Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.Br[CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)CCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 25 mL round bottom flask was charged with polymer bound 7-chloro-3-(piperidin-4-yl)-1H-indole (1.0 g, 0.98 mmol), triethylamine (80.2 mL), tert-butyl 3-bromopropionate and dry acetonitrile (5 mL). The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3×10 mL) and dry dichloromethane (3×10 mL). The resin was treated for 20 minutes with 8 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w) (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (10 mL), a 1:1 mixture of dichloromethane:triethylamine (3×10 mL) and dry dichloromethane (3×10 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (1.0 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:20]=[C:10]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[N:11]=2)[CH:14]=1)[CH3:19]
Reactant: C=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Yield: 99.2 %

Procedure:
A solution of 60 mg of N-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide in 15 ml of methanol is hydrogenated at 25° C. for 45 minutes under 1 bar of hydrogen in the presence of 24 mg of 10% palladium-on-charcoal. As the reaction is incomplete, the product is recycled under the same conditions. After filtering, the reaction mixture is concentrated to dryness under reduced pressure. The residue is taken up in 50 ml of ethyl acetate. The organic phase is washed with water, separated by settling, dried and concentrated to dryness under reduced pressure to give 60 mg of 6-ethyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: OCCOCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCC(F)(F)F
Reaction time: 2 h

Procedure:
Combine 2-hydroxyethyl 2,2,2-trifluoroethyl ether (0.5 mmol) and N,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.6 mmol). After 2 hours, extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give 2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[NH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][CH:2]=1.C1([Mg]Br)C(C)=CC(C)=CC=1C.[CH:23](OC1C=CC=CC=1)=[O:24]>C1C2=CC3NC(C=C4N=C(C=C5NC(=CC(=N2)C1)C=C5)C=C4)=CC=3.C1COCC1>[CH:9]1[CH:8]=[C:7]([CH2:6][C:4]2[NH:3][C:2]([CH:23]=[O:24])=[CH:1][CH:5]=2)[NH:11][CH:10]=1
Reactant: c1c[nH]c(Cc2ccc[nH]2)c1
Reactant: O=COc1ccccc1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)CC4)[nH]3
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: O=Cc1ccc(Cc2ccc[nH]2)[nH]1

Procedure:
As part of our work in chlorin chemistry, we recently developed an efficient route for the synthesis of 1-formyldipyrromethanes.21 The formylation method entailed traditional Vilsmeier formylation or treatment of a solution of dipyrromethane in THF at room temperature with 2 molar equiv of MesMgBr and then at −78° C. with 2 molar equiv of phenyl formate. The subsequent workup and column chromatography afforded the desired 1-formyldipyrromethane in good yields.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:42](OCC)=[O:43])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[N:33]=3)=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)=O)C>C(O)C>[O:43]=[C:42]1[NH:5][C:3](=[O:4])[NH:2][C:9](=[O:8])[C:11]21[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[O:30][CH:31]=[C:32]([C:34]5[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=5)[N:33]=4)=[CH:25][CH:24]=3)=[N:18][CH:17]=1)[CH2:13][CH2:14][CH2:15]2
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(-c3nc(-c4ccc(C#N)cc4)co3)cc2)nc1
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(-c2coc(-c3ccc(Oc4ccc(N5CCCC56C(=O)NC(=O)NC6=O)cn4)cc3)n2)cc1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
To a flame dried flask was added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution was stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) was added and the solution was stirred at room temperature for 5 minutes. 1-(6-{4-[4-(4-Cyano-phenyl)-oxazol-2-yl]-phenoxy}-pyridin-3-yl)-pyrrolidine-2,2-dicarboxylic acid diethyl ester (300 mg, 0.54 mmol) was added as a solid and the solution was heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction was then quenched by the addition of 10 mL water and 1N hydrochloric acid was added to adjust the pH to 5. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce 290 mg of crude product. This material was chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40 s column) to provide 78 mg of a product which required further purification. Reverse-phase HPLC on a portion of this material provided 15 mg of the title compound as a white solid. MS m/z: ESI+ 521.1 (M+H)+; ESI− 519.3 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 72.5 °C
Yield: 83.4 %

