Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[N:11]1.[CH3:40][C:41]1[CH:45]=[C:44]([CH3:46])[NH:43][N:42]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:45]2[C:41]([CH3:40])=[N:42][NH:43][C:44]=2[CH3:46])[C:12]([NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[N:11]1
Reactant: Cc1cc(C)[nH]n1
Reactant: CCC(C)(C)c1ccc(OCCCC(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Br)c(C(C)(C)CC)c1
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(OCCCC(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2c(C)n[nH]c2C)c(C(C)(C)CC)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
66 g of 1-(2,4,6-trichlorophenyl)-3-[4-(2,4-di-tert-amylphenoxy)butyramido]-4-bromo-5-oxo-2-pyrazoline and 27 g of 3,5-dimethylpyrazole were mixed well with each other in a mortar, then stirred for 2 hours under heating at 100° C. To the reaction mixture was added 1 liter of ethyl acetate followed by washing several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from ethyl acetate, 35 g of Coupler (1) was obtained. The melting point of the coupler was 207° to 209° C.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:20]O>CN(C)C=O.O>[CH3:20][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][C:2]([CH3:1])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CO
Reactant: CC(C)(CC(=O)C(=O)O)c1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(=O)CC(C)(C)c1ccccc1
Reaction time: 15 h

Procedure:
10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159) in 250 ml of dimethylformamide is mixed at −5° C. with 4.1 ml of thionyl chloride and after 15 minutes with 4 ml of methanol. After 15 hours at room temperature, the batch is diluted with water and extracted with ethyl acetate. The organic extracts are washed with water, dried (Na2SO4) and concentrated by evaporation, whereby 9.3 g of 4-methyl-2-oxo-4-phenylpentanoic acid-methyl ester is obtained. The latter is mixed in 558 ml of DMF at −5° C. with 15.5 ml (104.63 mmol) of (trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate and stirred for 16 hours at room temperature. Water is added, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). The intermediate product that is concentrated by evaporation is taken up in 200 ml of THF and 50 ml of a 1 M solution of tetrabutylammonium fluoride in THF is added. It is stirred for 2 hours, water is added, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). After chromatography on silica gel with hexane-ethyl acetate (0-30%), 8.35 g of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid-methyl ester is obtained. The ester (8.3 g, 28.59 mmol) is dissolved in 180 ml of THF, and 1.52 g (36.20 mmol) of lithium aluminum hydride is added in small portions over a period of 2.5 hours. After complete conversion, 5 ml of ethyl acetate is added in drops, and after another 10 minutes, 10 ml of water is carefully added. The formed precipitate is filtered out and washed carefully with ethyl acetate. After chromatography on silica gel with hexane-ethyl acetate (0–35%), 5.40 g of 4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.6 g (21.35 mmol) of triphenylphosphine and, while being cooled with ice, 4.3 ml (27.31 mmol) of azodicarboxylic acid-diethyl ester are added to diol (5.40 g, 20.59 mmol) in 43 ml of THF. The reaction mixture is refluxed for 3 hours and, after cooling, it is concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0–15%), 4.18 g of product is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2=[N:11][S:12][N:13]=[C:9]2[C:8]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:29][C:27]1[CH:28]=[C:23]([C:17]2([C:19]([F:22])([F:20])[F:21])[O:16][N:15]=[C:14]([C:8]3[C:9]4[C:10](=[N:11][S:12][N:13]=4)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH2:18]2)[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nsnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nsnc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
To a solution of 7-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole-4-carboxylic acid methyl ester (Example 5.7) (4.01 g) in tetrahydrofuran (30 ml) was added aqueous sodium hydroxide (1M) (25.3 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours. Aqueous hydrochloric acid (1M) (100 ml) was added and the mixture diluted with ethyl acetate (150 ml). After separation of the layers, the aqueous layer was extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane/methanol) to give 7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole-4-carboxylic acid (1.29 g) as yellow solid. 1H-NMR (DMSO-d6, 400 MHz): 13.67 (bs, 1H), 8.37-7.26 (m, 5H), 4.76 (d, 1H), 4.53 (d, 1H) ppm.