Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:60])[C@@H:25]([N:33]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:51][CH:50]=4)[C:34](=[O:47])[CH:35]=[CH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.CCOC(C)=O>CN(C=O)C>[CH2:26]([C@H:25]([N:33]([CH2:48][C:49]1[CH:50]=[CH:51][C:52]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:53][CH:54]=1)[C:34](=[O:47])[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1)[C:24](=[O:60])[N:21]1[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
4-(2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.75 g, 2.15 mmol) was dissolved in DMF (47.5 mL) and piperidine (2.5 mL) was added. Stirring was continued at rt for 30 min. EtOAc (150 mL) was added and the mixture was washed with water (2×150 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silicagel, MeOH/DCM=1/99) to give 1.05 g (82.5%) of N—((S)-1-Benzyl-2-oxo-2-piperazin-1-yl-ethyl)-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=0.97 min; [M+H]+=592.19.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH3:24][Mg]Br>C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18]([OH:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COC(=O)C(C)(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Under a nitrogen atmosphere, a solution of methyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-oxoacetate (360 mg, 1.09 mmol) in anhydrous diethyl ether (5 mL) was cooled to 0° C. Methyl magnesium bromide 3.0 M in diethyl ether (0.73 mL, 2.18 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 15 minutes, before being quenched with a minimum of water. Ethyl acetate (8 mL) was added and the mixture was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 80/20) to provide the desired alcohol (42b) (206 mg, 0.59 mmol, 55%) as a colorless oil.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH3:36][Bi:37](Br)[CH3:38]>C1COCC1>[CH3:36][Bi:37]([CH3:38])[C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH3:7])=[O:5]
Reactant: C[Bi](C)Br
Reactant: COC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)[Bi](C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Under argon gas atmosphere, 2.86 g (28 mmol) of methyl isobutyrate was dissolved in 25 ml of THF, and the solution was cooled to −78° C. To the solution was slowly added dropwise (for 10 minutes) 14.0 ml (28 mmol) of lithium diisopropylamide (Aldrich, a 2.0M heptane/THF/ethylbenzene solution thereof). While the mixture was gradually warmed (for 1 hour), the solution of 8.9 g of dimethylbismuthanyl bromide synthesized in Synthesis Example 6 in 25 ml of THF was added dropwise within the range of −40° C. to −30° C. to the mixture. Thereafter, the reaction solution was stirred until the solution temperature reached 0° C. (for 1 hour). The solids precipitated in the reaction solution were filtered off with quartz wool, THF was removed under reduced pressure, and the product was distilled under reduced pressure, giving 4.45 g of yellow oily material (46.7% yield, bp 59° C./2.0 mmHg). It was confirmed that the product was the desired one by MS (GCMS), 1H-NMR and 13C-NMR.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([Br:18])=[CH:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[K+].[Br-]>>[Br:18][C:9]1[CH:8]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=1
Reactant: COC(=O)COc1c(-c2ccccc2)cc(Br)cc1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc(Br)cc1-c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.062 g, 83%) from (5′-bromo-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp>50° C. (decomp.); 1H NMR (CDCl3) δ 3.81 (s, 2H), 7.38–7.50 (m, 7H), 7.52–7.56 (m, 5H); IR (KBr) 3400, 3050, 2900, 1730, 1565, 1495, 1460, 1420, 1210, 1060, 875, 735, 700, and 610 cm−1; mass spectrum [(+) FAB], m/z 382 (M)+, 405 (M+Na)+; Anal. Calcd. for C20H15BrO3: C, 62.68; H, 3.95; N, 0.00. Found: C, 62.25; H, 4.01; N, 0.01.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[CH:4]([CH2:21][OH:22])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH2:14])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19].[CH3:24][C:25](N(C)C)=[O:26].C(Cl)(=O)C>O>[CH3:1][NH:2][C:3](=[O:23])[CH:4]([CH2:21][OH:22])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH:14][C:25](=[O:26])[CH3:24])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19]
Reactant: CNC(=O)C(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)N(C)C
Solvent: CC(=O)Cl
Solvent: O
Product: CNC(=O)C(CO)NC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Reaction time: 20 h

