Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl-].[NH4+]>C(O)C.C(Cl)Cl.[Fe]>[NH2:30][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: N#CCC[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A suspension of trans 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl]-propionitrile (3.83 g, 8.50 mmol) in ethanol (28.5 mL, IMS grade) was treated with water (9.5 mL) followed by ammonium chloride (2.71 g, 50.7 mmol) and iron powder (1.89 g, 33.8 mmol) and the mixture was heated to 80° C. for 45 minutes. The solid was filtered and washed with ethanol (IMS grade). The filter cake was extracted repeatedly with DCM. The DCM extracts were washed with water and the aqueous layer was back-extracted with DCM (×2). The combined DCM extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum to give 2.08 g of crude product. The filtered cake, from above, was extracted repeatedly with 2M NH3 in MeOH. The washings were concentrated under vacuum and worked up to provide a further 190 mg of crude product. The remaining filter cake was stirred with DCM (35 mL) and the DCM decanted off, and then 20% [2N NH3 in MeOH] in DCM. The combined chlorinated extracts were filtered through Celite® to remove traces of iron residue and concentrated under vacuum to give a third batch of crude product (0.66 g). The three batches of crude product were dissolved in DCM, combined and concentrated under vacuum to give 2.97 g (83%) of trans 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl]-propionitrile as a pale brown solid that was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ: 8.01 (d, 2H), 7.66 (t, 1H), 7.57 (t, 2H), 7.54 (s, 1H), 7.46 (d, 1H), 6.66 (d, 1H), 5.10 (d, 1H), 4.33 (s, 2H), 3.68-3.56 (m, 1H), 2.01-1.91 (m, 2H), 1.81-1.72 (m, 2H), 1.50 (q, 2H), 1.38-1.19 (m, 3H), 1.17-1.04 (m, 2H) plus 2H obscured by solvent peak.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:7][N:6]=1)=[O:4].[OH-].[K+]>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Oc2ccccc2F)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Oc2ccccc2F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
5-(2-Fluoro-phenoxy)-pyrazine-2-carboxylic acid methyl ester (Preparation 44, 57.9 g, 233 mmol) was added to a solution of KOH (15 g, 267 mmol) in 78% ethanol (330 mL). The solution was stirred at room temperature for 18 hours, and the formed precipitate was collected by filtration. The resulting solid was dissolved in water (200 mL), and the solution was acidified with aqueous hydrochloric acid. The formed precipitate was collected by filtration, dried and recrystallised from 41% ethanol (265 mL) to give the title compound (28.3 g, 120.8 mmol) in 51.8% yield.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:44])[CH2:21][CH2:22][CH2:23][O:24]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:19])[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:44])[CH2:21][CH2:22][CH2:23][OH:24])=[O:19])[N:9]=1
Reactant: CN(CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCO)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.7 %

Procedure:
To a solution of 1-(2-iodophenyl)-N-methyl-N-(3-triphenylmethoxy-propyl)-3-isoquinolinecarboxamide (107 mg, 0.16 mmol) in CH2Cl2 (10 mL) was added dropwise TFA (1 mL). The mixture was stirred at room temperature for 40 min. Then it was transferred into a separatory funnel and washed with saturated NaHCO3 solution (2×10 mL), water (20 mL), and brine (20 mL), then dried (MgSO4), and filtered. After removing the solvent in vacuo, the residue was purified on column (silica gel, 2% MeOH/CH2Cl2, 0.1% Et3N), thereby affording starting material (5.2 mg) and the titled compound (51.2 mg, 73%). mp 51-52° C. 1H NMR (CDCl3) d 1.78-1.95 (m, 2 H, CH2), 3.12, 3.19 (two s, total 3 H, N--Me), 3.52-3.74 (m, 3 H), 3.82-4.32 (m, 2 H), 7.19-7.31 (m, 1 H, aromatic), 7.35-7.42 (m, 1 H, aromatic), 7.48-7.63 (m, 3 H, aromatic), 7.72-7.81 (m, 2 H, aromatic), 8.17, 8.26 (two s, total 1 H, aromatic). HRMS Cacld. for C20H19IN2O: 446.0491. Found: 446.0501.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:18][CH2:19][CH3:20])/[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH:28][C:29](=[O:41])[N:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:18][CH2:19][CH3:20])/[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:30]([CH3:31])[C:29]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:41])[CH:33]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)O)ccc1I
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2OCCCC)c1
Temperature: 80 °C
Yield: 23.5 %

Procedure:
0.2 g (0.5 mmol) of (Z)-3-(3-butoxy-4-iodophenyl)-2-ethoxyacrylic acid prepared as described in Example 23a and 0.2 g (0.6 mmol) of 3-(3-heptyl-1-methylureido)phenylboronic acid prepared as described in Example 25b are dissolved in 4 mL of a 75/25 solution of ethylene glycol dimethyl ether/water. After addition of 0.2 mL (1.1 mmol) of aqueous 2 M potassium carbonate solution, 0.004 mg (0.005 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium are added and the reaction medium is heated at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2, 7/3 and then 5/5 heptane/ethyl acetate mixture. 60 mg (23%) of (Z)-3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylic acid are obtained in the form of a beige-colored solid with a melting point of 103° C.
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[NH3:21]>CO>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([NH2:21])[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: N
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Solvent: CO
Product: CC(N)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 100 °C
Yield: 10 %

Procedure:
5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.2 g, 0.49 mmol) was dissolved in ammonia in MeOH (2 M, 8 mL). The resulting mixture was sealed in a steel bomb and was heated at 100° C. for 2 hours. The reaction mixture was concentrated and the crude solid was purified by silica gel chromatography using a 98:2 mixture of dichloromethane and methanol as eluent to afford the title product (16 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.38 (1H, m), 8.08 (1H, m), 7.99 (1H, m), 7.82 (1H, s), 7.71 (1H, m), 4.61(1H, m), 1.45 (3H, d). MS m/z: 331.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:11]=[C:10]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccc(F)cc1Cl
Reactant: CN1CCNCC1
Product: CNC(=O)c1ccc(N2CCN(C)CC2)cc1Cl
Yield: 52.5 %

Procedure:
A mixture of 316 mg (1.68 mmol) 2-chloro-4-fluoro-N-methyl-benzamide and 0.94 ml (8.4 mmol) 1-methylpiperazine was heated at 140° for 7 h in a sealed glass tube. After cooling to room temperature excess 1-methylpiperazine was removed by distillation at 50°/0.5 mbar. The residue was partitioned between 25 ml CH2Cl2/2 N NaOH solution. The layers were separated and the aqueous layer was extracted with 3 15-ml portions of dichloromethane. The combined organic extracts were dried (Na2SO4) and evaporated. Chromatography (SiO2, CH2Cl2/methanol 19:1) yielded 236 mg (52%) 2-Chloro-N-methyl-4-(4-methyl-piperazin-1-yl)-benzamide as a light yellow solid, MS (EI): 267 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].CN(C)C=O.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>C(#N)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[C:30]([F:29])([F:39])[F:40])[CH:10]=1)=[O:8]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3C(F)(F)F)c3ccccc3c2=O)cc1C

Procedure:
Compound 4kk was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 138.6 mg (0.50 mmol) of 3-(3,4-Dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 155.4 mg (0.65 mmol) of 2-trifluoromethylbenzylbromide. The crude product was purified by flash chromatography to yield 96 mg of 4kk as a colorless solid: LC-MSD, m/z for C26H20F3NO2, [M+H]+=436.5, [M+2H]+=437.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.709 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.32 (d, 6H), 5.60 (s, 2H), 6.92 (m, 1H), 7.17 (t, 2H), 7.39-7.47 (m, 3H), 7.54-7.60 (m, 2H), 7.65 (s, 1H), 7.79 (m, 1H), 8.22 (s, 1H), 8.50 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Br[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>O1CCOCC1.[Cu]I>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Brc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 125 °C
Yield: 87 %

Procedure:
A mixture of 4-bromobenzoylchloride (4.84 g, 22 mmol), 2-bromoaniline (3.8 g, 22 mmol), CuI (0.21 g, 1.1 mmol), Cs2CO3 (14.3 g, 44 mmol) and 1,10-phenathroline (0.398 g, 2.2 mmol) in anhydrous 1,4-dioxane (80 mL) was degassed and heated at about 125° C. under argon overnight. The mixture was cooled and poured into ethyl acetate (˜200 mL) and filtered. The filtrate was absorbed on silica gel, purified by column chromatography (hexanes/ethyl acetate 4:1), and precipitated by hexanes to give a white solid (5.2 g, in 87% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:13][C:12]2[C:11]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[CH:19][CH:18]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1>[F:33][C:31]([F:32])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][NH:14][C:11]2[C:12]3[S:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:8]=[CH:9][N:10]=2)=[CH:22][CH:21]=1)=[O:35]
Reactant: COC(=O)c1cc2ncnc(NCCc3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CCNc2ncnc3cc(C(=O)O)sc23)cc1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
To a solution of compound 26.1 (0.72 mmol) in THF (5.0 mL) was added aqueous 1.0 M LiOH (6.0 equivalents). The reaction mixture was stirred at 70° C. until all of the starting material was consumed. The reaction was cooled, neutralized with 10% HCl and concentrated to dryness under reduced pressure to provide 4-{2-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-ethylamino}-thieno[3,2-d]pyrimidine-6-carboxylic acid (compound 26.2).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[N:19][CH:20]=1)=[N+:13]=[N-:14]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:21][C:18]1[N:19]=[CH:20][C:15]([N:12]2[CH:2]=[C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][N:4]=3)[N:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)nc1
Reactant: C#Cc1n[nH]c2ccccc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cn1
Temperature: 80 °C

Procedure:
3-Ethynyl-1H-indazole (249 mg; 1.75 mmol; 1.0 eq.) and 5-azido-2-chloropyridine (270 mg; 1.75 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (11 mL). D-(−)-isoascorbic acid sodium salt (69 mg; 0.35 mmol; 0.2 eq.) was added followed by copper sulfate pentahydrate (17.5 mg; 0.07 mmol; 0.04 eq.) in water (3.7 mL) and the reaction mixture was heated at 80° C. for 2 days. The precipitate obtained was filtered, washed with water and EtOAc and dried under vacuum to afford the title compound as a beige powder. m.p.=272-280° C. 1H NMR (300 Mz, DMSO-d6) δ 13.40 (s, 1H), 9.44 (s, 1H), 9.16 (d, J=2.8 Hz, 1H), 8.56 (dd, J=2.9, 8.8 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.44 (m, 1H), 7.26 (m, 1H). HPLC (Condition A): Rt 3.30 min (purity 100%).
Reaction SMILES: [N:1]#[C:2][C@@H:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:4].[CH:10](OC(=O)C)=[O:11]>CCOCC>[CH:10]([NH:4][C@H:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]#[N:1])=[O:11]
Reactant: CCOC(=O)[C@@H](N)C#N
Reactant: CC(=O)OC=O
Solvent: CCOCC
Product: CCOC(=O)[C@H](C#N)NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-nitriloalaninate (26.9 g, 210 mmol) is dissolved in anhydrous ether (200 mL), and cooled in an ice/water bath. Acetic formic anhydride (prepared as a mixture as described above) is added dropwise. When the addition is finished, the reaction mixture is allowed to warm to RT and stirred at RT overnight. Most volatiles are removed in vacuo, and the residue solvents are removed by co-evaporation with toluene (100 mL×4). The red oil obtained precipitates upon scratching in ether, and the resulting solids are recrystallized in ether to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 8.32 (1H, s), 7.26 (1H, s), 6.46 (1H, bs), 5.56 (1H, d, J 7.8), 4.39 (2H, q), 1.37 (3H, t).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:15]([C:17]([O:19]C(C)(C)C)=[O:18])[N:16]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:13][C:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3)[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1ccc(-c2nc(C(=O)O)c(-c3ccc(Cl)cc3)[nH]2)cc1
Temperature: 25 °C

Procedure:
tert-Butyl 2-(4-acetoxymethylphenyl)-5-(4-chlorophenyl)-imidazole-4-carboxylate is dissolved in trifluoroacetic acid, and the solution is stirred at room temperature to give the objective 2-(4-acetoxymethylphenyl)-5-(4-chlorophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][N:33](C)[CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: Cc1ccccc1-c1cc(N2CCNCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 57.3 %

Procedure:
To a solution of 100 mg (0.173 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide (example 14 g) and 7 mg (0.035 mmol) 1,8-bis(dimethylamino)naphthalene in 1 ml 1,2-dichloroethane at 0° C. were added 26 mg (0.181 mmol) 1-chloroethyl chloroformate. After heating the reaction mixture for 1 h at 80° C. the solvent was removed in vacuo and the intermediate was purified by flash chromatography, re-dissolved in 1 ml methanol and refluxed for 3 h. Flash chromatography gave 56 mg (57%) of the title compound as white foam.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[C:25]2[C:26]3=[C:27]4[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[C:18]4[CH:17]=[CH:16][C:15]3=[CH:14][CH:13]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O>[O:7]=[C:1]([C:19]1[C:18]2[C:27]3=[C:26]4[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[C:25]4[CH:24]=[CH:23][C:22]3=[CH:21][CH:20]=1)[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1ccc2ccc3cccc4ccc1c2c34
Yield: 81.6 %

Procedure:
To a solution of 0.5 g (5 mmol) of succinic anhydride in 60 ml of nitrobenzene, 1.32 g (5 mmol) of anhydrous AlCl3 and 1 g (5 mmol) of pyrene were added at 0° C. After a reaction time of 18 hours at room temperature, the solution was poured onto 30 ml of iced hydrochloric acid (25%), forming a precipitate. Filtration and recrystallization from EtOH yielded 1.233 g (82%) of 4-oxo-4-(pyrene-1-yl)-butyric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH:13]=[C:12]([C:19]3[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=3[O:17][CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Reactant: COc1cc(OC)cc(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(N2CC=C(c3c(OC)cc(OC)cc3OC)CC2)cc1
Temperature: 90 °C

Procedure:
Compound of example 117 (19.0 g, 92 mmol) was added to a solution of 1,3,5-trimethoxybenzene (21.8 g, 130 mmol) in glacial acetic acid (50 mL) at 25° C. HCl gas was bubbled through the reaction mixture for 1 h, slowly raising the temperature up to 90° C. Acetic acid was removed under reduced pressure and the semisolid residue was poured over crushed ice (300 g). The resulting solution was made basic using an aqueous 50% NaOH solution. The precipitated solid was filtered, washed with water and dried. The solid was added slowly to boiling methanol, stirred for fifteen minutes and filtered to remove traces of trimethoxybenzene and the filtrate was concentrated to get the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:18])=[O:19])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:45])[NH2:39])=[CH:36][CH:37]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-5-(quinoline-8-sulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)([O-:22])=[O:21]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1nc(-c2ccccc2)cs1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-4-phenylthiazole (12.5 g, 80.9 mmol), 1-fluoro-2-nitrobenzene (12.5 g, 89.0 mmol), potassium carbonate (13.4 g, 97.1 mmol) was stirred at 150° C. for 24 h. Water (100 ml) was added and the mixture was extracted twice with 1,2-dichloroethane (50 ml). The crude extract was purified by chromatography on silica gel using toluene as eluent. The product was isolated as the free base. Yield 7.95 g, 33%. M.p.114-116° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH2:39][OH:40])[CH:35]=[C:36]([Cl:38])[CH:37]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:40][CH2:39][C:34]1[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([CH2:31][O:30][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(CO)c1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Cl)cc(COS(C)(=O)=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (7.8 mL, 56 mmol) and methanesulfonyl chloride (2.9 mL, 37 mmol) were added to a solution of [3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorophenyl]methanol (7.65 g, 18.6 mmol, from Step 2) in DCM (50 mL) at 0° C. The cooling bath was removed and after reaction mixture warmed to room temperature, the reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with two further portions of DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-40% EtOAc/hexanes. Yield: (6.8 g, 75%).