Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[CH:7]=[N:6]1.[OH-].[Li+]>C1COCC1.O.CO.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4F)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.3 %

Procedure:
N-(3-(3-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) methanesulfonamide (200 mg) dissolved in 12.5 ml of THF-water-methanol (1:1:0.5) mixture and added lithium hydroxide (40.8 mg, 0.97 mmol) at 0° C. and stirred at room temperature for 15 h. The reaction was monitored by TLC (100% ethyl acetate in hexane) until TLC indicated that reaction was complete. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with water (2×25 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford crude product. Purification by preparative TLC (5% methanol in DCM) afforded 17 mg (14.99% yield) of tilted compound. 1H NMR (DMSO-d6, 300 MHz): δ 9.83 (s, 1H), 8.479-8.472 (d, 1H), 8.38 (s, 1H), 8.33-8.32 (d, 1H), 7.95-7.78 (m, 2H), 7.53-7.43 (m, 4H), 7.27-7.18 (m, 3H), 5.44 (s, 2H), 3.05 (s, 1H). MS: m/z=462.1 (M+1), HPLC: 95.83% in method A.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:11]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)N1CCCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride [5.14 g (50% oil dispersion); 0.107 mol] in 100ml of dry toluene was added to a 500 ml, 3-necked flask fitted with a mechanical stirrer. Azacycloheptan-2-one (10.07 g; 0.089 mol) was dissolved in 50ml of dry toluene with slight warming and added to the sodium hydride suspension dropwise at room temperature. The suspension was stirred at room temperature for 1 hour. n-Dodecanoyl chloride (19.39 g; 0.089 mol) in 10ml of dry toluene was added dropwise to the mixture and after the addition was complete, the mixture was stirred overnight at room temperature. The mixture was then washed with water, and the organic layer separated, dried with MgSO4, and concentrated. The resulting yellow oil was distilled 160° C./0.35mm to yield 1-n-dodecanoylazacycloheptan-2-one as clear oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([OH:13])=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:39]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:42]1[CH2:41][CH2:40][N:39]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43]1)=[O:13]
Reactant: O=C(O)[C@H]1COc2ccccc2O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2COc3ccccc3O2)CC1
Reaction time: 12 h

Procedure:
5 g of (2R)-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid (27.8 mmol) are dissolved in 300 ml of acetonitrile. 6 g of N,N′-dicyclohexylcarbodiimide (29.1 mmol) and then 4.1 g of 1-hydroxybenzotriazole (30.6 mmol) are added. Finally, 6.2 g of tert-butyl piperazine-1-carboxylate (33.4 mmol) are added and stirring is carried out for 12 hours at ambient temperature. The reaction mixture is subsequently filtered and the filtrate is then evaporated to dryness. The oil thereby obtained is purified by flash chromatography on silica (eluant: toluene/ethyl acetate 80/20) to yield the expected product in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:32])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:18][C@@H:17]([OH:19])[C@@H:16]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)[CH2:15]2)=[N:4][CH:3]=1>[Pd]>[NH2:21][CH2:20][C@@H:16]1[C@H:17]([OH:19])[CH2:18][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:32])[CH2:15]1
Reactant: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O)OCc1ccccc1
Agent: [Pd]
Product: NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reaction time: 18 h
Yield: 110.2 %

Procedure:
To a solution of phenylmethyl ({(3S,4S)-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)carbamate (1.7 g; 3.85 mmol) was added 10% Pd/C, degassed and placed under 1 atm of H2 for 18 h. The reaction mixture was filtered through Celite and concentrated to obtain the title compound as a yellow oil (1.3 g; 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])([O-])=O.NC1SC=C(C2C=CC(N)=CC=2)N=1.CCO>CN(C=O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14]
Reactant: O=C1NC(=O)C(=Cc2cccc([N+](=O)[O-])c2)N1
Agent: [Ni]
Agent: Nc1ccc(-c2csc(N)n2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cccc(C=C2NC(=O)NC2=O)c1

Procedure:
2.3 g (10 mmol) of crude 3-nitro-benzylidene-hydantoin, melting point 280-284° C., (prepared as described in Example 6 in (a)) are hydrogenated in 60 ml of DMF and 40 ml EtOH on 2 g of Raney nickel for 36 hours at 20° C. and 3.5 bar. It is filtered over kieselguhr and the filtrate is evaporated down in vacuo. The evaporation residue is crystallised with ether.
Reaction SMILES: [CH:1]1([N:6]([C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:7]2[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].Cl.CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]2[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)=[O:25])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(N(C(=O)c2ccc([N+](=O)[O-])cc2)C2CCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(N(C(=O)c2ccc(N)cc2)C2CCCC2)cc1
Reaction time: 4 h
Yield: 95.4 %

