Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 1771.5 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60 ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65° C. for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHCO3 solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30% EtOAc/hexane) to provide the title compound as white solid (4.85 g, 89%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[OH-:13].[Na+]>S(=O)(=O)(O)O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH2:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Yield: 83 %

Procedure:
A solution of 2-oxoindoline-5-carbonitrile (2.4 g, 15 mmol) in sulphuric acid (85%, 16 mL) was heated at 80° C. for 6 h and then allowed to reach room temperature over night. The mixture was poured into an ice/water mixture and the pH was adjusted to 5 with an aqueous sodium hydroxide solution (50%). The solid product was collected by filtration, washed with water, and dried in vacuo at 60° C. over night to afford 2.2 g (83% yield): 1H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H), 7.88-7.72 (m, 3H), 7.23-7.11 (br s, 1H), 6.88 (d, J=8 Hz, 1H), 3.56 (s, 2H).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[CH3:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20](Cl)=[O:21].FC(F)(F)C(O)=O.[OH-].[NH4+]>>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20](=[O:21])[C:19]([CH3:26])([CH3:18])[CH2:23][CH2:24][CH3:25])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CCCC(C)(C)C(=O)Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O

Procedure:
By insteracting 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride with 8.0 g. of 2,2-dimethylpentanoyl chloride in 30 ml. of trifluoroacetic acid on a steam bath for 1 hour and treating the resulting product with ammonium hydroxide there was obtained 3-hydroxy-4-(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone. This product was converted to the acetate salt (10.5 g.) and this salt was converted to the corresponding methanesulfonate salt [8.3 g., m.p. 250° C. (dec.)(uncorr.)], by treatment with a slight excess of methanesulfonic acid. When this methanesulfonate (8.0 g.) was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst, there was obtained 5.8 g. of 3-hydroxy-4-(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 128°-130° C. (uncorr.).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][C@@H:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:5]1
Reactant: [H][H]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Yield: 100.1 %

Procedure:
A mixture of tert-butyl [(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (1.14 g, 3.39 mmol) in MeOH was hydrogenated in the presence of 10% Pd on carbon (0.14 g) under 45 psi of hydrogen overnight. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the sub-title compound (1.04 g, 100%). LCMS calc. for C16H27N4O2 (M+H)+: m/z=307.2. found: 307.3.
Reaction SMILES: [OH:1]CCN1CCCC1.[CH:9]([N:12]([CH:15]([CH3:17])C)[CH2:13][CH3:14])([CH3:11])C.CS(Cl)(=O)=O.C([NH:26][C@:27]1([C:44](NC(C)(C)C)=[O:45])[C@@H:31]([CH2:32][CH2:33][CH2:34][B:35]2[O:39]C(C)(C)C(C)(C)[O:36]2)[CH2:30][NH:29][CH2:28]1)(=O)C>C(#N)C>[NH2:26][C@:27]1([C:44]([OH:45])=[O:1])[C@@H:31]([CH2:32][CH2:33][CH2:34][B:35]([OH:36])[OH:39])[CH2:30][N:29]([CH2:17][CH2:15][N:12]2[CH2:9][CH2:11][CH2:14][CH2:13]2)[CH2:28]1
Reactant: OCCN1CCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Product: N[C@@]1(C(=O)O)CN(CCN2CCCC2)C[C@@H]1CCCB(O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A cooled (0° C.) solution of N-(2-hydroxyethyl)pyrrolidine (92 mg, 0.80 mmol) and diisopropylethylamine (0.32 mL, 1.8 mmol) in anhydrous acetonitrile (12 mL) under nitrogen was treated with methanesulfonyl chloride (92 mg, 0.80 mmol), stirred 3 h, and treated with (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and heated to 60° C. for 15 h. The reaction mixture was concentrated, deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(2-(pyrrolidin-1-yl)ethyl)pyrrolidine-3-carboxylic acid (127 mg, 60%) as a white foam. NMR (D2O) δ 3.80-4.00 (m, 2 H), 3.50-3.80 (m, 4 H), 3.40 (t, J=11 Hz, 1 H), 3.05 (m, 2 H), 2.55-2.75 (m, 4 H), 2.05 (m, 2 H), 1.90 (m, 2 H), 1.60 (m, 1 H), 1.10-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 314.0; MS (m−H2O+1): 296.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH3:39]>>[NH2:39][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (20.7 g, 36.5 mmol) and ammonia hydroxide (500 mL) was heated in a steel reactor to 100° C. After 3 h, the reaction cooled and checked by HPLC. The reaction mixture was concentrated. The reaction mixture wad diluted with CH2Cl2 (300 mL) and water (300 mL) then acidified with 6 N HCl to pH=1. The mixture was extracted with 1% MeOH in CH2Cl2 (4×). The CH2Cl2 layer were dried over Na2SO4 and filtered and concentrated to 400 mL. Ethanol (400 mL) was added to the reaction mixture and concentrated to dryness. Ethanol (400 mL) was added again to the reaction mixture and concentrated to dryness. Ethanol (500 mL) was added to the reaction mixture and refluxed. After 4 h, the reaction mixture was cooled to 0° C., filtered, and wash with EtOH. The product was dried under vacuum at 60° C. for 2 days. Title compound was obtained as an off-white solid (17 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (br. s., 1H), 7.98 (d, J=5.3 Hz, 1H), 7.56-7.84 (m, 1H), 6.93-7.54 (m, 5H), 6.77 (br. s., 2H), 5.85 (d, J=4.6 Hz, 1H), 3.92 (d, J=9.9 Hz, 2H), 3.46 (t, J=11.2 Hz, 2H), 3.20-3.32 (m, 1H), 1.90-2.06 (m, 2H), 1.57-1.81 (m, 2H). MS (ESI): 548.10 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](O)([OH:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: OC1(O)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 2-methylbenzoyl chloride (800 mg, 5.2 mmol) in 5 mL of DICHLOROMETHANE was added a mixture of piperidine-4,4-diol hydrochloride salt 800 mg, 5.2 mmol) and potassium carbonate (716 mg, 5.2 mmol) in 5 mL H2O and stirred at room temperature for 2 hours. Layers were separated and aqueous layer was extracted with dichloromethane (3×10 mL). Organic layers were combined, dried, filtered and the filtrate was concentrated in vacuo to give the tile compound (1.2 g) as light yellow oil. MS (M+1): 218.0
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.CC[O:14][C:15]([CH2:17][CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:16]>>[Cl:1][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:10]2[C:19]3[CH:18]([CH2:17][C:15]([OH:14])=[O:16])[CH2:23][CH2:22][CH2:21][C:20]=3[C:6]3[C:5]2=[C:4]([S:3][CH3:2])[CH:9]=[CH:8][CH:7]=3)=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: Cl
Reactant: CSc1ccccc1NN
Product: CSc1cccc2c3c(n(Cc4ccc(Cl)cc4)c12)C(CC(=O)O)CCC3

