Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[N:51][C:50]([NH:54][C:55]1[N:56]=[CH:57][C:58]([C:61]#[N:62])=[N:59][CH:60]=1)=[CH:49]2.[CH2:63]([CH2:65][NH2:66])[OH:64].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:64][CH2:63][CH2:65][NH:66][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[N:51][C:50]([NH:54][C:55]1[N:56]=[CH:57][C:58]([C:61]#[N:62])=[N:59][CH:60]=1)=[CH:49]2
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Reactant: NCCO
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1cnc(Nc2cc3cccc(NCCO)c3cn2)cn1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.020 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (23 mg, 0.040 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 5-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), ethanolamine (61 mg, 1.00 mmol) and caesium carbonate (130 mg, 0.40 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 140° C. for 40 minutes in a microwave reactor. Upon cooling the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%) and filtered through celite. The aqueous phase was re-extracted with ethyl acetate and then the combined organic phases were washed sequentially with aqueous sodium hydrogencarbonate and brine. The organic phase was dried (Na2SO4) and passed sequentially through two PS-Thiol cartridges and concentrated to dryness. Preparative HPLC gave the title compound (8.14 mg, 0.034 mmol, 17%). 1H NMR (d6-DMSO, 400 MHz) δ 10.94 (br s, 1H), 9.41 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.29 (s, 1H), 7.43-7.46 (m, 1H), 6.98 (d, 1H, J=8.4 Hz), 6.70 (br t, 1H), 6.50 (d, 1H, J=7.6 Hz), 4.82 (t, 1H, J=5.8 Hz), 3.65-3.70 (m, 2H), 3.25-3.30 (m, 2H, partially obscured by water signal). LC-MS (2) Rt=2.27 min; m/z (ESI+) 308 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:18]>C1COCC1.O>[C:2]1([NH:1][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:18])=[O:8])=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCCCC(=O)O1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
Aniline (0.6 g, 6.4 mmol) was added at room temperature to a stirred solution of oxonane-2,9-dione (1.0 g, 6.4 mmol) in THF anhydrous. After stirring at RT for 0.5 h, the resulting mixture was diluted with water (100 mL). The formed white solid was filtered and collected. Purification by silica gel column chromatography using as eluent EtOAc:cyclohexane=80:20 to 100:0 afforded 7-(phenylcarbamoyl)heptanoic acid as a white solid (174 mg, 11% yield).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[CH:19]([C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)=O.[OH-].[K+].Cl>CCO>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])/[CH:17]=[CH:19]/[C:21]3[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)c1ccc(CC2CCN(C)CC2)cc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A mixture of 1-[4-(1-methyl-piperidin-4-ylmethyl)-phenyl]-ethanone hydrochloride (prepared as described in Preparation 2, 426 mg, 1.59 mmol), 4-formylcinnamic acid (280 mg, 1.59 mmol) and 1.7 M KOH (2.8 ml) in EtOH (7 ml) was stirred at room temperature overnight. The mixture was acidified with 10% HCl and the resulting precipitate was filtered off to give 388 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][NH2:48]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:48][CH2:47][C:39]1[N:38]([CH3:37])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: Cn1c(CN)nc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nc3ccccc3n2C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1-methyl-1H-benzoimidazol-2-yl)-methylamine.
