Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)(=[O:27])=[O:26].[S].C(N(CC)CC)C>CN(C)C=O.C(#N)C>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([C:31]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: [S]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (125 mg, 0.3 mmol) in anhydrous N,N-dimethylformamide (2.5 mL) was added 3-(methylsulfonyl)benzaldehyde (76 mg, 0.4 mmol). The solution was stirred at 80° C. for 1 h. Sulfur was added (25 mg, 0.8 mmol) followed by triethylamine (140 μL, 1.0 mmol). The mixture was stirred at 85° C. for 24 h followed by stirring at room temperature for another 24 h. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (20-100% ethyl acetate in heptanes gradient followed by 0-10% methanol in dichloromethane). The residue was repurified via flash chromatography (0-10% methanol in dichloromethane) to afford a yellow solid that was stirred in acetonitrile (3 mL) at 40° C. for 2.5 h. The solid was filtered, washed with cold acetonitrile and dried under high vacuum at 40° C. to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 1.60-1.74 (m, 1H) 1.77-1.89 (m, 2H) 1.89-2.11 (m, 4H) 2.81 (br s, 1H) 2.97-3.09 (m, 2H) 3.17-3.26 (m, 3H) 3.41-3.52 (m, 2H) 3.52-3.63 (m, 1H) 3.74 (br s, 1H) 4.37 (br s, 1H) 4.64 (d, 1H) 6.91 (br s, 1H) 7.74-7.89 (m, 2H) 8.05 (d, 1H) 8.35 (br s, 1H) 8.65 (br s, 1H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=O)C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[Si:11]([O:10][CH2:9][C@@H:8]([N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7][CH2:6][CH2:5][OH:4])([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:12])[CH3:13]
Reactant: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (0.124 mol) in THF (200 mL) and MeOH (50 mL) was added sodium hydroxide (2 N, 93 mL, 0.186 mol) at RT The reaction was stirred at RT for 2 h and LC-MS indicated the reaction was completed. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel column using a mixture of hexanes and EtOAc to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl(methyl)carbamate (37.9 g, 88%). LRMS (M+H+-Boc) m/z 248.2.
Reaction SMILES: O.[N+:2]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc(CCC(=O)O)cc1
Reaction time: 2 h

Procedure:
15 g of palladium on carbon (10% and 30 ml of water are added to a mixture of 155 g of 4-nitrocinnamic acid in 1 l of methanol, and hydrogenation is carried out at room temperature under 3 bar until no further hydrogen is taken up, after about 2 hours. After filtration and evaporation of the solvent in a rotary evaporator, residual water is removed by twice adding 300 ml portions of toluene and distilling off the solvent in a rotary evaporator.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:14]=[C:13]([O:28][CH:29]([CH3:31])[CH3:30])[CH:12]=2)=[N:7][CH:8]=1.P(Br)(Br)Br.[CH2:37]([O:39][P:40]([O:44]CC)[O:41][CH2:42][CH3:43])[CH3:38]>ClC(Cl)C.C(Cl)Cl>[CH:29]([O:28][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[CH:14]=1)[C:10]([NH:9][C:6]1[CH:5]=[N:4][C:3]([CH2:2][P:40](=[O:44])([O:41][CH2:42][CH3:43])[O:39][CH2:37][CH3:38])=[CH:8][N:7]=1)=[O:32])([CH3:30])[CH3:31]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2cnc(CO)cn2)c1
Reactant: CCOP(OCC)OCC
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOP(=O)(Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)cn1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.4 %

