Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:28]([O-:30])=[O:29])=[C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].C1N=C[N:33](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[OH:1][C:2]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:28]([O-:30])=[O:29])=[C:16]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([NH2:33])=[O:27])[CH2:23][CH2:24]3)[CH:17]=2)[CH2:9][CH2:10]1)([CH3:4])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(=O)O)CC3)c2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(N)=O)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid (0.53 g, 1.263 mmol) in DMF (5 mL) was added CDI (0.410 g, 2.53 mmol). The reaction was stirred at RT for 1 hour, and then concentrated aqueous ammonium hydroxide (0.098 mL, 2.53 mmol) was added, and the reaction was stirred overnight. After 16 hours, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with 50-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxamide as an orange powder (0.39 g, 73.8% yield). MS, m/z (C22H34FN4O4): calcd, 418.3. found, 419.1 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3C(OCC3C=CC=CC=3)=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(C3CCCN3)cc1)C2c1ccc(F)cc1
Yield: 11 %

Procedure:
Benzyl 2-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)phenyl)pyrrolidine-1-carboxylate (60 mg, 0.107 mmol) was dissolved in distilled methanol (15 mL), and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen in the presence of a catalytic amount of palladium on carbon (11 mg, 0.01 mmol) for 2 hrs. After the reaction was completed, the catalyst was removed by filtration through a pad of Celite, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM=1:10) to give the title compound (5 mg, yield 11%) as a white foam. LC-MS (ESI) m/z: 426 (M+1)+ 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.78-1.88 (m, 1H), 1.95-2.08 (m, 2H), 2.24-2.32 (m, 1H), 3.05-3.12 (m, 1H), 3.21-3.27 (m, 1H), 4.17-4.21 (m, 1H), 4.34-4.36 (d, J=8.0 Hz, 1H), 4.75-4.77 (d, J=8.0 Hz, 1H), 6.91-6.95 (m, 2H), 7.09-7.15 (m, 2H), 7.17-7.25 (m, 1H), 7.22-7.25 (m, 1H), 7.29-7.34 (m, 4H), 7.55-7.57 (m, 1H), 7.63-7.67 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Br:40][C:41]1[CH:42]=[C:43]([NH2:48])[C:44]([NH2:47])=[CH:45][CH:46]=1>C(Cl)Cl.O>[NH2:47][C:44]1[CH:45]=[CH:46][C:41]([Br:40])=[CH:42][C:43]=1[NH:48][C:14](=[O:16])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:13])[CH3:17]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(benzyloxy)carbonyl]-2-methylalanine (Preparation 56, 35 g, 0.15 mmol) in DCM (600 mL) was added HOBt (25 g, 0.18 mmol) followed by EDCI.HCl (35.5 g, 0.18 mmol) and the reaction stirred at room temperature for 30 minutes. 4-Bromobenzene-1,2-diamine (30.7 g, 0.16 mmol) was added and the reaction heated to reflux for 24 hours. The reaction was cooled and poured into water (500 mL). The organic layer was separated, washed with water (200 mL), brine (100 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound as a brown solid that was taken directly on to the next step (80 g, 66%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[K+].[C:10](=[O:17])([S:14][CH2:15][CH3:16])[O:11][CH2:12]I>>[C:10](=[O:17])([S:14][CH2:15][CH3:16])[O:11][CH2:12][O:7][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)[O-]
Reactant: CCSC(=O)OCI
Agent: [K+]
Product: CCSC(=O)OCOC(=O)CNC(C)=O
Reaction time: 48 h