Reaction SMILES: F[C:2](F)(F)[CH2:3][CH2:4][C:5]([N:7]([CH3:28])[S:8]([N:11]1[C:16]2([CH2:18][CH2:17]2)[CH2:15][N:14]([C:19]2[C:20]3[CH:27]=[CH:26][NH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9])=[O:6].[CH:31]1(C(Cl)=O)CCC[CH2:32]1.CCN(CC)CC.O=S1(=O)CCC(C(Cl)=O)C1>C(Cl)Cl>[CH3:28][N:7]([S:8]([N:11]1[C:16]2([CH2:18][CH2:17]2)[CH2:15][N:14]([C:19]2[C:20]3[CH:27]=[CH:26][NH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9])[C:5]([CH:4]1[CH2:32][CH2:31][CH2:2][CH2:3]1)=[O:6]
Reactant: CN(C(=O)CCC(F)(F)F)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: O=C(Cl)C1CCCC1
Agent: O=C(Cl)C1CCS(=O)(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CCCC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 4 (0.071 mmol) was dissolved in dry DCM (1 mL) and added commercial available cyclopentanecarbonyl chloride (0.085 mmol) and Et3N (0.21 mmol). Stirred at rt for 1 h and then at 40° C. for 1.5 h. More 1,1-dioxothiolane-3-carbonyl chloride was added (2×0.107 mmol) with 1 h in between each portion. After being stirred at 40° C. for 1 h the reaction mixture was concentrated in vacuo, added 2,2,2-trifluoroethanol (1 mL) and stirred at 60° C. for 16 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:16]([C:5]1([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21

Procedure:
1.25 g (3.85 mmol) of tetrabutyl ammonium bromide (TBAB) was added to a solution of 25 g (77 mmol) of 2,7-dibromofluorene and 36 g (185 mmol) of n-octylbromide in 100 mL of toluene, and a solution of 31 g (770 mmol) of NaOH in 50 mL of water was added and refluxed for 2 days.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([C:16]([N:18]2[CH2:23][CH2:22][C:21]4([CH2:32][C:31](=[O:33])[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:34]6[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=6)[CH:29]=5)[O:24]4)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[C:11]3[C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46]C)=[O:45])=[CH:42][CH:41]=2)[CH2:5][CH2:4]1.CO.Cl>C1COCC1>[CH:3]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([C:16]([N:18]2[CH2:19][CH2:20][C:21]4([CH2:32][C:31](=[O:33])[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:34]6[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=6)[CH:29]=5)[O:24]4)[CH2:22][CH2:23]2)=[O:17])[CH:12]=[C:11]3[C:40]2[CH:49]=[CH:48][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(-c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)nc3c(C4CC4)cccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5ccc(C(=O)O)cc5)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
Aqueous 1N NaOH (0.500 ml, 0.500 mmol) was added to a stirred solution of methyl 4-(8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl)benzoate (160 mg, 0.255 mmol) in THF (1 ml)-MeOH (1 ml) and the mixture was stirred at room temperature overnight. Aqueous 1N HCl (0.5 ml) was added to the mixture and the solvent was evaporated under reduced pressure. The residue was suspended in CHCl3-MeOH (8:2) and the mixture stirred for 1 h. at room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CHCl3/MeOH=92/8) and the product was precipitated with CHCl3/hexane to give intended compound (106 mg, 0.173 mmol, 67.8% yield) as a pale yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([CH2:14][CH3:15])[C:10]=1[C:11](O)=[O:12]>>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([CH2:14][CH3:15])[C:10]=1[C:11]([Cl:3])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CCn1ncc(Cl)c1C(=O)O
Product: CCn1ncc(Cl)c1C(=O)Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (5 ml) was added to 4-chloro-1-ethyl-1H-pyrazole-5-carboxylic acid (1 g) and the reaction was heated at 80° C. for 6 h then cooled to room temperature overnight. The reaction was evaporated, then azeotroped with toluene to give title compound, 970 mg.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si:23]([O:30][C@H:31](/[C:35](/[CH3:43])=[CH:36]/[C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1)[CH2:32][CH2:33][OH:34])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[Si:23]([O:30][C@H:31](/[C:35](/[CH3:43])=[CH:36]/[C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1)[CH2:32][CH:33]=[O:34])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: C/C(=C\c1csc(C)n1)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A suspension of 478 mg (1.127 mmol, 1.3 equivalents) of Dess--Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one) in 5.6 ml of absolute CH2Cl2 is mixed with a solution of 284 mg (0.87 mmol) of 14 in 5.0 ml of absolute CH2Cl2 and stirred for 60 minutes at room temperature. After the solvent is distilled off in a vacuum, the residue is flash-chromatographed by a silica gel column with pentane/Et2O (4:1). 222 mg (0.68 mmol, 78%) of 15 is obtained.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:41][CH:40]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(Cl)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-(4-chlorophenyl)-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 61% yield, m.p. 195-196° C. MS [(+)ESI, m/z]: 590.20 [M+H]+
