Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:18]1[CH:19]=[CH:20][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:17]=1)=[O:23]
Reactant: O=C(O)c1ccn(-c2ccccc2)n1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 30.5 %

Procedure:
DIPEA (130 mg, 0.17 mL, 1.0 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-3-carboxylic acid (47 mg, 0.25 mmol) in DMF (5 mL). HOBT (37 mg, 0.27 mmol) and EDCI (120 mg, 0.62 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (97 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 37 mg (30.5% yield) of 1-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 96.28%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.7 (d, 3H), 7.68-7.54 (m, 2H), 7.44 (t, 2H), 7.32 (d, 2H), 6.8 (d, 1H), 4.42-4.2 (m, 2H), 4.1-3.86 (m, 2H), 3.82-3.4 (m, 4H), 3.2 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:22]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COCCOc1cc(N)ccc1OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc(Nc2ncnc(Cl)n2)ccc1OC
Temperature: 0 °C
Reaction time: 0.38 h

Procedure:
2,4-Dichloro-1,3,5-triazine (89.1 mg, 0.5944 mmol) was dissolved in DMF (0.5 ml) and cooled to 0° C. To this solution were added DIEA (104 μl), 4-methoxy-3-(2-methoxy-ethoxy)phenylamine (TFA salt)(264 mg, ˜0.59 mmol) and DIEA (208 μl) in DMF (1 ml). The reaction mixture was kept at 0° C. for 15 to 30 min and then at RT for 15 min to 2 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo, to give (4-chloro-[1,3,5]triazin-2-yl)-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH:9]1[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>CC(O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([N:11]2[CH2:12][CH:9]([N:7]([CH3:8])[C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10]2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2cc(Cl)ncn2)C1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
Azetidin-3-yl-methyl-carbamic acid tert-butyl ester (1.97 g, 11 mmol) in IPA (5 mL) was added dropwise to a stirred solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) in IPA (20 mL) followed by dropwise addition of TEA (2.11 mL, 15.1 mmol) at ambient temperature under N2. The resulting milky yellow solution was heated to 80° C. and maintained at 80° C. for 2 hours. The solution was allowed to cool and evaporated to give a yellow oil. The crude material was partitioned between DCM (70 mL) and water (30 aqueous extract was re-extracted with DCM (70 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate (30 mL), dried (MgSO4), filtered and evaporated to give a coloured oil. The crude oil was purified by flash column chromatography on silica gel eluting with DCM:MeOH (99:1 changing to 96:4 by volume) to yield the title compound as a solid (1.93 g, 64%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29][O:30]C1C=C(C2C=C(C(O)=O)NN=2)C=CC=1>>[ClH:2].[CH3:29][O:30][C:4]1[CH:5]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: COc1cccc(-c2cc(C(=O)O)[nH]n2)c1
Agent: Cl
Product: COc1cccc(-c2cc(C(=O)Nc3ccc([C@@H]4CNCCO4)cc3)[nH]n2)c1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 3-(3-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (CAS-890591-64-7) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. White solid. MS (ISP): 379.2 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)CCNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Yield: 89.9 %

Procedure:
To a solution of 1.84 g of 3-(benzyloxycarbonyl)amino-N-({(3R)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl)propanamide in 2 ml of chloroform, 2 ml of trifluoroacetic acid was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered basic with 4N aqueous sodium hydroxide solution. Extracting the product with chloroform, the product was dried over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 1.26 g of the title compound was obtained.
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)(O)=[O:2].C[N:22]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1.CN1C(=O)N(C)CCC1.O1CCOCC1>[NH2:22][C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)=[O:2]
Reactant: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1COCCO1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Alternative stage 10.1: A mixture of 2.165 g (7.5 mmol) of 6-carboxy-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine in 60 ml of THF and 10 ml of DMPU is heated under reflux for 30 min and then cooled to 0° C., whereupon a fine suspension is obtained. 824 μl (7.5 mmol) of N-methylmorpholine followed by 981 μl (7.5 mmol of isobutyl chloroformate in 10 ml of THF and, after 1 h at 0° C., 824 μl (7.5 mmol) of N-methylmorpholine followed by 981 μl (7.5 mmol) of isobutyl chloroformate again are added dropwise. The mixture is stirred for 1 h and then added dropwise to 70 ml of a saturated solution of ammonia in dioxane. After 3 h, the mixture is concentrated in vacuo. The residue is poured into water, and the precipitate is filtered off and washed with water and boiling isopropanol, whereupon 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine is obtained. Further product is obtained from the isopropanol filtrate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)cc1OC
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(C)cc1OC)C(F)(F)F

