Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[CH:14]=[CH:13]2)C.[OH-:21].[Na+].C(Cl)Cl.C1[CH2:30][O:29][CH2:28][CH2:27]1>>[NH2:20][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:30]([O:29][CH2:28][CH3:27])=[O:21])[CH:11]=2)[N:16]=1
Reactant: C1CCOC1
Reactant: CCOc1ccccc1-c1ccc2nc(N)ccc2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1-c1ccc2nc(N)ccc2c1
Reaction time: 72 h

Procedure:
To a microwave reaction vessel was added ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.7 g, 13 mmol), 6-bromoquinolin-2-amine (2.0 g, 9.0 mmol), PdCl2(PPh(t-Bu)2)2 (0.084 g, 0.13 mmol), potassium acetate (1.8 g, 18 mmol), EtOH (9.9 ml, 170 mmol) and water (2.4 ml, 134 mmol). The reaction mixture was heated at 85° C. for 8 h, and was then partitioned between EtOAc and water. The organic layer was washed with water and brine and allowed to stand for 72 h. The supernatant was decanted from the resulting precipitate and the precipitate was dried in vacuo to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 2 6-(2-Ethoxyphenyl)quinolin-2-amine (1.0 g, 3.8 mmol) was taken up in THF and then 5N NaOH was added and the solution was stirred for 72 h. DCM was added and the solid was filtered to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 3 A solution of 2-(2-aminoquinolin-6-yl)benzoic acid (50 mg, 0.19 mmol), 4-fluoropiperidine (25 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), DIEA (100 uL, 0.57 mmol), and DMF (1 mL) was heated in a shaker oven at 60° C. for 1 h. The resulting solution was purified by HPLC (CH3CN/water modified with 0.1% TFA) to give (2-(2-aminoquinolin-6-yl)phenyl)(4-fluoropiperidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])C)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25].C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:6][NH:7][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13]
Reactant: CN(CCNC(=O)c1nc(Cl)c(N)nc1N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A mixture comprising {2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester in DCM:TFA (60 mL of a 5:1 DCM/TFA solution) is stirred at RT for 3 h. The solvent is removed in vacuo and the resulting yellow oil is dissolved in water with heating. Any undissolved material is removed by filtration and the filtrate is concentrated in vacuo to afford the title compound. [M+H]+245.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([OH:15])[CH:13]=[CH2:14].C1(N(C)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH2:14][CH2:13][CH:12]=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCO
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=CCCc1ccc2ncccc2c1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Tris(dibenzylideneacetone)dipalladium (480 mg, 0.52 mmol) and tri-tent-butyl-phosphonium tetrafluoroborate (300 mg, 1.0 mmol) in a flask was evacuated and refilled with nitrogen (2 times). 1,4-dioxane (31 mL) was added followed by consecutive addition of 6-bromoquinoline (7.2 g, 35 mmol), 2-propen-1-ol (4.7 mL, 69 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (8.9 mL, 42 mmol). The reaction vessel was evacuated and refilled with nitrogen (2 times). The reaction mixture was stirred at 30° C. for 24 h. Diethyl ether (30 mL) was added to the reaction mixture and then filtered and washed with diethyl ether. The organic extract was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (0-50%) to afford the desired product. (˜55%) LCMS: (M+H)=186.0; (M+H2O+H)+=204.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].CO>O1CCOCC1>[ClH:24].[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:17]1[NH:16][N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3nccs3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1csc(-c2nc(C3CCNCC3)n[nH]2)n1

Procedure:
The mixture of 7.59 g of the crude product obtained in step 4 is dissolved in dioxane and 68 ml hydrogen chloride 4M sol. in dioxane is added slowly. The product appears as an oil. After addition of 542 ml methanol the oil is dissolved. The solution is stirred over night until precipitation of the crystalline product.
Reaction SMILES: [CH3:1][C:2]([OH:21])([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[N:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][N:8]=1)[CH3:3].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:3][C:2]1([CH3:1])[O:21][C:30](=[O:32])[N:6]([C:7]2[CH:12]=[N:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][N:8]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(O)CCNc1cnc(C#Cc2ccccc2)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CCN(c2cnc(C#Cc3ccccc3)cn2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
A solution of 2-methyl-4-(5-(phenylethynyl)pyrazin-2-ylamino)butan-2-ol (Example 168, step 2) (84 mg, 0.30 mmol) and triethylamine (91 mg, 125 μl, 0.90 mmol, 3 equiv.) in 2 ml of THF was cooled to 0-5° C. and triphosgene (89 mg, 0.30 mmol, 1 equiv.) was added in portions. The mixture was stirred for 1 hr at 0-5° C. and for 2 hours at room temperature. The reaction mixture was quenched with saturated sodium carbonate solution followed by workup with ethyl acetate/water. The organic layers were combined, dried and concentrated. The crude product was chromatographed over a prepacked 20 g Silica column eluting with a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (66.1 mg, 72% yield) as an off-white solid, MS: m/e=308.3 (M+H+).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:19]([N:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCNCCCCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CCCCC)CCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and diamylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([CH:19]1[CH2:21][CH2:20]1)=O)(=O)OC.O.[NH2:23][NH2:24]>>[CH:19]1([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:24][N:23]=2)[CH2:21][CH2:20]1
Reactant: COP(=O)(CC(=O)C1CC1)OC
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Solvent: O
Product: c1c(C2CC2)nnc2c1C1CCC2C1