Reaction SMILES: CC(C)(OC(=O)[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([C:45]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[C:46]([OH:48])=[O:47])=[O:44])C.FC(F)(F)C(O)=O.O.C(#N)C>C(Cl)Cl>[NH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([C:45]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[C:46]([OH:48])=[O:47])=[O:44]
Reactant: CCCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
2-((2,2-Dimethyl-4-oxo-3,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-5-azatetracontan-40-yl)carbamoyl)-2-undecyltridecanedioic acid (5 mg, 4.68 μmol) was dissolved in DCM (Volume: 2 mL), then trifluoroacetic acid (25 μl, 0.324 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen atmosphere for about 2 hours. Complete conversion was observed by LCMS (Acidic Eluent A: Water+0.05% Trifluoroacetic Acid, Eluent B: ACN, column Sunfire C18 3.5 μm 3.0×30 mm −40° C., 5-95% gradient 2 minutes, retention time 1.45 min) The reaction mixture was concentrated under reduced pressure, then rinsed with DCM and concentrated again 3 times. Dissolved in a mixture of acetonitrile and DMSO. Purified on a MS-triggered HPLC (Sunfire 30×50 mm Sum column ACN/H2O w/0.1% TFA 75 ml/min 1.5 ml injection, 45-70% ACN 3.5 min gradient, retention time 2.50 minutes) and the fractions pooled and lyophilized to give 2.5 mg clean product in 55% yield. Clear oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:34])[C:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)([OH:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[CH:7]=1)=O)C.[H-].[Li+].[Al+3].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:3][CH2:4][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:34])[C:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)([OH:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18]2)[CH:7]=1
Reactant: CCOC(=O)c1ccnc(CN2CCC(NC(=O)C(O)(c3ccccc3)C3CCCC3)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(NC1CCN(Cc2cc(CO)ccn2)CC1)C(O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 92 mg of N-[1-(4-ethoxycarbonyl-2-pyridylmethyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide in 2 ml of tetrahydrofuran, 15 mg of aluminium lithium hydride was added at 0° C., followed by 2 hours' stirring at room temperature. To the reaction mixture 30 μl of 3N sodium hydroxide solution and anhydrous sodium sulfate were added, and the mixture was filtered with celite. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol=10/1] to give 36 mg of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][N:14]([CH3:30])[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C:19]([CH3:24])=[C:18]2[CH2:25][C:26]([O:28]C)=[O:27].CC(C)([O-])C.[K+]>COCCOC.CCOCC>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:20]2/[C:19]([CH3:24])=[C:18]([CH2:25][C:26]([OH:28])=[O:27])[C:17]3[C:21]/2=[CH:22][CH:23]=[C:15]([N:14]([CH3:30])[CH3:13])[CH:16]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: COC(=O)CC1=C(C)Cc2ccc(N(C)C)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1=C(CC(=O)O)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
p-Methylsulfonylbenzaldehyde (1.5 g) is added to a solution of methyl 5-dimethylamino-2-methyl-3-indenylacetate (2.5 g) from Example 3 Part B in 1,2-dimethoxyethane (1.5 ml) at 0° C. followed by the addition of potassium t-butoxide (1.1 g). The reaction mixture is kept in the ice-bath for 4 hours and at room temperature for 18 hours. The mixture is diluted with ether (15 ml), and the potassium salt is filtered off. The salt is dissolved in 30 ml of water and neutralized with dilute hydrochloric acid to pH 6-6.5. The crude acid precipitates, is collected by filtration and is recrystallized to give pure (Z)-1-(p-methylsulfonylbenzylidene)-5-dimethylamino-2-methyl-3-indenylacetic acid.