Procedure:
Analogously to Example 7, 14.68 g of ethyl-4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate is reacted with 21.6 ml of (trifluoromethyl)trimethylsilane and 9.7 ml of tetrabutylammonium fluoride solution (1 M in THF) in 195 ml of THF to form 13.73 g of ethyl-4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoate. The product is reduced with 2.84 g of lithium aluminum hydride in 560 ml of diethyl ether to form 11.62 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol. The oxidation of the diol is carried out analogously to Example 7 under Swern conditions with 3.8 ml of oxalyl chloride, 7.1 ml of DMSO and 26.5 ml of triethylamine to 5.91 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1.O1CCOCC1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100° C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 274 [M+H]+, rt 5.20 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>CN(C=O)C.CC(CC(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)C
Product: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 92 %

Procedure:
3-Chloro-4,5-difluorobenzotrifluoride (99 g) was dissolved in dry MBIK (100 cm3) and 25 drops of dry DMF and dry potassium carbonate (48 g) added. The mixture was stirred and brought to reflux when a solution of 4-methyl-3-nitrophenol (35 g) in dry MIBK (70 cm3) was added over 1 hour. When the addition was complete stirring and reflux were continued for 2 hours. The solvent was removed from the reaction mixture under vacuum and the residue triturated with water (500 cm3). The solid obtained was filtered off, washed with water and air dried. The crude solid was recrystallised from ethanol to give 4-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrotoluene (73.5 g) as an off white solid, m.p. 112.8°-115.4° C.
Reaction SMILES: O=C(CC)CC(OCC)=O.C(O)(=O)C(O)=O.C1(NN)CC1.[CH:22]1([C:25]2[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=[CH:27][C:26]=2[CH:33]=[O:34])[CH2:24]C1>>[CH:30]1([N:29]2[C:25]([CH2:22][CH3:24])=[C:26]([CH:33]=[O:34])[CH:27]=[N:28]2)[CH2:31][CH2:32]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: CCOC(=O)CC(=O)CC
Agent: NNC1CC1
Agent: O=C(O)C(=O)O
Product: CCc1c(C=O)cnn1C1CC1

Procedure:
1-Cyclopropyl-5-ethyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl 3-oxopentanoate and cyclopropyl hydrazine oxalate (Gever, G. and Hayes, K. J. Org. Chem, 1949, 14, 813-818) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]#N)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[OH-:17].[Na+].C[OH:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]([OH:20])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccnc2C#N)c1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COc1cccc(-c2cccnc2C(=O)O)c1

Procedure:
A mixture of 3-(3-methoxyphenyl)-pyridine-2-carbonitrile (12.00 g), 15 M aqueous NaOH solution (40 mL), and methanol (60 mL) is stirred at reflux temperature for 7 h. After cooling to room temperature, most of the methanol is evaporated and the residue is cooled in an ice bath and adjusted to pH value ca. 4-5 by the careful addition of concentrated hydrochloric acid. The resulting mixture is concentrated to ca. 50 ml by evaporation and extracted with dichloromethane/methanol (9:1) several times. The aqueous phase is then adjusted to pH value 2-3 using concentrated hydrochloric acid and extracted again with dichloromethane/methanol (9:1). The combined extracts are dried (Na2SO4) and the solvent is evaporated to give the title compound as a foam-like solid. Yield: 11.88 g (91% of theory); LC (method 1): tR=1.70 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][Zn+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([CH3:14])[N:8]=[C:7]([O:15][CH3:16])[N:6]=1>O1CCCC1.O>[CH3:16][O:15][C:7]1[N:8]=[C:9]([CH3:14])[C:10]([N+:11]([O-:13])=[O:12])=[C:5]([CH3:2])[N:6]=1
Reactant: C[Zn+]
Reactant: COc1nc(C)c([N+](=O)[O-])c(Cl)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)c([N+](=O)[O-])c(C)n1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 93.4 %

Procedure:
Methylzinc chloride (2.0 M solution in tetrahydrofuran, 14.8 mL, 29.6 mmol) was added dropwise to a solution of 4-chloro-2-methoxy-6-methyl-5-nitropyrimidine (4.01 g, 19.7 mmol) and tetrakis(triphenyl phosphine)palladium (2.20 g, 1.90 mmol) in tetrahydrofuran (60 mL) at 0° C., and the mixture was stirred at 50° C. for 50 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (3-0.37 g, 18.4 mmol, 93%).
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=1)[CH2:3][NH:4][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[CH:6][N+:7]([O-:9])=[O:8].[H][H]>C(O)C>[NH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH:2]([OH:1])[CH2:3][NH:4][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)=[CH:6][N+:7]([O-:9])=[O:8])=[CH:33][CH:32]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C=C(NCCCOc1cccc(CN2CCCCC2)c1)NCC(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Nc1ccc(C(O)CNC(=C[N+](=O)[O-])NCCCOc2cccc(CN3CCCCC3)c2)cc1
Yield: 39.9 %