Procedure:
MS (EI): 186.2 (M+), off-white crystalline solid. Prepared from bicyclo[2.2.1]heptane-2,3-dione, (2-cyclopropyl-2-oxo-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:4]1=[O:28])[CH3:2].Cl>CCOC(C)=O>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([N:5]3[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:11]4[N:3]([CH2:1][CH3:2])[C:4]3=[O:28])=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (100 mg) in EtOAc (2 mL) was added 4N HCl in AcOEt solution (2.0 mL). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was treated with sat.NaHCO3aq. and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. This residue was used for the next reaction.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].[H-].[Na+].Cl>C(OC(=O)C)C>[CH:8]1([C:7]2[C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[CH:3][C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a solution of 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b, 680 mg, 3.44 mmol) were added 2,2,2-trifluoroethanol (CAN 75-89-8, 1.03 g, 746 μl, 10.3 mmol) and sodium hydride 60% (551 mg, 13.8 mmol) by portions. The reaction mixture was stirred at room temperature for 30 min and then stirred at 120° C. for 18 h. The reaction mixture was cooled down, diluted with ethylacetate and poured in a separatory funnel. The mixture was extracted with an aqueous 4.0M solution hydrochloric acid (6.88 ml, 27.5 mmol). The organic phase was collected. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (420 mg, 47%) as light brown solid. MS (ESI, m/z): 260.2 (M−H+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH3:21])[CH:13]=3)[C:5]([F:24])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:20]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([C:6]3[C:5]([F:24])=[CH:4][N:3]=[C:2]([NH:1][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[C:7]=3[F:8])[C:10](=[O:23])[N:11]2[CH3:22])=[CH:16][N:15]=1)[CH3:21]
Reactant: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N)c1F)c(=O)n2C
Reactant: CCCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ncc(F)c(-c2cc3cnc(NCC)cc3n(C)c2=O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution 3-(2-Amino-3,5-difluoropyridin-4-yl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (15 mg, 0.05 mmol), triethylamine (3 ml), and DCM (10 mL) was treated with n-propanesulfonyl chloride (0.05 ml, 0.4 mmol) at 0° C. The mixture was allowed to warm to rt and was stirred for 16 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (10 mL) and potassium carbonate (2 g) was added. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate, then the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (2% to 3% methanol in DCM eluant) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[CH:19]=[O:20]>CN(C)C=O>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:19]=[O:20]
Reactant: Fc1ccc(S)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of 4-fluorobenzenethiol (0.93 g), potassium carbonate (3.1 g) and N,N-dimethylformamide (25 mL) was treated with 3,4-difluorobenzaldehyde (1.0 g), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate, and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a colourless gum (0.18 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Solvent: c1ccncc1
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
2-({1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (80 mg, 0.225 mmol) was dissolved in pyridine and propane-1-sulfonyl chloride (29 μl, 0.25 mmol) were added. The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. Toluene was added to the residue and the solvent was evaporated in vacuo (repeated twice). The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 36 mg (0.078 mmol, 35%).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4([C:29](=[O:38])[NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:19][C:18]=3[F:39])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.Cl.Cl.[N:43]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44]1.C(N(CC)CC)C.O>CN(C)C=O>[N:43]1([CH:47]2[CH2:52][CH2:51][N:50]([C:8]([NH:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]5([C:29]([NH:30][C:31]6[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=6)=[O:38])[CH2:27][CH2:28]5)=[O:25])=[CH:19][C:18]=4[F:39])[CH:15]=3)=[O:7])[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44]1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Reactant: C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)N1CCC(N2CCC2)CC1
Reaction time: 21 h
Yield: 68.8 %