Procedure:
A solution of N-cyclopentyl-N-(4-nitrobenzoyl)-p-anisidine (1.0 g), 10% palladium on carbon (100 mg) and 2 drops of conc. hydrochloric acid in methanol (10 ml) was stirred under 3 atmospheric pressure of hydrogen at ambient temperature. After 4 hours, the reaction mixture was filtered through a bed of Celite, and concentrated to give N-(4-aminobenzoyl)-N-cyclopentyl-p-anisidine (870 mg), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])N.N([O-])=[O:12].[Na+]>S(=O)(=O)(O)O.O>[OH:12][CH:4]([CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CC(O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
805 mg (5.54 mmol) of 4-methylleucine (racemate) were initially charged in 11 ml of sulphuric acid (1M) and cooled to 0° C. 2.30 g (33.3 mmol) of sodium nitrite as a solution in 6.5 ml of water were then slowly added dropwise over a period of 90 min. The solution was stirred at RT for another 24 h. The mixture was carefully diluted with 10 ml of water and the aqueous phase was extracted five times with 10 ml of methyl tert-butyl ether. The combined organic phases were washed with 25 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was used for the next step without further purification. Yield: 667 mg (82% of theory)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.ClCCl>C(N(CC)CC)C>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:12])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCNC(=O)c2ccc3ccccc3n2)cc1
Yield: 27.5 %

Procedure:
Quinoline-2-carbonyl chloride (0.28 g in 10 ml dichloromethane, 1.46 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.49 g, 1.3 mmol), dichloromethane (140 ml) and triethylamine (0.5 ml). The reaction was maintained for 17 hours and then concentrated in vacuo. The yellow residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic fraction was dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash column chromatography (silica gel, gradient elution using dichloromethane to 95:5 Dichloromethane\methanol) to provide 0.19 g of N2-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-2-quinolinecarboxamide as an off white solid, m.p. 95.1-97.4° C. 1H NMR (360 MHz, DMSO-d6) δ 8.97 (t, J=6.0 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.16-8.07 (m, 3H), 7.96 (d, J=7.7 Hz, 1H), 7.87 (m, 1H), 7.72 (m, 1H), 7.58 (dd, J=8.3, 1.1 Hz, 1H), 7.31 (m, 1H), 7.23 (d, J=8.7 Hz, 2H), 7.08 (m, 1H), 6.82 (d, J=8.7 Hz, 2H), 6.58 (broad s, 2H), 4.50 (m, 2H), 4.33 (s, 2H), 3.63 (s, 3H), 3.34 (m, 2H), 1.65 (m, 4H); MS (EI) m/e 530.2431 (530.2430 calcd for C32H30N6O2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29](O)=[O:30].ClC(OC)=O.O.[NH2:38][NH2:39]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[O:24][N:23]=[C:22]([CH:25]([CH3:26])[CH3:27])[N:21]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29]([NH:38][NH2:39])=[O:30]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)n1
Reactant: NN
Agent: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)NN)c(F)c3)CC2)n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution [2-fluoro-4-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)phenyl]acetic acid (500 mg, 1.152 mmol) in 5 mL of THF cooled to −10° C. via dry ice/methanol bath was added TEA (0.177 mL, 1.268 mmol) followed by methyl chloroformate (0.098 mL, 1.268 mmol) and the resulting mixture stirred for 30 minutes at −10° C. (Precipitate formed after 1 minute of stirring). Filter off the precipitate and wash the solids with 10 mL THF. The filtrate was concentrated under reduced pressure and the residue was used as is for the next reaction sequence. To a solution of this mixed anhydride (265 mg, 0.539 mmol) in 1 mL DMF was added hydrazine monohydrate (0.052 mL, 1.077 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was diluted with ethyl acetate (3 mL) and washed with water (2 mL) followed by brine (2 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via preparative TLC plate (1000 μM, silica gel) developing with 5% methanol in DCM. The band containing the product was washed with 10% methanol in DCM to elute off the product. The solution was concentrated under reduced pressure to afford the product as a white solid. HPLC/MS; 1.35 min (2 minute run), 446 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@H:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:19][C:20]([C:22]2[N:23]([CH3:31])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[O:12])[C:8]#[N:9])=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CN1CCOCC1>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:8]([C@@H:7]([NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:19][C:20]([C:22]1[N:23]([CH3:31])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:12])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:33][CH:32]=1)#[N:9]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(N)cc2)cc2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(NS(C)(=O)=O)cc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
To 62 mg (0.14 mmol) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-(4-amino-benzyl)cyano-methyl]-carbamoyl}cyclohexyl)-amide dissolved in 1 mL DMF was added 16 mg (0.14 mmol) of methanesulfonyl chloride, 2 mg (0.014 mmol) of 4-dimethylaminopyridine, and 0.031 mL (0.28 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate, and concentrated. Reverse phase column chromatography was employed to separate the pure title compound from the unreacted starting material, and provided 10 mg of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-cyano-(4-methanesulfonylamino-benzyl)-methyl]-carbamoyl}-cyclohexyl)-amide. HPLC: 100% pure, yield: 14%, MS: 522 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([CH2:15]Br)=[CH2:14])=[CH:11][CH:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([CH2:15][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH2:14])=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: C=C(CBr)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 0.5 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride/oil (28 g, 0.7 mol @ 60%) in 800 ml of DMF, add in portions 1,2,4-triazole (50 g, 0.72 mol) at -10° to 0° C. Stir at 0.5° C. for 1 hour until soultion is clear brown. Add rapidly at -5° to 5° C. p-chloro-α-bromomethyl styrene (200 g, 0.86 mol total bromide, 0.56 mol allyl @ 65%). Stir and warm to room temperature over 2 hours. Evaporate off the DMF. Add saturated NaCl and extract the product with 2×300 ml of ethyl acetate. Dry the combined extracts over MgSO4 and filter. Evaporate the ethyl acetate and chromatograph the resultant oil on 2 Waters prep. 500 cartridges using ethyl acetate:hexane (1:1) as the eluent to obtain p-chloro-α-1H-1,2,4-triazolylmethyl styrene: 'HNMR (90 mHz, CDCl3) 8.06 (1 H, S), 7.93 (1H, S), 7.3 (H H, S), 5.59 (1H, S), 5.16 (3H, br S).
Reaction SMILES: [Si]([O:8][CH:9]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:10][CH:11]([OH:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(C(C)(C)C)(C)C.[SiH3]O[SiH3]>Cl.CO.CCO>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43]/[CH:42]=[CH:41]\[CH2:40]/[CH:39]=[CH:38]\[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:9]([OH:8])[CH2:10][CH:11]([OH:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(CCCCCCC/C=C\C/C=C\CCCCC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [SiH3]O[SiH3]
Solvent: CO
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(O)CCCCCCC/C=C\C/C=C\CCCCC
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
The silyl ether (6Z,9Z,29Z,32Z)-21-((tert-butyldimethylsilyl)oxy)octatriaconta-6,9,29,32-tetraen-19-ol (6) (2.44 g, 3.62 mmol) was dissolved in HCl—CH3OH (1%, 100 mL) and EtOH (40 mL). After stirring (45 min) the solution was concentrated and subjected to chromatography (10%→15% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-octatriaconta-6,9,29,32-tetraene-18,20-diol (7) (1.54 g, 76%) as a clear colorless oil. Rf 0.12 (10% EtOAc-hexanes), FW 558.96, C38H70O2.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCCCCCNc1ccc(Cl)cc1
Product: O=c1c(NCCCCCCNc2ccc(Cl)cc2)c(Nc2ccncc2)c1=O
Yield: 89 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and N-(4-chlorophenyl)-hexane-1,6-diamine.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].[CH:27](N1CCOCC1)=[O:28]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:27]=[O:28])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: O=CN1CCOCC1
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.0 ml (35.3 mmol) of TMP are initially introduced at −20° C. in 30 ml of THF, and 21.5 ml (34.2 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 11.8 g (34.0 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 70 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 90 min. The solution is cooled to −60° C., and 3.6 ml (36.0 mmol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 2 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is recrystallised from toluene. 5-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
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]([CH3:34])[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].CS(C)=O.[NH2:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.C(OCC)C>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:41][CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCc1cccnc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1C
Yield: 74.7 %

