Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2 carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (42.8 mg, 34%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][N:12]=[C:11]2[C:7]=1[CH2:8][CH:9]1[C:14]([CH3:16])([CH3:15])[CH:10]12)=[O:5])C.CO.[OH-].[Li+]>C1COCC1>[CH3:15][C:14]1([CH3:16])[CH:9]2[CH2:8][C:7]3[C:11]([CH:10]12)=[N:12][NH:13][C:6]=3[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C2Cc3c(n[nH]c3C(=O)O)C21

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (0.0390 g, 0.177 mmol) was stirred for 18 hours at room temperature in a solution of 1:5:1 methanol:THF:1M aqueous lithium hydroxide (14 mL). Solvent was removed under reduced pressure, the residue was taken up in 1M aqueous hydrochloric acid (5 mL) and extracted into ethyl acetate (40 mL). Solvent was removed under reduced pressure and the residue purified by preparative HPLC to give a white solid. m/z (ES+): 215 [M+Na]+, 193 [M+H]+, 175 [M−OH]+; 1H NMR (CD3CN): δ 2.91 (dd, 1H, J1=17.4, J2=6.8), 2.66 (d, 1H, J=17.4), 2.11 (dd, 1H, J1=6.3, J2=1.2), 2.05–1.95 (m, 1H), 1.19 (s, 3H, exo-CH3), 0.77 (d, 3H, J=2.0, endo-CH3).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])(=O)C.C[CH2:24][N:25](C(C)C)[CH:26](C)C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[CH3:24][N:25]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH3:26]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2C)c(CN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To a solution of methyl 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylate obtained in step 3 (2.12 g; 8.27 mmol) in DCM (63.6 mL) was added at 0° C. DIEA (7.03 mL; 41.36 mmol) and methanesulfonyl chloride (768 μL; 9.93 mmol) at 0° C. and stirred at 25 min. After this time, dimethylamine (12.41 mL; 2 M; 24.81 mmol) was added to the reaction mixture and stirred at RT for 16 hours. Reaction mixture was partitioned between DCM and an aqueous solution of NaOH (5 M). Purification by silica column chromatography (DCM/[DCM/MeOH 2:1] gradient) gave the title compound as a light yellow solid (2.03 g, 86%). 1H NMR (DMSO-d6) δ 8.27 (d, J=1.4 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H), 7.32-7.18 (m, 4H), 7.06 (d, J=7.3 Hz, 1H), 3.94 (s, 3H), 3.24-3.10 (m, 2H), 2.11 (s, 6H), 2.01 (s, 3H). HPLC (Method A) Rt 2.90 min (Purity 100.0%). LC/MS (Method B): 284.1 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:33][C:27]1[CH:26]=[C:25]2[C:30]([N:31]=[CH:32][C:23]([C:2]#[C:1][C:3]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[N:4]=3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#Cc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Yield: 49.1 %

Procedure:
A mixture of 3-ethynyl-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (115 mg, 407 μmol, Eq: 1.00), 2,7-dichloroquinoxaline (89.2 mg, 448 μmol, Eq: 1.1) and triethylamine (61.8 mg, 85.2 μl, 611 μmol, Eq: 1.5) in tetrahydrofuran (3 ml) was purged with argon, then copper (I) iodide (3.1 mg, 16.3 μmol, Eq: 0.04), bis(triphenylphosphine)palladium(II) chloride (11.4 mg, 16.3 μmol, Eq: 0.04) and triphenylphosphine (4.27 mg, 16.3 μmol, Eq: 0.04) were added, the vessel was capped and heated for 18 hours to 75° C. The crude material was applied on silica gel and purified by flash chromatography to give 7-Chloro-2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylethynyl]-quinoxaline (89 mg, 49.1%) as yellow solid. MS: m/z=445.4 (M+H+)
Reaction SMILES: [H][H].[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3.CO.[OH-].[K+]>C(O)C.[Pd]>[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: [H][H]
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: C[C@]12CCCC[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12

Procedure:
250 mg of 16β fluoro-5-α-androsten-17-one in 50 ml of ethanol was treated with 50 mg of 5% palladium on carbon and hydrogen gas for 21/2hours. The reaction mixture, as indicated by the IR, is compatible with 16β-fluoro-5α-androstan-17-one. This crude product was treated with 5 ml methanol and 5 ml of 1N methanolic KOH for one hour. The mixturewas partitioned between methylene chloride and water and subjected to HPLC as indicated above. Crystallization of the less mobile component from methanol gave 30 mg of 16β-fluoro-5β-androstan-17-one as prismatic needles, melting point 148°-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(Cl)cc1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(Cl)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=310.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-chlorobenzene.
Reaction SMILES: OS(O)(=O)=O.[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7].[N+:17]([O-])([O-:19])=[O:18].[K+]>O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccccc1N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: -10 °C