Procedure:
Finely powdered potassium N-acetylglycinate (5.8 g, 37 mmol) and TBA I (1.2 g, 3.4 mmol) are thoroughly mixed and shaken for 5 min with 5b (8.3 g, 34 mmol). The mixture is left for 48 h at room temperature and then extracted with Et2O (4×40 mL). The combined extracts are filtered and evaporated. The residue (6.4 g) is thoroughly extracted with pentane (4×25 mL) to remove unreacted 5b. The residue is freed from remaining traces of pentane by evaporation leaving 3.7 g of 6tb (46%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>CC(C)=O.BrCCCCC(OC)=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
A mixture in acetone of 4-phenylphenol (0.85 g, 5.0 mmol) and potassium carbonate (0.76 g, 5.5 mmol) was stirred for 30 minutes. Neat methyl 5-bromovalerate (0.78 mL, 5.5 mmol) was added dropwise via syringe and the reaction mixture was stirred for 2 hours at ambient temperature and overnight at reflux. Catalytic KI was then added and the reaction mixture was heated overnight at reflux. An additional 10 drops of methyl 5-bromovalerate was then added and reflux was continued for 8 hours. The reaction mixture was cooled to ambient temperature and filtered. The collected solid was washed with acetone and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between ethyl ether and water. The aqueous phase was extracted with ethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(4-phenylphenoxy)pentanoic acid methyl ester (1.66 g) as a white powder.
Reaction SMILES: [C:1]1(=[O:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5](=[O:14])[C:4]=2[C:3](=[O:15])O1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:18]1([N:17]2[C:1](=[O:16])[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[NH:6][C:5](=[O:14])[C:4]=3[C:3]2=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2c1c(=O)[nH]c1ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1c2c(c3ccccc3[nH]c2=O)C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of Furo[3,4-c]quinoline-1,3,4(5H)-trione (215 mg) and aniline (93 mg) in dry dimethylformamide (3 mL) was heated at 100° C. for 5 min. After coolong to room temperature 1,1'-Carbonyidiimidazole (200 mg) was added. The reaction mixture was then heated again to 100° C.. for an additional 5 min. After cooling the reaction mixture was poured onto water to afford 2-Phenyl-pyrrolo[3,4-c]quinoline-1,3,4(5H)-trione (Compound 1) as yellow crystals melting at >390° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[O:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].CO.NN>C1COCC1>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[O:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)co1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)co1
Reaction time: 24 h

Procedure:
N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-furancarboxamide (200 mg, 0.38 mmol) was dissolved in THF (10 mL) and MeOH (10 mL) at RT and treated with hydrazine (0.19 mL, 3.8 mmole). After 24 h, the solution was concentrated and purified on silica using 8% MeOH in DCM (1% NH4OH) to give the title compound as a white solid. The free base was dissolved in DCM (5 mL) and treated with 4M HCl in dioxane (4 mL). After 5 min, the reaction solution was concentrated under vacuum to give the title compound (55 mg) as a di-HCl salt: LC-MS (ES) m/z=393 (M+H)+, 1H NMR (d6-DMSO) δ 8.78 (d, J=8.9 Hz, 1H), 8.38 (s, 1H), 8.16 (bs, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.59 (m, 2H), 7.49 (s, 1H), 7.44 (m, 1H), 7.35 (s, 1H), 6.58 (s, 1H), 4.52 (m, 1H), 3.99 (s, 3H), 3.22 (m, 2H) and 3.07 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])=[CH:4][CH2:5][CH2:6][C:7]([CH3:11])(O)[CH:8]=[CH2:9])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:21]>CCCCCC>[Br:21][CH2:9][CH:8]=[C:7]([CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]([CH2:12][CH3:13])[CH2:1][CH3:2]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(CC)CC