Procedure:
To a solution of N-(5-hydroxymethyl-pyrazin-2-yl)-3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzamide (130 mg, 0.28 mmol) in 2.8 mL of dichloroethane was added 0.56 mL of a 1 M solution of PBr3 in CH2Cl2 and the solution stirred for 4 h at rt. Then triethylphosphite (0.5 mL, 2.8 mmol) was added and the resulting solution microwave heated at 120° C. for 5 min. Then the mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3, brine, dried (MgSO4) and evaporated. The residue was adsorbed to SiO2 and subjected to MPLC on a 12 g SiO2 column eluting with % EtOAc in hexanes (time): 65-95 (30 min ramp) to provide 33 mg (20%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 6H, J=6 Hz), 1.30 (d, 6H, J=6 Hz), 3.22 (s, 3H), 3.50 (d, 2H, J=21 Hz), 4.02 (m, 4H), 4.78 (septet, 1H, J=6 Hz), 6.97 (t, 1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz), 7.35 (t, 1H, J=2 Hz), 7.51 (t, 1H, J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.41 (dd, 1H, J=1, 2 Hz), 9.29 (d, 11-1, =1 Hz). 11.17 (s, 1H); LCMS (m/z): 578.6 [C26H32N3O3PS+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:23]=1)[CH:7]=[CH:8][C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)=[O:12])([O-:3])=[O:2].[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH2:29][O:30][C:31](=[O:36])/[CH:32]=[C:33](\[NH2:35])/[CH3:34].[CH2:37](O)[CH3:38]>>[O:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH2:14][O:13][C:11]([C:10]1[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:23]=2)[C:32]([C:31]([O:30][CH2:29][CH:25]2[CH2:26][CH2:27][CH2:28][O:24]2)=[O:36])=[C:33]([CH3:34])[NH:35][C:37]=1[CH3:38])=[O:12]
Reactant: C/C(N)=C/C(=O)OCC1CCCO1
Reactant: CCO
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)CC(=O)OCC1CCCO1
Product: CC1=C(C(=O)OCC2CCCO2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC2CCCO2)=C(C)N1
Temperature: -10 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 15 g (0.05 mol) of tetrahydrofuran-2-ylmethyl 3-nitrobenzylidenacetoacetate and 8.7 g (0.05 mol) of (tetrahydrofuran-2-ylmethyl)-3-aminocrotonate in 50 ml of abs ethanol, was refluxed with stirring, in the absence of light, along 8 hours. The reaction mixture was then cooled to −10° C. A yellow soild (mp 122-3° C., EtAcO) was obtained with a yield of 80%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][C:32]=1[C@@H:38]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH3:7].[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:32]([C@@H:38]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:39][CH2:40][N:41]([CH:42]([CH3:44])[CH3:43])[CH:45]([CH3:46])[CH3:47])[CH:33]=2)=[CH:12][CH:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: C=CCCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/CCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 90 °C

Procedure:
tert-butyl{2-[4-(pent-4-en-1-yloxy)phenyl]ethyl}carbamate (Preparation 56, 1.2 g, 3.9 mmol), (3R)-3-[2-(benzyloxy)-5-bromophenyl]-N,N-diisopropyl-3-phenylpropan-1-amine (Prepared according to WO9411337, 1.9 g, 3.9 mmol), palladium acetate (90 mg, 0.4 mmol), tri(o-tolyl)phosphine (200 mg, 0.8 mmol), and diisopropylethylamine (1.0 ml, 5.9 mmol) were mixed in acetonitrile (12 ml), degassed with argon and the heated to 90° C. for 5 hours. The reaction was cooled to room temperature, filtered through Arbocel and solvent removed in vacuo. The residue was taken up in water and ethyl acetate, the organics were separated, dried (magnesium sulphate) and the solvent removed in vacuo, the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (981210.2 to 95151.5 by volume) to furnish the title compound as a pale yellow foam, 2.5 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl.[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]([OH:36])[CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](OCC)=[O:32])=[CH:25][CH:24]=3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]([OH:36])[CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:32])=[CH:25][CH:24]=3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)COc1ccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)cc1
Reactant: COCCN
Agent: Cl
Product: COCCNC(=O)COc1ccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)cc1
Temperature: 25 °C
Reaction time: 71 h
Yield: 98.6 %

Procedure:
2-Methoxyethylamine (320 mg) was added to the (1R)-1-(3-chlorophenyl)-2-[3-(4-ethoxycarbonylmethoxyphenyl) cyclohexylamino]ethanol hydrochloride (trans-H) obtained in Example 28 (100 mg), and the mixture was stirred at room temperature for 71 hours. The reaction solution was separated and purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 97 mg of (2R)-2-[4-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy]-N-(2-methoxyethyl) acetamide (90% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:52]=[CH:51][C:50]([N:53]=[C:54]=[O:55])=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:55])=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)Nc3ccc(Oc4ccccc4)cc3)CN2C1=O
Yield: 38 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-phenoxyphenyl isocyanate (111 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 52 mg (38%) of 18-(4-phenoxyphenylaminocabonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.0% pure (HPLC), MS m/z 780 (M−H)−, HRMS: calcd. 799.3337 and found 799.3316 (M+NH4)+, mp 163-165° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)=O)CC1
Reaction time: 48 h
Yield: 45 %