Procedure:
To H2SO4 (98%, 389 mL) in a 500 mL 3-neck flask was added 2-tert-butyl aniline (40.6 mL). The reaction was cooled to −10° C. and KNO3 in 3.89 g aliquots was added every 6 min for a total of 10 aliquots. Tried to maintain temperature at −5° C. to −10° C. After final addition of KNO3, stirred the reaction for five min then it was poured onto ice (50 g). The black mix was diluted with H2O and extracted with EtOAc. The aqueous layer was basified with solid NaOH slowly then extracted with EtOAc (2×). The combined organic layers were washed with 6N NaOH and then with a mix of 6N NaOH and brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain crude 2-tert-butyl-5-nitro-aniline as a dark red-black oil which solidified when standing at RT. The crude material was triturated with about 130 mL hexanes. After decanting the hexanes, the material was dried to obtain a dark-red black solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.CON(C)[C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: Fc1ccccc1CBr
Reactant: CON(C)C(=O)c1ccc(I)cc1
Product: O=C(Cc1ccccc1F)c1ccc(I)cc1

Procedure:
The product was prepared from 2-fluorobenzyl bromide and O,N-dimethyl-4-iodobenzenehydroxamic acid (see Preparation 30) by a similar method to Preparation 20(i) as a colourless solid, m.p. 112-114° C.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[CH2:1]([S:8]([NH:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Br:19])=[O:28])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NS(=O)(=O)Cc1ccccc1
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)Cc1ccccc1
Yield: 23.9 %

Procedure:
The urea was synthesized from 2-(benzyl sulfonyl amino) aniline (1 mmol) and 2-bromo phenyl isocyanate (1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound (0.11 g, 23%). EI-MS m/z 460 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]C)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[C:33]#[N:34])=[CH:16][CH:15]=2)=[O:13])=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[C:33]#[N:34])=[CH:35][CH:36]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccc(Cl)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3CC3c3ccc(Cl)cc3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.2 %

Procedure:
methyl 7-(4-((2-(4-chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (50.7 mg, 0.101 mmol) was dissolved in THF (3 ml). A 1M solution of LiOH—H2O (0.202 ml, 0.202 mmol) was added and the mixture was stirred for 17 hours at ambient temperature. HCl (4M in dioxane) (0.0756 ml, 0.302 mmol) was added to the mixture. The solution was stirred additional 30 minutes and concentrated. The residue was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 47 mg of the title compound as a solid (95%). MS (apci) m/z=486.7 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CNc1cc([N+](=O)[O-])ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CNc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Reaction time: 1.25 h

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)-formamide (26 g, 0.143 mol) in DMF (180 mL) is added potassium carbonate (22 g, 0.159-mol), followed by benzyl bromide (27 g, 0.158 mol) at 60° C. The mixture is stirred for 1.25 h. The mixture is diluted with water. The precipitated solid is separated by filtration and washed with 1N HCl, water and hexanes, and air dried for 18 h to afford N-(2-benzyloxy-5-nitrophenyl)-formamide as a white solid: (M−H)−=271.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([F:9])([F:20])[F:21])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1C(F)(F)F
Yield: 91.5 %

Procedure:
4.57 g 3-amino-2-chloropyridine (36 mmol) and 30 mL pyridine were mixed in an ice bath. 8.24 g 2-trifluoromethyl benzoyl chloride (40 mol) was then added. After return to room temperature and reaction for 4 hr, the reaction was quenched by water. After extraction three times by ethyl acetate, an ethyl acetate layer was collected and washed by 1M HCl solution. After drying, filtration, concentration, and purification by silicon-gel column, 9.9 g solid was obtained, with a yield of 92%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29](CC3C=CC=CC=3)[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Solvent: CC#N
Product: CN(CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Yield: 82 %