Procedure:
82.4 g. (0.125 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-serine methylamide (IVb), m.p. 259°-260° C. (decomposition), is dissolved in 200 ml. of dimethylacetamide; under agitation, 33.4 ml. of acetyl chloride is added dropwise thereto. The reaction mixture is agitated for 20 hours, mixed with 40 ml. of water, and, after another 30 minutes of agitation, concentrated under vacuum. The residue is stirred overnight with 150 ml. of water, the precipitate is vacuum-filtered, stirred in 150 ml. of 1 N sodium hydroxide solution with the addition of 15 ml. of 37% strength sodium hydroxide solution and activated carbon for 2 hours, the activated carbon is removed, and the filtrate is brought to pH 1 with concentrated hydrochloric acid. After allowing the reaction mixture to stand overnight at 0° C., the precipitate is vacuum-filtered, washed with ice water, and dried under vacuum at 70° C.
Reaction SMILES: CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:28][C:29]1[C:34]([N+:35]([O-])=O)=[CH:33][C:32]([N:38]2[C:42](=[O:43])[N:41]([CH3:44])[N:40]=[N:39]2)=[C:31]([C@@H:45]2[CH2:47][C@H:46]2[C:48]([F:51])([F:50])[F:49])[CH:30]=1.CCO>[Pd].CC(O)=O>[NH2:35][C:34]1[C:29]([F:28])=[CH:30][C:31]([C@@H:45]2[CH2:47][C@H:46]2[C:48]([F:50])([F:49])[F:51])=[C:32]([N:38]2[C:42](=[O:43])[N:41]([CH3:44])[N:40]=[N:39]2)[CH:33]=1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2[C@@H]2C[C@H]2C(F)(F)F)c1=O
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1nnn(-c2cc(N)c(F)cc2[C@@H]2C[C@H]2C(F)(F)F)c1=O
Reaction time: 168 h
Yield: 80.2 %

Procedure:
Palladium on charcoal, wet (Degussa grade E101; 29 mg) was added to a mixture of trans-1-(4-fluoro-2-(2-(trifluoromethyl)cyclopropyl)-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (145 mg, 0.46 mmol), EtOH (10 mL) and AcOH (75 μL) under nitrogen. The mixture was evacuated and filled with hydrogen—this procedure was repeated another two times. The mixture was hydrogenated at 30 psi for 7 days (topping-off the hydrogen if necessary). More Pd on charcoal, wet (Degussa grade E101; 15 mg) was added and the mixture hydrogenated at 30 psi for another 10 days (LC/MS was used to monitor the progression of the reaction over the 2 week experiment). After complete reaction, the mixture was filtered through a small plug of Celite and the filter cake washed with EtOH (3×10 mL). The filtrate was concentrated under vacuum (dry-loaded on to silica) and purified by column chromatography on silica gel using EtOAc/hexane (1:4 to 2:3) as eluent to give the product (117 mg, 89%) as a solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[N:21]1[CH:26]=[C:25]([NH:27][C:28](=O)[O:29]C2C=CC([N+]([O-])=O)=CC=2)[CH:24]=[N:23][CH:22]=1>CC#N>[N:21]1[CH:26]=[C:25]([NH:27][C:28]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:29])[CH:24]=[N:23][CH:22]=1
Reactant: O=C(Nc1cncnc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: CC#N
Product: O=C(Nc1cncnc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.30 mmol, example 30 (step 1)) and 4-nitrophenyl pyrimidin-5-ylcarbamate (93.8 mg, 0.36 mmol) in MeCN (3 mL) was heated to 70° C. overnight, and then was subjected to microwave irradiation at 120° C. for 15 min. The mixture was filtered and the filtrate was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound in solution of H2O (0.1% TFA) and MeCN (0.1% TFA). The solvent was partially removed and saturated NaHCO3 (10 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 399 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:31])[C:3]=1[OH:32].O[C@@H:34]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([O:37]C)=[O:36].BrBr>>[Br:31][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:32][C@H:34]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([OH:37])=[O:36]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: CN(C)CCSc1c2ccccc2c(-c2cc(Br)c(O)c(Br)c2)c2c1sc1ccccc12
Agent: BrBr
Product: CN(C)CCSc1c2ccccc2c(-c2cc(Br)c(O[C@H](Cc3ccccc3)C(=O)O)c(Br)c2)c2c1sc1ccccc12

Procedure:
Prepared from of 2,6-dibromo-4-[6-(2-dimethylamino-ethylsulfanyl)-benzo [b]naphtho[2,3-d]thiophen-11-yl]-phenol (Example 66) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp 169-174° C.; NMR (DMSO-d6); δ13.3 (broad s, 1 H), 8.64 (d, J=8 Hz, 1 H), 8.04 (d, J=8 Hz, 1 H), 7.81 (ddd, J=8,7,1 Hz, 1 H), 7.76 (dd, J=16,1 Hz), 7.72-7.48 (m, 4 H), 7.42-7.22 (m, 7 H), 6.64 (d, J=8 Hz, 1 H), 5.32 (t, J=7 Hz, 1 H), 3.36-3.14 (m, 6 H); 2.64 (s, 6 H); MS (+FAB): [(M+H)+], 2 bromine isotope pattern, 734-(55%), 736 (100%), 738 (70%). Anal. calc. for C35H29Br2NO3S2; C, 54.45, H, 3.92, N, 1.81. Found: C, 54.46, H, 3.76, N, 1.66.
Reaction SMILES: [OH:1][C@@H:2]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][OH:5]>C(OCC)(=O)C.[Pd]>[OH:1][C@@H:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:4][OH:5]
Reactant: CCCCCCCCCCCCCC#C[C@H](O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCC[C@H](O)[C@H](CO)NC(=O)OC(C)(C)C