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21]/[N:22]=[C:23](/[C:25]1[CH:42]=[CH:41][C:28]([CH2:29][N:30]2[CH2:33][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)=[CH:27][CH:26]=1)\[NH2:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:18]3[O:21][N:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:29][N:30]5[CH2:31][CH:32]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33]5)=[CH:41][CH:42]=4)[N:24]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4-c4ccccc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A mixture of 4,5-diphenylisoxazole-3-carboxylic acid (26.5 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (30.5 mg, 0.100 mmol), HOBT (16.85 mg, 0.110 mmol) and EDC (21.09 mg, 0.110 mmol) in DMF (1 mL) was stirred at rt for 18 hr. The reaction mixture was warmed to 60° C. for 2 hr and 70° C. for 2 hr. After cooling to rt overnight, the reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-60% EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 1-(4-(5-(4,5-diphenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 0.069 mmol, 69.2% yield) as a white solid. HPLC retention time=1.90 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCCC(NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(-c2nc3cc(C(=O)N4CCCC(N)C4)ccc3n2C)cc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(1-(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (104 mg, 0.207 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.367 mL, 4.76 mmol) and the reaction stirred at room temperature for 2 h. LCMS (A1) showed no desired product but reaction had progressed to 1 major product. The reaction mixture was concentrated in vacuo to afford a colourless oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow solid—(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (81 mg, 0.201 mmol, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].[CH3:24][C:25]([CH3:27])=O>>[CH:25]([NH:17][CH2:16][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:14][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([CH3:13])[CH:9]=1)([CH3:27])[CH3:24]
Reactant: COc1cccc2c(NC(CN)c3ccccc3)cc(C)nc12
Reactant: CC(C)=O
Product: COc1cccc2c(NC(CNC(C)C)c3ccccc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 79. Starting materials were N*1*-(8-methoxy-2-methylquinolin-4-yl)-1-phenylethane-1,2-diamine (Example 75) and acetone.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:24][NH:25][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: NCC1CCCCC1
Product: O=C(NCC1CCCCC1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 7.5 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 47 μL (0.36 mmol) of C-cyclohexyl-methylamine. After recrystallization from methanol, 8 mg (8%) of N-(cyclohexylmethyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41](Br)=[CH:42][CH:43]=1)(=[O:38])=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:42][CH:43]=1)(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and [2-(5-bromo-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.51) (193 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as a yellow solid (89 mg, 32%). MS (ISN) 558.0 [(M−H)−]; mp 196° C.
Reaction SMILES: [Br:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[NH:10]2.[CH3:24][Li].[NH4+].[Cl-].O.[CH2:29]1[CH2:33][O:32]CC1>>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:33]([OH:32])([CH3:29])[CH3:24])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[Cl:15]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (4.14 g, 10.5 mmol) in THF (200 mL) cooled in a dry ice-acetone bath was treated portionwise over 30 min with 1.6 M methyllithium in hexanes (45.8 mL, 73.2 mmol). The mixture was stirred at −78° C. for 60 min, then was treated portionwise with saturated aqueous NH4Cl. Water was added and the mixture was extracted twice with EtOAc. The combined organic phases were washed twice with water. All aqueous phases were combined and extracted with DCM, and this organic phase was washed with water. All organic phases were combined, dried and concentrated. The residue was crystallized from EtOAc to give a solid. The residue from concentration of the mother liquor was purified by chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-100%), to give additional solid. The two solids were combined to give 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a light yellow solid (3.13 g, 78% yield). Mass spectrum m/z 363, 365, (M+H—H2O)+. 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.29 (br. s., 1H), 8.17 (s, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.66 (br. s., 1H), 7.42 (dd, J=8.6, 1.8 Hz, 1H), 1.52 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14](N)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:20])([CH3:19])[CH:9]=2)=[CH:4][CH:3]=1.[ClH:21].N([O-])=O.[Na+].[S:26](=[O:28])=[O:27]>C(#N)C.O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:26]([Cl:21])(=[O:28])=[O:27])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:20])([CH3:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(S(=O)(=O)Cl)cc2O1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a solution of the compound obtained in (5) described above (1.5 g) in acetonitrile (30 mL) was added acetic acid (2.62 mL) and then thereto was added hydrochloric acid (2.62 mL) over a period of 2 minutes at room temperature. To the mixture was added an aqueous solution of sodium nitrite (4.24 g) in water (1.62 mL) over a period of one minute, and the mixture was stirred at 5° C. for 20 minutes. The reaction vessel was pressurized with sulfur dioxide gas for 35 minutes (the inner temperature was below 10° C.). Then an aqueous solution (1.62 mL) of cupric chloride(II) (754 mg) was added to the reaction solution, and the mixture was stirred at room temperature for one hour. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL×3). The combined organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo to give the titled compound (2 g) as a crude product, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCCC1[O:20][NH:21][C:22](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([C:36]2[CH:47]=[CH:46][C:39]([CH2:40]OS(C)(=O)=O)=[CH:38][CH:37]=2)=[O:35])=[CH:28][CH:27]=1)=[O:23]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]3[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:22]([NH:21][OH:20])=[O:23])=[CH:27][CH:28]=3)=[CH:47][CH:46]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCN(Cc4ccccc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