Procedure:
With 15 ml of ethanol was mixed 0.8 g of N-[2-hydroxy-2-(4-nitrophenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine, and hydrogen gas was introduced thereinto in the presence of 0.1 g of 5% (by weight) palladium carbon at ordinary temperature and under atmospheric pressure for 7 hours until the absorption of hydrogen gas ceased. Subsequently, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by a column chromotography (Wako Silica Gel C-200, eluent; chloroform:methanol=5:1 by volume) to obtain 0.3 g (yield 40%) of amorphous N-[2-(4-aminophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:17][CH:16]=[CH2:15])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
1.65 g (55 mmol) of sodium hydride (80% in oil ) and 50 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 8.2 g (50 mmol) of 4-acetylbenzoic acid, dissolved in 100 ml of DMF, are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. 4.6 ml (55 mmol) of allyl bromide are then introduced and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (80:20). After evaporation of the solvents, 7.2 g (71 % ) of allyl ester are collected in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:9][N:10]([CH2:18][CH2:19][OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O[C:30]1[CH:38]=[C:37]2[C:33]([C:34]([CH:46]3[CH2:48][CH2:47]3)=[N:35][N:36]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(=O)([O-])[O-]>C1(C)C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:21][Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:27][CH3:28])[CH2:9][N:10]([C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH2:18][CH2:19][O:20][C:30]2[CH:38]=[C:37]3[C:33]([C:34]([CH:46]4[CH2:48][CH2:47]4)=[N:35][N:36]3[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])=[CH:32][CH:31]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(C3CC3)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
(R)-Tert-butyl 2-(3-aminophenyl)-2-(triethylsilyloxy)ethyl(2-hydroxyethyl)carbamate (1.6143 g) which can be prepared according to the method described in Reference example 59, etc. and tert-butyl 6-hydroxy-3-cyclopropylindazole-1-carboxylate (924 mg) which can be prepared according to the method described in Reference example 7, etc. and triphenylphosphine (1.1419 g; manufactured by Kanto Chemical Co., Inc.) were dissolved in dehydrated toluene (18 mL), added with DIAD (808 μL; manufactured by Sigma-Aldrich Co.), and stirred overnight at room temperature. The reaction solution was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=82:18→61:39) to obtain a crude product (1.669 g), which was then dissolved in CH2Cl2 (20 mL). After adding MP-Carbonate [5.15 g (2.73 mol/g); manufactured by Argonaut] to the mixture, it was stirred overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain the title compound (1.0644 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C:13](=[O:36])[C@H:14]([NH:28]C(=O)OC(C)(C)C)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CC(O)=O>CS(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:28][C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13]([NH2:12])=[O:36])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccncc2)cc1)C(N)=O
Reactant: N#Cc1cc(F)c(F)cc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(N[C@H](Cc2ccc(-c3ccncc3)cc2)C(N)=O)cc1Br
Yield: 47.2 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (85 mg, 0.390 mmol), (R)-tert-butyl 1-amino-1-oxo-3-(4-(pyridin-4-yl)phenyl)propan-2-ylcarbamate (72 mg, 0.299 mmol) and DIEA (0.200 mL, 1.15 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (62 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[C:24]([OH:27])(=[O:26])[CH3:25]>>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:10]2[CH2:11][CH2:12][N:8]([CH2:25][C:24]([OH:27])=[O:26])[CH2:9]2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1ccc(CC2CCN(Cc3ccccc3)C2)cc1
Reactant: CC(=O)O
Product: O=C(O)CN1CCC(Cc2ccc(C(F)(F)F)cc2)C1

Procedure:
Prepared in analogy to Example A1(d) from 1-Benzyl-3-(4-trifluoromethyl-benzyl)-pyrrolidine (CAS: 336182-64-0) by replacing HCl with acetic acid to yield the title compound as an light brown oil. MS (m/e): 230.4 (M+H+, 100%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])(=[O:25])=[O:24])[C:14]1=[O:36].O>C(Cl)Cl>[C:8]([NH:12][C:13]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])(=[O:25])=[O:24])[C:14]1=[O:36])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)ccc32)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NC(C)=O)(c3ccccc3)c3cc(Cl)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.051 g of triethylamine and then 0.04 g of acetyl chloride are added to a solution of 0.234 g of the compound obtained in EXAMPLE 1 in 2 ml of DCM and the reaction mixture is stirred for two hours at RT. It is poured into water, extracted with DCM, washed with water, dried over sodium sulfate and evaporated under vacuum to give the expected product after crystallization and recrystallization from a DCM/iso ether/ MeOH mixture. m=0.146 g. M.p.=253° C.