Procedure:
Following the procedure of Example 34, but using 1-(2-methylthiophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared. m.p. 141°-142° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1.Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2ccc(N3CCNCC3)nc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
To a solution of 197c (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 4.0 M HCl/dioxane (10 mL). The reaction mixture was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford 197d (358 mg, 91%). MS-ESI: [M+H]+ 365.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[C:40](/[CH:46]([CH3:48])[CH3:47])=[CH:41]\[C:42](OC)=[O:43])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])/[CH:41]=[C:40](\[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)/[CH:46]([CH3:48])[CH3:47])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C(\c1cccc(C#N)c1)C(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (139 mg, 0.46 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.69 ml, 1.38 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of crude methyl (2Z)-3-(3-cyanophenyl)-4-methylpent-2-enoate (105 mg, 0.46 mmol) in 2 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 20 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate, filtered and concentrated to give (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methylpent-2-enamide (190 mg, 82%) as an off-white foam which was sufficiently pure to be used without further purification. ES-MS (M+H): 501.2.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: CCCC(CC(O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 61, 228 mg (0.71 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal, 150 mg (0.85 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.5 ml of titanium tetraethoxide are reacted to give 4-(3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol. 185 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-25%) are cyclized in the same way as in Example 61 at −20° C. with 3 ml (3 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-65%) yields 27 mg of product and 38 mg of the corresponding 5α,6α,8α) compound (Example 64).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8](N(CC)CC)C.[C:15]([C:17]([C:35]#[N:36])=[C:18]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1)SC)#[N:16].C(=O)([O-])O.[Na+]>C(O)C>[CH2:2]([O:3][C:4](=[O:7])[CH2:5][NH:6][C:18]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[CH2:22]1)=[C:17]([C:35]#[N:36])[C:15]#[N:16])[CH3:8]
Reactant: CCN(CC)CC
Reactant: COC(=O)CN
Reactant: CSC(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNC(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Glycine methyl ester hydrochloride (3.3 g) and triethylamine (3.7 ml) were added to a solution of tert-butyl {(3R)-1-[2,2-dicyano-1-(methylthio)vinyl]-piperidin-3-yl}carbamate (1.3 g) in ethanol (30 ml), and the resulting mixture was heated under reflux. After 4 hours, triethylamine (1.5 ml) was added thereto, followed by heating under reflux for another 7 hours. After the reaction solution was cooled to 25° C., a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (360 mg) as a white amorphous substance.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1.[F:30][C:31]([F:36])([F:35])[C:32](O)=O.FC(F)(F)COS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:32][C:31]([F:36])([F:35])[F:30])[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(C3CCN(CC(F)(F)F)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) (as prepared in Example 35, 25 mg, 0.040 mmol), trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (9.8 mg, 0.042 mmol) and Na2CO3 (21 mg, 0.20 mmol) in 1 mL of DMF was stirred at RT for 8 h. Treated with 30 mL of EtOAc, the mixture was washed with H2O (2×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (40% EtOAc/hexane) gave 11 mg (55%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 10.7 (s, 1H), 9.20 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.47 (dd, 1H, J=3.1, 1.4 Hz), 7.10 (d, 1H, J=1.8 Hz), 7.04 (dd, 1H, J=8.4, 1.8 Hz), 6.87 (dd, 1H, J=3.1, 1.4 Hz), 2.90-3.14 (m, 6H), 2.72 (dd, 2H, J=11.5, 11.5 Hz), 2.41-2.52 (m, 3H), 1.74-1.90 (m, 6H), 1.60 (br s, 1H), 1.34-1.44 (m, 2H), 1.09 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C25H30F3N5O, 474.2 (M+H), found 474.1.
Reaction SMILES: Br[C:2]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1.[B:20](OC)([O:23]C)[O:21]C.O>CCCCCC.C1COCC1>[CH:19]1[C:14]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]([B:20]([OH:23])[OH:21])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cc2ccc3ccccc3c2c2ccccc12
Reactant: COB(OC)OC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Reaction time: 2 h