Procedure:
A 204 ml (1.6 mol) portion of ethyl acetoacetate and 138 ml (1.6 mol) of 1,2-dibromoethane were dissolved in 3 liters of N,N-dimethylformamide, and the solution was mixed with 460 g (3.3 mol) of potassium carbonate at room temperature and stirred at the same temperature for 2 days. After completion of the reaction, insoluble material was removed by filtration and then N,N-dimethylformamide was evaporated under a reduced pressure of 50 mmHg. The resulting residue was mixed with 1.5 liters of diethyl ether, washed with water (500 ml×3) and then dried over anhydrous sodium sulfate. By evaporating diethyl ether, 113.43 g (45%) of the title compound was obtained as an oily substance.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.C(O)(=O)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:27])[C:25]=1[CH3:26])[NH:22][CH2:21][C:20]1([CH2:30][CH2:29][CH2:28]1)[CH:19]2O>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:27])[C:25]=1[CH3:26])[NH:22][CH2:21][C:20]1([CH2:28][CH2:29][CH2:30]1)[CH2:19]2
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(c(C)c1C)NCC1(CCC1)C2
Reaction time: 0.25 h

Procedure:
To a cold solution of 6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (2 g) in a mixture of 13 mL of THF and 5 mL of CH3OH cooled in ice bath, was added NaBH4 (2.4 g). After 2 hours, the mixture was quenched with ice, evaporated to dryness to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol as a crude mixture (11 g). NaBH4 (3 g) was added in portions to a mixture of trifluoroacetic acid and acetic acid (25 mL, v/v:1/1) cooled in ice bath, and to this mixture was added the above obtained mixture of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol dissolved in 10 mL of THF. After 15 min, the mixture was quenched with ice, extracted with dichloromethane, and washed with brine. The organic phase was then washed with NaOH (2 M) and brine, dried, evaporated to dryness and passed through a silica column (Hexane: EtOAc; 10:1) to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.3 g) as a liquid with slightly yellow color. 1H-NMR (300 MHz, CDCl3) δ=6.44071 (s, 1H), 3.74 (s, 3H), 3.59-3.24 (s, 1H), 3.18 (s, 2H), 2.75 (s, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 2.01-1.73 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=149.88, 136.21, 123.51, 131.91, 118.09, 110.83, 56.51, 51.91, 40.82, 36.09, 30.84, 15.25, 13.07, and 12.03 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>O1CCCC1.CN(C)C=O>[OH:36][C:28]1([CH2:27][NH:26][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[N:3]=2)=[O:13])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1
Reactant: NCC1(O)CN2CCC1CC2
Reactant: Cn1nc(C(=O)O)c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nc(C(=O)NCC2(O)CN3CCC2CC3)c2ccccc21
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A suspension of 1-methyl-1H-indazole-3-carboxylic acid (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (2×30 ml) containing some 2-propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20% methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39%) of the title compound as a pale yellow solid; mp 147°-149° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](C=C)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[CH2:12]([OH:14])[CH3:13].[O-:15][Mn](=O)(=O)=O.[K+]>O>[CH3:1][N:2]1[C:6]([CH:13]([OH:15])[CH2:12][OH:14])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: CCO
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=Cc1cnc([N+](=O)[O-])n1C
Agent: [K+]
Solvent: O
Product: Cn1c(C(O)CO)cnc1[N+](=O)[O-]

Procedure:
To a solution of 6.2 g. of 1-methyl-2-nitro-5-vinylimidazole in 570 ml. of ethanol cooled to about -10° C., a solution of 5.46 g. of KMnO4 and 8.85 g. of MgSO4.7H2O in 750 ml. of H2O is added with stirring. The reaction mixture is filtered through Celite and washed with ethanol. The filtrate is concentrated to dryness under vacuum at 50° C., and the residue is taken up with acetone. The resulting solution is filtered and concentrated to dryness under vacuum. The resulting solid is crystallized from methyl ethyl ketone. Yield 3.15 g. (41.6%), m.p. 119°-121° C.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH2:18].O>ClCCl>[CH2:20]([O:19][CH:17]=[CH:18][C:3](=[O:4])[C:2]([F:10])([F:1])[C:6]([F:9])([F:8])[F:7])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Reactant: C=COCCCC
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOC=CC(=O)C(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 15 h