Procedure:
[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (35.5 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (21 mg), triethylamine (0.0198 ml) and water (0.10 ml) were added thereto in this order, followed by stirring for 21 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (26.5 mg, 68.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][C:14]([O:16]CC2C=CC=CC=2)=O)[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][C:27]=1[O:35][CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1>>[CH3:1][O:2][C:3]([C:5]1([NH:13][C:14](=[O:16])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[C:27]([O:35][CH2:36][CH2:37][C:38]3[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=3)[CH:28]=2)[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CCCC(=O)CC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCCC(=O)CC1

Procedure:
1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester was hydrogenated in analogy to step 3 of example 51 and transformed into the title compound by reaction with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 3 of example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:16]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:16])=[N:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1
Reactant: CSc1cnc(N)cn1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1cnc(N)c(Br)n1
Reaction time: 0.5 h
Yield: 71967.6 %

Procedure:
To a solution of the compound obtained in Example 34 (1) (100 mg) in chloroform (18 ml), pyridine (56.0 mg) was added and then a solution of bromine (113 mg) in chloroform (18 ml) was added dropwise at 15 to 30° C. over 1 hour under light-shielding and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 112 g (72%) of the desired product as a white powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH2:27]([N:29]([CH2:39][CH3:40])[CH2:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH2:39]([N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:37][CH:38]=1)[CH3:40]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCN(CC)CCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-diethylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[C:25](I)=[CH:24][NH:23][C:17]=4[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([OH:30])(=[O:29])[CH3:28]>C([O-])(=O)C.[Ag+]>[C:27]([O:30][C:25]1[C:16]2[C:15]([C:13]3[CH:12]=[N:11][N:10]([C@@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:14]=3)=[N:20][C:19]([O:21][CH3:22])=[N:18][C:17]=2[NH:23][CH:24]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: COc1nc(-c2cnn(C(CC#N)C3CCCC3)c2)c2c(I)c[nH]c2n1
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: COc1nc(-c2cnn([C@H](CC#N)C3CCCC3)c2)c2c(OC(C)=O)c[nH]c2n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-cyclopentyl-3-[4-(5-iodo-2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.25 g, 0.54 mmol) in acetic acid (3 mL) was treated with silver acetate (0.27 g, 1.6 mmol) and heated to 70° C. for 16 h. The mixture was filtered, rinsed with MeCN, water was added to the filtrate and this mixture was stirred for 20 min, Solid sodium chloride was added to this solution. The product was obtained by extraction of this aqueous mixture with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. A portion of the product was used in the hydrolysis step (Step 4) without further purification. 1H NMR (300 MHz, CDCl3): δ 9.87 (br s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.33 (s, 1H), 4.22 (dt, 1H), 4.06 (s, 3H), 3.14 (dd, 1H), 2.94 (dd, 1H), 2.64-2.47 (m, 1H), 2.36 (s, 3H), 2.03-1.86 (m, 1H), 1.79-1.12 (m, 7H); LCMS (M+H)+: 395.1.
Reaction SMILES: C(OC(N[CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15]C1C=CC(CC(OCC)=O)=CC=1)=[O:14])=O)C1C=CC=CC=1.IC1C=CC(S(Cl)(=O)=O)=CC=1>[Pd]>[O:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[O:29][CH2:28][CH2:12][C:13]([NH2:15])=[O:14]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=S(=O)(Cl)c1ccc(I)cc1
Product: NC(=O)CCOC1CCCCO1
Yield: 307.7 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-iodobenzenesulfonyl chloride (1.31 g) to obtain (RS)-N-(4-(ethoxycarbonyl-methyl)phenyl)-2-(4-iodobenzenesulfonylamino)-N-(3-(tetrahydropyran-2-yloxy)propanamide (1.10 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([C@@H:13]3[CH2:15][C@H:14]3[C:16]#[N:17])[N:10]=[CH:9]2)C=CC=CC=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:16]([C@@H:14]1[CH2:15][C@H:13]1[C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)#[N:17]
Reactant: N#C[C@@H]1C[C@H]1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1C[C@H]1c1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of N-triphenylmethyl-4-(trans-2-cyano-cyclopropyl)imidazole (200 mg, 0.54 mmol) and trifluoroacetic acid (TFA) (10 mL) was stirred at room temperature for 1-3 hours. The TFA was evaporated under reduced pressure. The resulting mixture was diluted with distilled water (5 mL) and extracted with ether (3×15 mL). The aqueous layer was lyophilized to give the product as a solid (73 mg, 55% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)O)cc2)c1

Procedure:
3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7 g) and acetic anhydride (180 mg) and, after 14 hours, volatile fractions were removed. The residue was taken up in sodium hydroxide solution (2N) and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 255.28 (C15H13NO3); MS (ESI): 256 (M+H+).