1-Benzyl-piperazine (40 mg, 0.22 mmol) was added to a stirred mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester (prepared as described in Preparation 5, 90 mg, 0.185 mmol) and TEA (0.052 ml, 0.37 mmol) in DMF (2 ml). The resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with hot AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was triturated with di-isopropylether/DCM, filtered and the resulting powder was suspended in DCM and treated with HCl/Et2O for 1 h. The solid was filtered and washed with DCM to give 28.1 mg of (E)-3-(4-{(E)-3-[4-(4-benzyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:19])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)=[CH:28][C:23]=2[O:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH2:3][CH2:2][C:1]([N:5]4[CH2:6][CH2:7][N:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:19])[CH:12]=5)[CH2:9][CH2:10]4)=[O:4])[CH2:31]3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: C=CC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Reactant: c1cc2c(cc1CC1CCCNC1)OCO2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(C(=O)CCN3CCCC(Cc4ccc5c(c4)OCO5)C3)CC2)cc1F

Procedure:
A solution of 4-(4-acryloyl-piperazin-1-yl)-2-fluoro-benzonitrile (0.125 g, 0.48 mmol), (+)-3-benzo[1,3]dioxol-5-ylmethyl-piperidine (0.106 g, 0.48 mmol) and triethylamine (0.088 ml, 0.629 ml) in THF (1.6 ml) is stirred at rt for 25 h. The mixture is diluted with CH2Cl2 and washed with sat. aq. Na2CO3 solution The organic layer is separated off, dried over Na2SO4 and evaporated. The residue is purified by MPLC (60 g silica gel, eluent CH2Cl2:MeOH 9:1) to give the title compound, (+)-4-{4-[3-(3-benzo[1,3]dioxol-5-ylmethyl-piperidin-1-yl)-propionyl]-piperazin-1-yl}-2-fluoro-benzonitrile, as a colourless foam:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>FC(F)(F)C(O)=O.ClCCl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=2)(=[O:42])=[O:41])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C(F)(F)F)c1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (2.0 g, 4.68 mmol) in 20% trifluoroacetic acid/dichloromethane (50 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo, azeotroping three times with toluene (˜20 mL), to give a dark orange oil. The oil was dissolved in dichloromethane (50 mL) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.900 ml, 5.61 mmol) was added followed by diisopropylethylamine (4.09 ml, 23.39 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then solvent removed in vacuo to give a dark orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-45% ethyl acetate in isohexane) to afford (R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (931 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.62 min, m+H=536.2.
Reaction SMILES: O[C:2]1C2C(=CC(OC)=CC=2)N=C(C2SC=C(C(C)C)N=2)C=1.C(O)(=O)CCCCCC=C.N1CCC[C@H]1C(O)=O.[CH:40]([C:43]1[N:44]=[C:45]([C:48]2[CH:57]=[C:56]([O:58][CH:59]3[CH2:77][CH:76]4[N:61]([C:62](=[O:82])C[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH:69]=[CH:70][CH:71]5[C:73]([C:79]([OH:81])=[O:80])([NH:74][C:75]4=[O:78])[CH2:72]5)[CH2:60]3)[C:55]3[C:50](=[CH:51][C:52]([O:83][CH3:84])=[CH:53][CH:54]=3)[N:49]=2)[S:46][CH:47]=1)([CH3:42])[CH3:41]>>[CH:40]([C:43]1[N:44]=[C:45]([C:48]2[CH:57]=[C:56]([O:58][CH:59]3[CH2:77][CH:76]4[N:61]([C:62](=[O:82])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH:69]=[CH:70][CH:71]5[C:73]([C:79]([OH:81])=[O:80])([NH:74][C:75]4=[O:78])[CH2:72]5)[CH2:60]3)[C:55]3[C:50](=[C:51]([CH3:2])[C:52]([O:83][CH3:84])=[CH:53][CH:54]=3)[N:49]=2)[S:46][CH:47]=1)([CH3:42])[CH3:41]
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: C=CCCCCCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(4-isopropylthiazol-2-yl)-7-methoxyquinoline, oct-7-enoic acid and intermediate 5 following the procedure (Step D-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=619 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC.O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
576 μl of 1-bromo-2,4-dimethoxybenzene was dissolved in 5.8 ml of tetrahydrofuran and 3 ml of 1.6 mol/l solution of n-butyl lithium in hexane was added dropwise at −78° C. under argon atmosphere. Then, 1.1 ml of triisopropylborate was added, and after stirred at −78° C. for 40 minutes, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 40 ml of water and 1 ml of 5N-hydrochloric acid was added, and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 610.2 mg of the title compound.