Procedure:
Charge 4-[1-[2-(benzyl-methyl-amino)-ethyl]-4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.8 g; 0.0035 mol; 1.0 equiv) in ACN (40 mL) under nitrogen and add benzyl chloroformate drop wise at 0° C. Stir the reaction for 30 min and bring to RT. Stir at RT for 1.5 h. After completion, quench the reaction with saturated sodium bicarbonate solution and extract in EA. Wash with water and brine, dry over anhydrous sodium sulfate and evaporate off the solvent under vacuum. Purify on silica column using 15% EA/hexane to get the title compound (1.6 g; 82%). (ES+): m/z=555 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CCN(CC)CCN
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: CCN(CC)CCNC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(diethylamino)ethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1-diethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.55 (s, 1H), 8.48 (s, 1H), 8.10 (d, 1H), 7.56 (s, 1H), 7.47-7.50 (m, 1H), 7.33 (s, 1H), 7.10-7.14 (m, 2H), 3.44 (t, 2H), 3.25 (t, 2H), 3.08-3.14 (m, 4H), 2.62-2.72 (m, 4H), 2.42 (s, 3H), 2.27 (s, 3H), 1.05 (t, 6H). LRMS [M+H]=470.3
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:20][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to example 2.2 (b) from 2-chloro-5-methanesulfonyl-benzoic acid and cyclopentanol.
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>ClCCl>[N:35]1([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: CCCCCCCCCCCCC(O)CCCCC(=O)OC
Reactant: c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(CCCCC(=O)OC)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Methanesulfonyl chloride (0.39 ml, 4.99 mmol) was added dropwise to a stirred solution of methyl 6-hydroxyoctadecanoate (1.55 g, 4.94 mmol) and triethylamine (0.89 ml, 6.42 mmol) in dry dichloromethane (30 ml) at 0° C. The reaction mixture was warmed to room temperature after the addition, and stirred for 2 h. The reaction mixture was quenched with water, diluted with 50 ml of dichloromethane, and the organic layer was washed with water and brine solution, dried on anhydrous MgSO4, concentrated and evaporated under vacuum. This crude compound was combined with imidazole (0.67 g, 9.88 mmol) and heated at 80° C. for 16 h. Crude compound was purified on silica gel (2% methanol in dichloromethane) to obtain a light brown liquid (605 mg, 33.7%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]/[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Solvent: COCCOC
Solvent: O
Product: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2Z,6E)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6E,10Z)-2,3-epoxy-2,6,10-trimethyl-12 -[(tetrahydro-2H-pyran-2-yl)oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours and, after cooling to room temperature, poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6E,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3445 cm-1, 1648 cm-1, 1441 cm-1, 1375 cm-1, 901 cm-1.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:10]([N:12]([CH:14]([CH:39]([CH3:41])[CH3:40])[C:15]([NH:17][CH:18]([C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([CH3:38])[N:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1)=[O:16])[CH3:13])=[O:11])=O)CCC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:10]([N:12]([CH:14]([CH:39]([CH3:41])[CH3:40])[C:15]([NH:17][CH:18]([C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([CH3:38])[N:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1)=[O:16])[CH3:13])=[O:11]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nc(C)cc(=O)[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(=O)[nH]c(C(Cc2ccc(O)c(C(C)(C)C)c2)NC(=O)C(C(C)C)N(C)C(=O)C(N)Cc2ccc(F)cc2)n1
Yield: 88.3 %

Procedure:
To a solution of 2-(1-(2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methyl-butyrylamino)-2-(3-tert-butyl-4-hydroxyphenyl)ethyl)-6-methyl-4-pyrimidinone (B) (93 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The resultant mixture was stirred at room temperature for 1.5 hours and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (70 mg, 91.8%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[CH:34]=[C:35]([C:47]([O:49][CH3:50])=[O:48])[C:36]2[NH:37][C:38]3[CH:39]=[C:40]([OH:46])[CH:41]=[CH:42][C:43]=3[C:44]=2[N:45]=1.[O:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([C:47]([O:49][CH3:50])=[O:48])[C:36]2[NH:37][C:38]3[CH:39]=[C:40]([O:46][CH2:58][CH2:57][N:54]4[CH2:55][CH2:56][O:51][CH2:52][CH2:53]4)[CH:41]=[CH:42][C:43]=3[C:44]=2[N:45]=1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OCCN3CCOCC3)ccc12
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Diethyl azodicarboxylate (790 μL, 5.0 mmol) was added to a solution of triphenylphosphine (1.31 g, 5.0 mmol), methyl 2-bromo-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (800 mg, 2.49 mmol) and 2-morpholinoethanol (610 μL, 5.0 mmol) in dry THF (12 mL) at room temperature under nitrogen. After 1 hr, the reaction was partitioned between EtOAc and water and the organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was taken up in a 1:1 mixture of DCM:MeOH and the product was captured on a SCX cartridge and released with a 1:1 mixture of 2 N NH3 in MeOH:DCM. The solvent was removed and the product was purified by radial chromatography (step gradient elution with DCM containing 0 to 3% MeOH) to afford methyl 2-bromo-7-(2-morpholinoethoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (577 mg, 1.33 mmol, 53% yield) as a tan solid. MS (ESI) m/z 434.0 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 9.48 (1H, s), 8.21 (1H, d, J=9.32 Hz), 7.88 (1H, s), 6.89-7.00 (2H, m), 4.22 (2H, t, J=5.67 Hz), 4.04 (3H, s), 3.70-3.80 (3H, m), 3.69-3.81 (4H, m), 2.86 (2H, t, J=5.67 Hz), 2.55-2.65 (4H, m).