carbon (wet, 2.35 g, 1.707 mmol) in a stainless steel pressure bottle and was stirred at 50° C. for several days at 50 psi hydrogen. The mixture was filtered through a nylon membrane and concentrated. The residue was dissolved in 30 mL 1,4-dioxane and treated with 2 mL 20% sodium hydroxide. The mixture was heated at 90° C. for 4 hours and was concentrated. The residue was treated with water and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified using an ISCO Companion flash system on silica eluting with dichloromethane/ethyl acetate (5:5 to 4:6) to afford the title compound. MS (ESI+) m/z 425.9 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:59])([CH3:58])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:57])([C@@:20]4([CH3:56])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][NH:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]2)[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:56][C@:20]12[C@@:19]3([CH3:57])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:58])([CH3:59])[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=3)=[CH:31][CH2:30]4)[CH2:27][CH2:26][C@@H:25]1[C@H:24]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]1([CH2:39][NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]1)[CH2:22][CH2:21]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
To a solution of tert-butyl 4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methylamino)ethyl)piperazine-1-carboxylate (136 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 5 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by prep. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. HPLC showed some impurities were still present, so the reaction was repurified by prep. HPLC. The fractions were concentrated under reduced pressure to give the title compound as a white solid (18 mg, 0.027 mmol, 16.43% yield). LCMS: m/e 656.6 (M+H)+, 2.24 min (method 6). 1H NMR (500 MHz, Acetic) δ ppm 8.03 (d, J=8.24 Hz, 2H),7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.50-3.67 (m, 6H), 3.40 (d, J=12.82 Hz, 1H), 3.22-3.29 (m, 6H), 2.99 (d, J=13.12 Hz, 1H), 2.49-2.58 (m, 1H), 1.76 (s, 3H), 1.19 (s, 3H), 1.16-2.23 (m, 22H), 1.10 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.Br>CC(O)=O>[O:15]1[C:11]2=[N:10][C:9]3[C:4]([C:3](=[O:2])[C:12]2=[CH:13][CH2:14]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: COc1c2ccccc2nc2occc12
Agent: Br
Solvent: CC(=O)O
Product: O=C1C2=CCOC2=Nc2ccccc21
Yield: 36 %

Procedure:
The hydrolysis of compound 1 with HBr in AcOH at 110° C. for 1 h gave furo[2,3-b]quinolin-4-one (2) with 36% yield (B. Klier, O. Schimmer, Mutagenesis 1999, 14, 181). The yield was increased up to 91% by refluxing the reaction mixture for 8 h. This improvement is crucial because the supply of starting dictamnine could be reduced.
Reaction SMILES: N1(S([Br:8])=O)CCC1=O.[C:9]1(=[O:34])[N:13]([CH:14]2[C:27](=[O:28])[N:16]3[CH:17]([C:23]([O:25][CH3:26])=[O:24])[C:18](=[CH2:22])[CH2:19][S:20](=[O:21])[C@H:15]23)[C:12](=[O:29])[C:11]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:10]12>C(Cl)Cl>[CH3:19][C:18](=[CH2:22])[CH:17]([N:16]1[C:27](=[O:28])[CH:14]([N:13]2[C:12](=[O:29])[C:11]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:10]3[C:9]2=[O:34])[CH:15]1[S:20]([Br:8])=[O:21])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC
Reactant: O=C1CCN1S(=O)Br
Solvent: ClCCl
Product: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Br

Procedure:
The azetidinone sulfinyl bromide from above was dissolved in 20 ml. of methylene chloride; 0.6 ml. of stannic chloride was added to the solution. After 45 minutes at room temperature the reaction mixture was washed with water and brine, dried over anhydrous MgSO4, and evaporated in vacuo to dryness to provide 1.15 g. of methyl 7-phthalimido-3-methylenecepham-4-carboxylate-1-oxide (a mixture of R- and S-sulfoxide isomers). For the predominant isomer: nmr (CDCl3) δ3.64, 4.20 (ABq, 2, J=13.0 Hz, C2 --H), 3.84 (s, 3, COOCH3), 4.90 (d, 1, J=4.0 Hz, β-lactam H), 5.3-5.7 (m, 3), 5.97 (d, 1, J=4.0 Hz, β-lactam H), and 7.84 (bs, 4, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:33])[CH:27]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([CH:32]([OH:33])[C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2 mmol) was dissolved in 15 mL THF in a dry 100 mL flask fitted with a rubber septa and nitrogen inlet and cooled to 0° C. in ice water bath for 25 minutes. A solution of 2.5M BuLi in hexane (17.0 mL, 42.6 mmol) was added and the mixture stirred for 45 minutes. To the thick yellow precipitate that formed was added a solution of pyridine-3-carboxaldehyde (3.03 g, 28.4 mmol) in 15 mL THF. The ice bath was removed and the mixture was allowed to stir at room temperature for 45 minutes and the reaction was quenched with 25 mL H2O. The mixture was transferred to a separating funnel, and the aqueous phase was discarded. The organics were dried in vacuo to yield product as an orange oil. 1H NMR (CDCl3) δ 8.85 (m, 1H) 8.54 (m, 1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz, 2.8 Hz, 1H) 7.50 (d, J=8.0 Hz, 1H) 7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m, 1H) 5.85 (m, 1H) 1.70 (d, 1H) 1.08 (s, 9H); MS (ES) m/z=319.1 (MH)+
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=O)C.O.[NH2:31][NH2:32]>>[CH2:23]([O:22][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:18]([CH2:19][O:20][CH3:21])=[C:6]([C:4]([NH:31][NH2:32])=[O:3])[N:7]=[CH:8][C:9]=1[NH:10]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NN
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Solvent: O
Product: COCc1c(C(=O)NN)ncc2[nH]c3cccc(OCc4ccccc4)c3c12

Procedure:
1.56 g of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid-ethyl ester is refluxed in 20 ml of hydrazine hydrate (80%) for 4 hours. After cooling, the precipitated crystals are suctioned off and dried. 1.2 g of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid-hydrazide of a melting point of 212°-213° C. is obtained.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]>>[F:29][C:24]([F:30])([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCI
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with diethyl 2-(6-heptenyl)malonate and the 1-iodo-5,5,6,6,6-pentafluorohexane prepared in Example 2, the same procedure as shown in Example 5 was repeated to give ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate.