Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([NH:5][C@H:6]([B:12]1[O:16][C@@H:15]2[CH2:17][C@@H:18]3[CH2:21][C@H:20]([C@:14]2([CH3:24])[O:13]1)[C:19]3([CH3:23])[CH3:22])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=[O:4].[CH3:32][C:33]([O:36][C:37]([NH:39][C@H:40]([C:49](O)=[O:50])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:25]([C@H:2]([NH:1][C:49]([C@@H:40]([NH:39][C:37](=[O:38])[O:36][C:33]([CH3:34])([CH3:32])[CH3:35])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:50])[C:3]([NH:5][C@H:6]([B:12]1[O:16][C@@H:15]2[CH2:17][C@@H:18]3[CH2:21][C@H:20]([C@:14]2([CH3:24])[O:13]1)[C:19]3([CH3:23])[CH3:22])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=[O:4])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@@H](N)Cc4ccccc4)O[C@@]3(C)[C@H]1C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Yield: 85 %

Procedure:
Into a 1-neck round-bottom flask was added (2S)-2-amino-N-{(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}-3-phenylpropanamide (217 mg, 0.511 mmol), Boc-homophe-OH (171 mg, 0.614 mmol), TBTU (246 mg, 0.767 mmol) and then N,N-dimethylformamide (14.5 mL, 0.187 mol) followed by N,N-diisopropylethylamine (0.187 mL, 1.07 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight The DMF was removed from the reaction mixture under vacuum and the resulting residue purified by preparative TLC in 40% EtOAc/Hexanes to give 298 mg (85% yield) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][C:4]1[N:5]=[C:6]([CH:15]([CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[N:7](S(N(C)C)(=O)=O)[CH:8]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]([CH3:31])([CH3:32])[CH2:3][C:4]1[N:5]=[C:6]([CH:15]([CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[NH:7][CH:8]=1
Reactant: CC(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)c[nH]1

Procedure:
A solution of 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide in 1.5 N hydrocholoric acid (1 mL) and THF (1 mL) was heated at 70° C. in a sealed tube overnight. The reaction mixture was basified with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification of the resulting crude product by silica preparatory plate chromatography eluting with 10% methanol/ethyl acetate afforded the title compound. LCMS: (M+H) found 352.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 80 °C
Yield: 100.2 %