Procedure:
The compound of Example 21 was also prepared according to the following method. To a solution of 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl)oxy]-2-fluorobenzoic acid (Preparation 265, 45.0 g, 131.52 mmol) in tetrahydrofuran (180 mL) at room temperature was added methansulphonamide (25.02 g, 263.04 mmol), N-ethyl-N-diisopropylpropan-2-amine (68.81 mL, 394.56 mmol) and 1-propanephosphonic acid cyclic anhydride (167.36 g, 263.04 mmol as a 50% solution in ethyl acetate) and the mixture stirred and heated at 70-75° C. for 16 hours. The reaction mixture was concentrated under reduced pressure at 45° C. and water added (450 mL), the resulting slurry was stirred for 30 minutes, filtered and dried. The crude product was dissolved in 2-propanol (1285 mL) at 85° C. and cooled slowly over 16 hours. The resulting slurry was filtered, washed with 2-propanol (2×40 mL) and dried to give the title compound as an off-white solid (46 g, 83%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[N:12]=1)(C)(C)C.[BrH:30]>C(O)(=O)C.CCOCC>[BrH:30].[BrH:30].[BrH:30].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[O:15])[N:12]=1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)OC(C)(C)C)n3)CC2)CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
47.2 To a stirred suspension of 3.9 g (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester was added 40 ml of 33% HBr in acetic acid. The reaction mixture was stirred at r.t. for 4 h. The mixture was left overnight in the fridge. Then it was concentrated to leave an off-white solid which was suspended in 50 ml Et2O, triturated and stirred at r.t. for 3 h. The product was collected by filtration, washed with Et2O and dried to give 5.6 g 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide. Off-white solid. MS 324.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Product: Cc1cc(C)cc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3,5-dimethylbenzene-1-sulfonyl chloride.
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].[CH3:21][NH2:22]>O1CCCC1>[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]([NH:22][CH3:21])[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CN
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Solvent: C1CCOC1
Product: CNC(C)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 80 °C
Yield: 34 %

Procedure:
To a solution of 5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.1 g, 0.243 mmol) in tetrahydrofuran (5 mL), was added N-methylamine (0.012 mL, 0.29 mmol). The resulting reaction mixture was heated at 80° C. under microwave irradiation (200 W) on a CEM Discovery™ microwave machine for 50 minutes. The reaction mixture was concentrated and the crude was purified by silica gel chromatography to afford the title compound as a yellow solid (30 mg, 33% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.83 (2H, m), 7.54 (1H, m), 7.49 (1H, s), 3.83 (1H, q), 2.44 (3H, s), 1.32 (3H, d). MS m/z: 376.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13](O)([C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][Si](C)(C)C>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([Cl:25])([C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(O)(c1ccc(OCc2ccccc2)cc1)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: CS(C)=O
Product: CC(C)(C)C(Cl)(c1ccc(OCc2ccccc2)cc1)C(C)(C)C

Procedure:
A reaction and post-treatment were conducted following the conditions of Example 71 using 5.40 g (13.65 mmol) of 4-benzyloxy-di-t-butylbenzyl alcohol, 80 ml of chlorotrimethylsilane, and 1.07 ml of dimethylsulfoxide, to obtain 4-benzyloxy-di-t-butylbenzyl chloride.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: C1CCNC1
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1CN1CCCC1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 41.2 mg, 0.126 mmol), pyrrolidine (52.6 μL, 0.630 mmol) and potassium carbonate (34.8 mg, 0.252 mmol) was suspended in anhydrous N,N-dimethylformamide mL), and the reaction mixture was stirred at 50° C. for 1 hour. After cooling down, it was diluted with ethyl acetate (50 mL). The whole was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (36.1 mg) as a colorless solid: (Yield 79%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1I.[F-].[K+].O>CN(C=O)C.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].C(Cl)Cl>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:26]=1[C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccnc1-c1cc(C(F)(F)F)ccc1Br
Yield: 64.6 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.233 g, 0.285 mmol), 1-methyl-2-(tributylstannyl)imidazole (2.189 ml, 6.84 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (0.919 ml, 5.70 mmol), and potassium fluoride (1.656 g, 28.5 mmol) in 6 mL DMF was heated to 80° C. overnight. LC/MS showed product, so the reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 2-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-imidazole (1.122 g, 3.68 mmol, 64.5% yield). m/z (ESI) 307.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCCC2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (20%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:10]([C:11]3[CH:12]=[C:13]([CH3:14])[CH:17]=[CH:18][CH:19]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Br)cc1O
Product: Cc1cccc(-c2nc3ccc(Br)cc3o2)c1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 3-methyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:23]([CH3:39])=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].CO.[OH-].[Li+].O>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:23]([CH3:39])=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn([C@H]4CC[C@H](C(=O)O)CC4)c3C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl trans-4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-3,5-dimethyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (9.00 mg, 0.0163 mmol) in MeOH (1 mL, 30 mmol) was added lithium hydroxide (1.95 mg, 0.0814 mmol) and H2O (0.4 mL, 20 mmol). The mixture was stirred at rt for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water at pH 2. The organic layer was concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=525.21/527.21 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:17])[C:8]1[C:13](I)=[CH:12][CH:11]=[N:10][C:9]=1[O:15][CH3:16])([CH3:4])([CH3:3])[CH3:2].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:15][CH3:16])[C:8]=2[C:7](=[O:17])[NH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccc(I)c1C(=O)NNC(C)(C)C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2C(C)(C)C
Yield: 53.8 %

Procedure:
A solution of N′-tert-butyl-4-iodo-2-methoxynicotinohydrazide (1.00 g), L-proline (0.066 g), potassium carbonate (0.792 g) and copper(I) iodide (0.055 g) in DMSO (30 mL) was stirred under nitrogen atmosphere at room temperature for 6 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (341 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:18]([CH3:21])([CH3:20])[CH3:19])=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])[CH:8]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:36])[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>CN(C=O)C.O>[F:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:2][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([CH3:36])[C:31]([OH:33])=[O:32])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2cc(COc3ccc(CC(C)C(=O)O)cc3)ccc2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction mixture of compound A (30.0 mg, 97.8 μmol), compound 12.3 (22.4 mg, 108 μmol) and cesium carbonate (38.2 mg, 117 μmol) in DMF (1.0 mL) was stirred at room temperature overnight. The resulting reaction mixture was treated with lithium hydroxide (23.4 mg, 978 μmol) in water (0.5 mL), and stirred at room temperature for 5 hours. The reaction mixture was purified by reverse phase preparative HPLC to give the title compound. MS ESI (neg.) m/e: 449 (M−H). 1H NMR (CD3CN) δ 7.61(d, 1H), 7.41(d, 1H), 7.11(d, 2H), 7.06(m, 2H), 6.93(m, 1H), 6.89(d, 2H), 6.81(d, 1H), 5.02(s, 2H), 3.77 (s, 3H), 2.86(dd, 1H), 2.63(m, 2H), 1.21(s, 9H), 1.09(d, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[C:48]([N:51]3[CH2:56][CH2:55][CH2:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]3=[O:64])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO>Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:15][CH:16]=2)[C:8]2[CH:47]=[C:48]([N:51]3[CH2:56][CH2:55][CH2:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]3=[O:64])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 55 from 4'-[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine (100 mg, 0.304 mmol), succinic anhydride 31 mg, 0.304 mmol) and triethylamine in methylene chloride was stirred at rt. overnight. The mixture was quenched with water, and extracted with methylene chloride. The organic layer was separated, dried and concentrated to give a solid. The title compound was isolated as a white crystal after silica gel column chromatography.