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (8.0 g, 15 mmol) and dimethyl sulfoxide (5.3 mL, 75 mmol) in dry acetonitrile (90 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (3.1 mL, 30 mmol) and the reaction mixture was heated to reflux for 48 hours. The cooled mixture was concentrated in vacuo, the oily residue redissolved in ethyl acetate (400 mL), washed with 1M sodium hydroxide (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a red foam. Purification by flash chromatography using a solvent gradient of 50 to 100% ethyl acetate in hexane gave a pale yellow foam. Trituration with hot diethyl ether (150 mL) afforded the title compound (5.9 g, 75%) as a pale yellow solid, m.p. 147-149° C. Alternatively, the title compound could be purified by HPLC (normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane, m.p. 148-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[CH:3][C:2]([C:27]2[C:22]([CH:21]=[O:20])=[C:23]([N:37]3[CH2:49][CH2:48][N:40]4[C:41]5[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=5[CH:47]=[C:39]4[C:38]3=[O:50])[N:24]=[CH:25][CH:26]=2)=[CH:7]1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3C=O)cn(C)c2=O)n[nH]1
Temperature: 100 °C
Yield: 35 %

Procedure:
A sealed tube was charged with 115a (280 mg, 1 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (420 mg, 1.1 mmol), PdCl2(dppf) (41 mg, 0.056 mmol), K3PO4 (100 mg), and NaOAc (50 mg) in CH3CN (10 mL) and H2O (3 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 115b in 35% yield (190 mg) as a pale yellow solid. MS: [M+H]+ 542.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[O:49][CH3:50]>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:43]([F:42])[CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(C(=O)N(C)C)c2)cc1F

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3-fluoro-4-methoxyphenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.