Reaction SMILES: [CH2:1]([N:8]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([N:8]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:9][C@H:10]([O:11][C:39](=[O:41])[CH3:40])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(N(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2C1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2ccccc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(R)-2-[Benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol (2.75 g) is dissolved in pyridine (15 mL). Acetic anhydride (1.66 g) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 18 hours. Water (10 mL) is added to quench the reaction. Ethyl acetate(250 mL) is added and the solution is washed with 1M KHSO4 (3×100 mL), saturated NaHCO3 (100 mL), water (100 mL) and brine (100 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 4:1 Rf=0.40).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:4]=1>Cl>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: COC(=O)CCc1c[n+](C)ccn1
Agent: Cl
Agent: [I-]
Product: C[n+]1ccnc(CCC(=O)O)c1
Yield: 57.6 %

Procedure:
1.0 g of 1-methyl-3-(2-carbomethoxyethyl)pyrazinium iodide was dissolved in 30 ml of 2N HCl and refluxed overnight. It was then concentrated, taken up in 100 ml of water and washed with methylene chloride. Concentration of the aqueous solution gave 0.55 g of 1-methyl-3-(2-carboxyethyl)pyrazinium iodide (3900) as an amorphous solid. UV H2O max: 226 (4.12), 281 (3.85).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:5][N:4]=1.[O:32]=[C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34](O)=[O:35]>CC(C)=O>[O:32]=[C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34]([O:30][C@@H:16]1[CH2:15][CH2:14][C@@H:13]2[C@@H:18]([C:19]3[C:24]([C:11]([C:6]4[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:31])=[N:4][CH:5]=4)=[N:12]2)=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:17]1)=[O:35]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1OC)=N[C@@H]1CC[C@@H](OC(=O)C(=O)CCC(=O)O)C[C@H]21
Yield: 71 %

Procedure:
(2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol ((42.7 mg, 0.1 mmol) are dissolved in 0.5 ml of acetone. 16.1 mg (0.11 mmol) of 2-oxo-pentanedioic acid (dissolved in 0.5 ml of acetone) are added. The crystals are filtered off and dried to obtain 40.6 mg (71%) of the title compound (m.p.: 124° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14](OC)=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21].[CH3:30][OH:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:18]([O:31][CH3:30])=[C:12]([CH:13]=[C:14]=[O:15])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(S(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Reactant: CO
Product: COC1=C(C=C=O)NC(C)=C(S(=O)c2ccc(OC)cc2)C1c1ccccc1Cl

Procedure:
A solution of (-)-4-methoxyphenylsulfinylacetone (10.0 g), prepared as in Preparation II above, 2-chlorobenzaldehyde (7.3 g), and NH4OAc (100 mg) in toluene (150 ml) was heated at reflux using a Dean-Stark water separator for 2 hours. About 90 ml of the solvent was removed in vacuo. Methyl β-aminocrotonate (11.5 g) and methanol (75 ml) were added to the remaining solution. After heating at reflux for 20 hours, the reaction mixture was cooled and evaporated to dryness. The residue was chromatographed on silica gel (1:1 dichloromethane/ethyl acetate) to give the two pure sulfinyldihydropyridine diastereomers in a ratio of approximately 10:1. The major isomer was (-)-4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfinyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, m.p. 188°-190° C., [α]D =-27° (C=0.060, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][C@H:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]([CH3:23])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+].C=O.C[O-].[Na+]>>[CH3:23][C@@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:24])=[CH:3][CH:4]=2)[CH2:14][C@H:13]([CH3:15])[N:12]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: C[C@@H]1CN(Cc2ccc(N)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: C=O
Agent: C[O-]
Agent: [BH4-]
Product: CNc1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R,6S)-4-[(4-aminophenyl)methyl]-2,6-dimethyl-1-piperazinecarboxylate (D8) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. for 48 h prior to addition of sodium borohydride then for 1 h after addition. Further paraformaldehyde (1 eq) and sodium methoxide (1 eq) were added; the reaction was heated at 50° C. for 12 h; further sodium borohydride (1 eq) was added and the reaction heated at 50° C. for 1 h. δH (CDCl3, 400 MHz) 7.16 (2H, d), 6.57 (2H, d), 4.05 (2H, m), 3.70 (1H, br s), 3.36 (2H, s), 2.82 (3H, s), 2.59 (2H, d), 2.06 (2H, dd), 1.49 (9H, s), 1.27 (6H, d). MS (ES+): 356.3 (MNa+), 234.3, no molecular ion (MH+) observed.