Procedure:
52 ml (130 mmol) of n-buthyllithium (2.5 M in n-hexane) are added dropwise to a suspension of 30.7 g (100 mmol) of 5-bromobenzo[c]phenanthrene in 1000 ml of THF at −78° C. with vigorous stirring, and the mixture is stirred for a further 2 h. 16.7 ml (150 mmol) of trimethyl borate are added to the red solution in one portion with vigorous stirring, the mixture is stirred at −78° C. for a further 30 min., then warmed to room temperature over the course of 3 h, 300 ml of water are added, and the mixture is stirred for 30 min. The organic phase is separated off and evaporated to dryness in vacuo. The solid is taken up in 100 ml of n-hexane, filtered off with suction, washed once with 100 ml of hexane and dried in vacuo. Yield: 24.8 g (91 mmol), 91%, purity about 90% (NMR) of boronic acid, with varying amounts of boronic anhydride and boronic acid. The boronic acid can be used in this form without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN([C@H]1CC[C@H](OCC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a suspension of 1 g (2.96 mmol) of trans-N-(4-hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide in 12 mL of toluene were added 0.9 ml (6.04 mmol, 2 eq) of bromo-acetic acid tert-butyl ester, 100 mg (0.3mmol, 0.1 eq) of tetra-N-butylammonium hydrogensulfate and 12 mL of 50% aqueous NaOH. The mixture was stirred at 500 for 1 h. The organic phase was dissolved in EtOAc, dried over Na2SO4, and the solvent evaporated. Column chromatography on silica gel gave 1.3 g (97%) of trans-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-acetic acid tert-butyl ester as an off-white solid, MS: 469 (M+NH4+).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=O)(=[NH:5])[NH2:4].Cl.[NH2:18][N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH2:24]>C(O)(C)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[N:18][N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH2:24])(=[NH:5])[NH2:4]
Reactant: NC1=NCCN1N
Reactant: N=C(N)c1cccc2c1CCCC2=O
Agent: Cl
Solvent: CC(C)O
Product: N=C(N)c1cccc2c1CCCC2=NN1CCN=C1N
Reaction time: 16 h

Procedure:
0.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is added, with stirring, to a solution of 0.25 g (0.001 mol) of 5-(amidino)-1-tetralone hydrochloride and 0.136 g (0.001 mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride in 5 ml of iso-propanol, and the mixture is stirred at 80°-90° C. for 16 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried, yielding the title compound, m.p. >220° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.15 (d, 1H); 7.67 (d, 1H); 7.55 (t, 1H); 4.17 (t, 2H); 3.68 (t, 2H); 3.23 (m, 2H); 3.15 (m, 2H); 1.9 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([C:14]3[NH:23][C:17]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:16]=4[N:15]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:24])[CH:5]=2)[CH2:3][CH2:2]1.[CH:25]1(C2C(C=O)=CC(C(OC)=O)=C(C)C=2)CCC1.C1(C2C(C=O)=CC(C(OC)=O)=C(C)C=2)CC1>>[CH:1]1([C:4]2[C:13]([C:14]3[NH:23][C:17]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:16]=4[N:15]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:24])[CH:5]=2)[CH2:3][CH2:25][CH2:2]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CN(C)CC3)c(C2CC2)cc1C
Reactant: COC(=O)c1cc(C=O)c(C2CCC2)cc1C
Agent: COC(=O)c1cc(C=O)c(C2CC2)cc1C
Product: COC(=O)c1cc(-c2nc3c([nH]2)CN(C)CC3)c(C2CCC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 87.4, except methyl 4-cyclobutyl-5-formyl-2-methylbenzoate (compound 82.5) was used in place of methyl 4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1).