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCC(=CCCC(C)=CCBr)CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
18.2 g. of 7-ethyl-3-methyl-1,6-nonadien-3-ol, 100 ml. of hexane and 1 ml. of anhydrous pyridine are cooled to -15° C. and treated dropwise in the course of 1.5 hours with a solution of 4 ml. of phosphorus tribromide in 50 ml. of hexane, the temperature being maintained at between -15° C. and -10° C. The mixture is stirred for a further 1.5 hours during which time it is allowed to warm up to room temperature slowly. For working up, the mixture is poured onto 50 ml. of ice-water, the organic phase separated and washed in turn with 20 ml. of 10% by weight aqueous sodium carbonate solution, 50 ml. of semi-saturated aqueous sodium chloride solution and 50 ml. of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. There is obtained 1-bromo-7-ethyl-3-methyl-2,6-nonadiene which is used in the process without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([Si:13]([CH3:16])([CH3:15])[CH3:14])[Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([Cl:17])[CH:3]=1.C([Li])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH2:37][CH2:38][CH2:39][CH3:40])[CH:35]=[O:36])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH2:37][CH2:38][CH2:39][CH3:40])[CH:35]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([Si:13]([CH3:16])([CH3:15])[CH3:14])[Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([Cl:17])[CH:3]=1)[OH:36])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1Cl)[Si](C)(C)C
Reactant: CCCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC1(C(O)c2ccc(N([Si](C)(C)C)[Si](C)(C)C)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chloro-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (0.484 g, 1.38 mmol) in ether (14 mL) at −78° C. and under nitrogen was added tert-butyllithium (2.03 mL, 1.43 M solution in pentanes, 2.91 mmol) dropwise. After 90 minutes, a solution of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.353 g, 1.38 mmol) in ether (3 mL) was added to the reaction mixture dropwise. After one hour, the reaction mixture was warmed to ambient temperature and stirred at ambient temperature for 30 minutes. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (10 mL) and extracted with EtOAc. The combined extracts were washed with brine, then dried (MgSO4), filtered, and concentrated in vacuo to an oil (0.75 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-butyl-2-{[3-chloro-4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-phenyl]-hydroxy-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.357 g, 0.678 mmol, 49%) as a colourless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:27][CH:26]=4)=[N:22][C:23]=3[C:14]=2[N:13]([CH3:38])[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C(OO)=[O:47])C=CC=1.C([O-])(O)=O.[Na+]>>[CH2:1]([NH:8][C:9]([C:11]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:32][CH2:33][N+:34]([CH3:37])([O-:47])[CH2:35][CH2:36]5)=[CH:29][CH:30]=4)=[N:22][C:23]=3[C:14]=2[N:13]([CH3:38])[N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)NCc5ccccc5)nn3C)CC4)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1nc(C(=O)NCc2ccccc2)c2c1-c1nc(Nc3ccc(N4CC[N+](C)([O-])CC4)cc3)ncc1CC2
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a solution of 39.4 mg (0.0774 mmol) of N-benzyl-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 17.4 mg (0.0774 mg) of 3-chlorobenzenecarboperoxoic acid were added and the mixture was stirred at room temperature. After 45 minutes an aqueous solution of NaHCO3 was added and the solvent removed. Treatment with methanol and filtration afforded 26.6 mg of the title compound (66% yield).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[OH-].[Na+].[H][H]>[Pd]>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 100 °C
Yield: 85 %