Procedure:
With stirring at −10° C., 17.0 g (93.2 mmol) of pentafluoropropionyl chloride—dissolved in 20 ml of dichloromethane—were added to a mixture of 8.11 g (102 mmol) pyridine and 9.33 g (93.2 mmol) of butyl vinyl ether in 200 ml of dichloromethane. After the addition, stirring was continued at room temperature for a further 15 h. 200 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated. This gave 18.9 g (82% of theory) of a yellowish oil.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH3:9][I:10]>C(Cl)Cl>[I-:10].[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][N+:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: CI
Reactant: CN(C)CC(O)CO
Solvent: ClCCl
Product: C[N+](C)(C)CC(O)CO
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 1 mol of 3-(dimethylamino)-1,2-propanediol 20 (1.2 g) dissolved in CH2Cl2 (5 mL), MeI (2 g, 1.5 mol) was added and the mixture stirred at rt for 1 h. The solution was then filtered and the filtrated recristalise in MeOH/Ether and dried in vacuo. (yield 100%). The characterization data were consistent with the proposed structure.
Reaction SMILES: [Cl-].C[O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:25][CH2:26][CH2:27][CH3:28].[C:29]([Si:33]([CH3:51])([CH3:50])[O:34][C@H:35]1[CH2:44][CH2:43][CH2:42][C@@:41]2([CH3:45])[C@H:36]1[CH2:37][CH2:38][CH2:39][C@@H:40]2[C@H](C)C=O)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([Si:33]([CH3:50])([CH3:51])[O:34][C@H:35]1[CH2:44][CH2:43][CH2:42][C@@:41]2([CH3:45])[C@H:36]1[CH2:37][CH2:38][CH2:39][C@@H:40]2[C@H:27]([CH3:28])[CH2:26][CH:25]=[O:3])([CH3:31])([CH3:30])[CH3:32]
Reactant: [Li]CCCC
Reactant: C[C@H](C=O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@H](CC=O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 1 h

Procedure:
A suspension of 6.54 g of (methoxymethyl)triphenylphosphonium chloride in 38 ml of abs. THF was cooled to -10° and treated with 11.3 ml of nBuLi (1.5 M, hexane). 15 minutes later, the deep red ylide solution was cooled down to -78° and 3.225 g of (S)-2-[(1R,4aR,5S,8aR)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propionaldehyde dissolved in 21 ml of abs. THF, were slowly added and the reaction mixture kept for 60 minutes at that temperature. Partition between hexane and EtOH/H2O=8/2, washing of the upper layer with EtOH/H2O=8/2, drying over sodium sulfate, evaporating i. V. and flash chromatography (SiO2, hexane/AcOEt=98/2) delivered 3.11 g of an enolether intermediate as E/Z-mixture, contaminated with some impurities which were removed after the next step. This enolether was hydrolyzed by dissolving it in 35 ml of THF containing 12.5 ml of 25% aq. HCl. After 2.5 h at ambient temperature, the reaction mixture was poured onto crushed ice, extracted with ether, washed with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=98/2) yielded 1.76 g of (R)-3-[(1R,4aR,5S,8aR)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-butyraldehyde as colourless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(N1CCNCC1)(=O)=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CS(=O)(=O)N1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (830 mg, 2.0 mmol), 1-(methylsulfonyl)piperazine (394 mg, 2.4 mmol) and triethylamine (0.85 mL) in DMF (10 mL) was added HATU (910 mg, 2.4 mmol). The reaction mixture was stirred at rt for 2 h, diluted with H2O (˜15 mL) and the solids were collected by filtration, washed with H2O and dried under vacuum overnight to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(methylsulfonyl)-1-piperazinyl]carbonyl]-, methyl ester (1.08 g, 1.9 mmol, 96%) as a yellow solid. LCMS: m/e 562 (M+H)+, ret time 2.85 min, column B, 3 minute gradient.