Procedure:
A solution comprising 2.49 g (6.08 mmole) of tert-Butyl (1S, 2S)-N-[2-hydroxy-1-(hydroxymethyl)-3-heptadecynyl]carbamate, Herold, Chim. Acta. 71: 354, 1988, and 20 mg of 20% Pd on carbon in 50 ml of ethyl acetate was hydrogenated on a Parr shaker at 3 atmospheres for 3 hours. The reaction mixture was filtered through Celite and the solvent removed under reduced pressure yielding tert-Butyl (1S, 2S)-N-[2-hydroxy-1-(hydroxymethyl) heptadecyl]carbamate having a mass of 2.53 g and of approximately 100%. Tert-Butyl (1S, 2S)-N-[2-hydroxy-1-(hydroxymethyl) heptadecyl]carbamate is a wax having a melting point of approximately 45° to 56° C. A 1H NMR analysis of the compound at 300 MHz using CDCl3 comprised the following peaks: δ0.887 (3H, t, J=6.7 Hz), 1.261 (26H, bs), 1.460 (9H, s), 2.054 (2H, bs), 3.589 (1H, bs), 3.820 (2H, bs), 3.941 (1H, bs) and 5.232 (1H, d, J=8.0 Hz). E;elemental analysis calculated for C23H47NO4 comprised the following constituents: C: 68.78, H: 11.79, N: 3.49. The values obtained experimentally comprised: C: 68.46,H: 11.71, N: 3.44.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:10][N:9]([C:11](=[O:32])[CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][C:15]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]3=[O:31])[CH2:8][C@@H:7]1[CH2:6][CH2:5][CH2:4][N:3]2C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@@:2]12[CH2:10][N:9]([C:11](=[O:32])[CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][C:15]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]3=[O:31])[CH2:8][C@@H:7]1[CH2:6][CH2:5][CH2:4][NH:3]2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CN(C(=O)CN3CCCC(c4ccccc4)(c4ccccc4)C3=O)C[C@]21C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]12CN(C(=O)CN3CCCC(c4ccccc4)(c4ccccc4)C3=O)C[C@@H]1CCCN2

Procedure:
The product from Example 88A was dissolved in methylene chloride and reacted with trifluoroacetic acid at ambient temperature for 1 hour. The reaction mixture was concentrated to yield the trifluoroacetic salt of the title compound. m/z 418 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.[Cl-].[Al+3].[Cl-].[Cl-].[BH4-].[Na+].O>O1CCCC1>[CH2:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:13])[F:14])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1O
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1c(Cc2ccccc2)cnc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of [4-hydroxy-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (17.0 g, 53.7 mmol) in tetrahydrofuran (270 mL), aluminum chloride (35.1 g, 263 mmol) and sodium borohydride (5.49 g, 145 mmol) were added at 0° C., stirred at room temperature for 30 minutes, and then refluxed for 5 hours. The reaction solution was brought to 0° C., added with water, and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was recrystallized with ethyl acetate, and the title compound (11.7 g, yield 72%) was obtained as a colorless crystal.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]1=[O:9].O.O.O.C([O-])(=[O:15])C.[Na+].C(=O)=O.CC(C)=O.C(OO)(=O)C.C(O)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[CH2:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3](=[O:9])[O:15]1
Reactant: C=C1C(=O)C2CCC1C2
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: O=C=O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: C=C1OC(=O)C2CCC1C2
Temperature: 0 °C
Yield: 247 %