Procedure:
The procedure was as in Example 5, but the 2,4-difluorocinnamic acid obtained was not isolated. The aqueous-acidic product suspension obtained was rendered alkaline using sodium hydroxide solution and treated with 2 g of Pd/C (5% strength) at 50° C. with further stirring and heated to 100° C. It was then pressurized to 5 bar of hydrogen. After constant pressure had been achieved, it was cooled to room temperature, the pressure was released and the palladium catalyst was filtered off. The alkaline product solution was acidified with sulfuric acid and the product precipitate was isolated by filtration. After drying in vacuo, 95.0 g of 3-(2,4-difluorophenyl)propionic acid (85% of theory) were obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:4]=2[O:3][CH2:2]1.[N+:12]([CH3:15])([O-:14])=[O:13]>>[N+:12]([CH:15]=[CH:10][C:9]1[C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=Cc1cccc2c1OCO2
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])C=Cc1cccc2c1OCO2

Procedure:
In close analogy to the procedure described above, Benzo[1,3]dioxole-4-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([N:7]([C:26]2[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1.N1C=CC=CC=1.[F:53][C:54]([F:67])([F:66])[S:55]([O:58]S(C(F)(F)F)(=O)=O)(=[O:57])=[O:56]>>[F:53][C:54]([F:67])([F:66])[S:55]([O:58][C:29]1[CH:28]=[CH:27][C:26]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:6][CH:5]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1)(=[O:57])=[O:56]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2-c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2-c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
N-([1,1′-biphenyl]-4-yl)-N-(4-methoxyphenyl)-[1,1′:3′,1″-terphenyl]-4′-amine (12.4 g, 24.7 mmol) and pyridine hydrochloride (28.8 g, 250.0 mmol) were purged with nitrogen for overnight. The mixture was refluxed for 2 h. After cooling, the precipitate was filtered and washed by excess water. The solid dissolved in DCM was filtered through a silica pad and washed with DCM. The solvent was removed in vacuo. The residue was dissolved in DCM (100 mL) and cooled down to 0° C. After that, pyridine (8.1 mL, 100.0 mmol) and trifluoromethanesulfonic anhydride (8.4 mL, 50.0 mmol) were added at 0° C. The mixture was stirred for 17 h from 0° C. to room temperature. The reaction mixture was quenched by the addition of saturated K2CO3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo and the residue was purified by flash chromatography using 15% toluene/hexane (containing 0.5% triethylamine) to afford 4-([1,1′-biphenyl]-4-yl([1,1′:3′,1″-terphenyl]-4′-yl)amino)phenyl trifluoromethanesulfonate (14.5 g, 95% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH:26]12[CH2:31][CH:30]1[CH2:29][NH:28][CH2:27]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[C:16]([C:26]34[CH2:31][CH:30]3[CH2:29][NH:28][CH2:27]4)=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: C1NCC2CC12
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1ccc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(C23CNCC2C3)c1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (compound 20b; 1.6 g, 4.2 mmol), 3-aza-bicyclo[3.1.0]hexane (1.00 g, 5.3 mmol), DIPEA (3.0 mL, 17 mmol) and dioxane (40 mL) at reflux (overnight).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[N:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][N:33]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]5[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=5[N:8]4[CH3:11])=[CH:4][CH:3]=3)[C:32](=[O:36])[CH:31]=2)=[N:28][CH:29]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(-c2ccc(Cl)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 47 %

Procedure:
tert-Butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (200 mg, 0.549 mmol) and 4-(5-chloropyridin-2-yl)pyridin-2(1H)-one (87 mg, 0.42 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (97 mg, 47%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.5, 2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.55 (overlapping dd, J=7.4 Hz, 2H), 7.36 (s, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 7.00 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16](C=C)C1=O)=O>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:12]1[CH2:14][CH2:18][CH2:17][N:16]=1
Reactant: C=CN1CCC(C(=O)Cc2c(Cl)cccc2Cl)C1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1CC1=NCCC1

Procedure:
To a mixture of water (45 ml) and HCl conc. (45 ml) at reflux temperature was added dropwise during 15 minutes a solution of 3-[2-(2,6-dichloro-phenyl)-acetyl]-1-vinyl-pyrrolidin-2-one (2.98 g; 10 mmol), which was prepared as described in example P19, in THF (25 ml). The solution was concentrated to dryness on a rotary evaporator. The residue was dissolved in dichloromethane (20 ml), washed with water (2×30 ml) and dried over Na2SO4 and filtered through silicagel (5 g). After removal of the solvent 2.60 g (>100% of theory) of 5-(2,6-dichloro-benzyl)-3,4-dihydro-2H-pyrrole was obtained in form of a brown liquid.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[O:8])C.[OH-].[K+].O>C(O)C>[CH2:14]([O:13][C:11]([CH2:10][CH2:9][N:6]([CH:7]=[O:8])[CH2:5][C:4]([OH:16])=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)CCN(C=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C=O)CC(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
115.5 g of N-ethoxycarbonylethyl-N-formylglycine ethyl ester are dissolved in 150 ml of ethanol, and the solution is cooled to 0° C. To it is then added dropwise a mixture of 28.0 g of potassium hydroxide, 60 ml of water and 120 ml of ethanol. The reaction mixture is stirred for 18 h at RT, and is subsequently concentrated by evaporation under reduced pressure. After the addition of a small amount of water, the mixture is acidified with concentrated hydrochloric acid to pH 1. By extraction with chloroform, drying, and concentration of the organic phase by evaporation,there is obtained N-ethoxycarbonylethyl-N-formylglycine in the form of a yellowish oil (compound No. 1.3).
Reaction SMILES: [CH3:1][C@@H:2]([NH:22]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH3:21])=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:22])=[CH:7][CH:8]=1
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
1,1-dimethylethyl {(1R)-1-methyl-2-[(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 15, 150 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (0.866 mL, 11.24 mmol). The reaction was stirred at 0° C. for 4 hours. The reaction mixture was evaporated. The residue obtained was purified with an SCX cartridge (the cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (129 mg).