Procedure:
98.7 g (0.81 mol) of 3-methylenebicyclo[2.2.1]heptan-2-one and 32.9 g (0.24 mol) of sodium acetate trihydrate in 400 ml of dichloromethane are used as the initial charge in a reaction vessel. While controlling the temperature (CO2/acetone bath), 230 g of 32% peracetic acid in acetic acid (0.97 mol) are then added dropwise in the course of 2.5 hours, at a temperature of from −8° C. to −10° C. with stirring. The reaction mixture is subsequently stirred at a temperature of −8° C. for a further hour. 200 g of ice are then added, followed by 20 g (0.16 mol) of sodium sulfite in 100 ml of water. The organic phase is separated off and washed with water, dried over magnesium sulfate and concentrated to yield, in the form of a liquid residue, 81.9 g of 4-methylene-3-oxabicyclo[3.2.1]octan-2-one with a 93% content and a yield of 68.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:21].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in 2 mL NMP and to this was added KOH (560 mg, 10 mmol) followed by 2-bromo-1-(4-chloro-phenyl)-ethanone (233 mg, 1 mmol) The reaction was kept overnight at RT. Water was added and the compound extracted with EtOAc. The organic layer was washed with water, concentrated and purified by column chromatography using silica gel (#100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified by reverse phase chromatography. 1HNMR (CD3OD, TFA salt) d (ppm): 8.10 (m, 2H), 7.60 (d, 2H), 7.50 (s, 1H), 7.30 (d, 1H), 7.10 (m, 1H), 5.80 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3.05 (s, 5H).
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](Cl)=[O:16])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.[F:24][C:25]1[C:30]([F:31])=[C:29]([C:32]#[N:33])[CH:28]=[CH:27][C:26]=1[OH:34].N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([O:34][C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[C:30]([F:31])[C:25]=2[F:24])=[O:16])[CH2:13][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: N#Cc1ccc(O)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C#N)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 0.1 mol of trans-4-octylcyclohexanecarbonyl chloride (prepared from the carboxylic acid with oxalyl chloride in toluene) and 75 ml of methylene chloride is added to a mixture of 0.1 mol of 2,3-difluoro-4-cyanophenol (prepared according to Example 4), 0.12 mol of pyridine, 10 mmol of 4-N,N-dimethylaminopyridine and 250 ml of methylene chloride. After the mixture has been stirred at room temperature for 10 hours, it is washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water. Customary working up gives 4-(trans-4-octylcyclohexanecarbonyloxy)-2,3-difluorobenzonitrile.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[C:7]([NH2:26])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([NH2:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(N)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC=CCC=CCCCCCCCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a 1-l flask equipped with a stirrer, a dropping funnel and a nitrogen gas inlet tube, 50 ml of tetrahydrofuran and 5.69 g (0.15 mol) of aluminum lithium hydride were charged, followed by the dropwise addition of 14.0 g (0.05 mol) of linoleic acid amide over 30 minutes while stirring at room temperature under a nitrogen gas atmosphere. After the completion of the dropwise addition, stirring was conducted for further 12 hours at 60° C. To the reaction mixture, 16 g (0.05 mol) of sodium sulfate decahydrate were charged, whereby excessive aluminum lithium hydride was decomposed. The solid content in the system was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 9.05 g of the title compound (11-v) were obtained in the form of a white solid (yield: 68% relative to linoleic acid amide).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][S:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]4=[O:36])=[CH:22][CH:21]=3)=[O:19])=[CH:16][N:17]=2)[CH:14]=1>O.CO>[CH3:7][S:8]([C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]4=[O:36])=[CH:24][CH:25]=3)=[O:19])=[CH:16][N:17]=2)[CH:14]=1)=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2ncc(C(=O)c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3)n2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3cnc4ccc(S(C)=O)cn34)cc2)C(=O)O1
Yield: 56.2 %

Procedure:
A solution of sodium periodate (0.067 g. 0.313 mM) in water (2.5 ml) was added to a stirred suspension of the title product from Example 37 (0.12 g. 0.283 mM) in MeOH (10 ml) and the mixture heated at gentle reflux for 3 hours. The mixture was filtered hot and allowed to cool. The solid which precipitated was filtered, washed with water and ether and purified by chromatography on a BondElut silica column with gradient elution increasing in polarity from dichloromethane to 10% MeOH/dichloromethane to give the title compound (0.07 g). MS: 441 (MH+); NMR 1.83 (3H, s); 2.9 (3H, s); 3.45 (2H, t); 3.83 (1H, m); 4.2 (1H, t); 4.75 (1H, m); 7.75 (2H, d) 7.9 (1H, m); 7.96 (2H; d); 8.05 (1H, d); 8.24 (1H, t); 8.36 (1H, s); 9.83 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:27][CH2:28][OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22](=[N:24][O:25]C)[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:27][CH2:28][OH:29])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]([C:22](=[N:24][OH:25])[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:14][CH:15]=1)=[O:6]
Reactant: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To a solution of 2 (1.49 g, 2.29 mmol), HBTU (1.3 g, 3.44 mmol), HOBt (530 mg, 3.44 mmol), and N,O-dimethylhydroxylamine HCl salt (340 mg, 3.44 mmol) in DMF (20 mL) was added DIEA (785 uL, 4.58 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The resulting residue was purified using silica gel (Hexanes/EtOAc=1:3) to give pure compound 3 (1.20 g, 78%) as an off-white, foamy solid.