Procedure:
To dry dimethylformamide solution (70 ml)of 23.7 g of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol (28a)was added 5.30 g of sodium azide, and the mixture was stirred with heating at 80° C. for 16 hours. The reaction mixture was added to ice-water, and extracted with diethyl ether. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 24.2 g of 2-azidomethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (29a) was obtained (yield about 100%). mp 84-85° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A163) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:28][C:29]1[C:34]2[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=2[CH:32]=[C:31]([CH:43]2[CH2:45][CH2:44]2)[N:30]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:28][C:29]1[C:34]2[N:35]=[C:16]([NH:15][C:4]3[CH:5]=[CH:6][C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)=[CH:8][C:3]=3[O:2][CH3:1])[N:37]=[CH:38][C:33]=2[CH:32]=[C:31]([CH:43]2[CH2:44][CH2:45]2)[N:30]=1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2cc(C3CC3)nc(Cl)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2cc(C3CC3)nc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
N-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 50 mg 0.21 mmole) was stirred in THF (1 mL). Sodium hexamethyldisilazide (0.25 mL of 1M solution in THF) was added and the reaction stirred at room temperature for 20 minutes. 8-Chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 179, 80 mg, 0.28 mmole) was added as a suspension in THF (1.5 mL) and the reaction was stirred at room temperature for 80 minutes. Methanol (1 mL) and 1M sodium hydroxide solution (1 mL) were added to the reaction and stirred for 55 minutes. The solvents were then concentrated in vacuo. The residue was partitioned between chloroform (10 mL) and water (10 mL). The layers were separated and the aqueous was again extracted with chloroform. The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 1:1 acetone:cyclohexane to afford the title compound (41 mg 44%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:8]1[CH:9]=[C:10]([N:20]([CH3:22])[CH3:21])[CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)(OC)[O:4]C.S(=O)(=O)(O)O>O>[Br:1][CH2:2][C:3]([C:8]1[CH:13]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:11]=[C:10]([N:20]([CH3:22])[CH3:21])[CH:9]=1)=[O:4]
Reactant: COC(CBr)(OC)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)c1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
[3-(2-Bromo-1,1-dimethoxyethyl)-5-pentafluorosulfanylphenyl]dimethylamine (230 mg) was suspended in water (2.3 ml) and then concentrated sulfuric acid (2.3 ml) was added dropwise with cooling. After stirring at RT for 2 h, the mixture was diluted with water (20 ml) and extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile/water, frozen and freeze-dried overnight. 170 mg of the desired compound were obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:77][CH2:76][CH2:75][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][CH2:60][CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH2:74])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[H][H]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:77][CH2:76][CH2:75][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][CH2:60][CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH2:74])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Reactant: [H][H]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
98 mg of Z-Arg-Arg-Pro-Phe-His-Sta-β-Ala-His-NH2 (from Example 20) are dissolved in 2 ml of 95% strength MeOH and hydrogenated with 20 mg of Pd-on-carbon (10% Pd), while stirring with a magnet and passing hydrogen through, until the starting material has disappeared. The catalyst is then filtered off, the filtrate is concentrated to dryness and the vitreous residue is dissolved in 2 ml of H2O and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-β-Ala-His-NH2 in the form of an amorphous powder; Rf (D)=0.05; Rf (M)=0.06; Rf (O)=0.06.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:53])CC2)CC1>>[OH:53][CH:5]1[CH2:4][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (see example 36) and amine 21.
Reaction SMILES: [Cl-].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[C:12]1([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)CCl>[C:12]1([S:18]([N:21]2[CH:22]=[CH:23][C:24]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=3)=[O:9])=[CH:25]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a suspension of alminium chloride (4.62 g, 34.7 mmol) in ethylene chloride (50 mL) was added under a nitrogen atmosphere p-toluoyl chloride (4.91 g, 31.8 mmol) in ethylene chloride (5 mL) at room temperature in a period of 10 minutes. After stirring for 30 minutes to the mixture was added 1-benzenesulfonyl-1H-pyrrole (6.00 g, 28.9 mmol) in ethylene chloride (10 mL) in a period of 10 minutes. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice water and the aqueous layer was extracted twice with dichloromethane. The organic layer combined was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the subject compound (9.9 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][N:15]=[C:16](Br)[C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2].[CH2:22]([N:24]([CH2:27][CH3:28])[C:25]#[N:26])[CH3:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:22]([N:24]([C:25]1[N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:15]=[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:26]=1)[CH2:27][CH3:28])[CH3:23]
Reactant: CCN(C#N)CC
Reactant: CC(C)(C)C(Br)=NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
7.4 g (0.02 mol) of 2,2-dimethylpropionyl bromide 2-nitro-4-trifluoromethylphenylhydrazone and 2.0 g (0.02 mol) of N,N-diethylcyanamide were added to 100 ml of toluene. Then, 2.2 g (0.022 mol) of triethylamine was dropwise added under stirring at room temperature. After completion of the dropwise addition, stirring was continued at room temperature for further 1 hour. Then, 100 ml of toluene was added and washed with water. The organic layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 6.5 g (yield: 84.4%) of the desired compound as a pale yellow liquid. Refractive index nD20 : 1.4911.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:16]([O:26][CH3:27])=[C:15]([NH2:28])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>CN(C=O)C>[NH2:28][C:15]1[N:14]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[F:1])[N:6]=2)[N:18]=[C:17]([N:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:43](=[O:44])[CH2:42][O:41][CH3:40])[C:16]=1[O:26][CH3:27]
Reactant: COCC(=O)Cl
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)N(c1ccncc1)c1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1OC
Temperature: 0 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4,6-diamine 2-1-4 (0.116 mmol, 1.0 eq.) and 12 mg of triethyl amine (0.116 mmol, 1.0 eq.) were dissolved in 600 μL DMF and were cooled to 0° C. After addition of 13 mg of methoxyacetyl chloride (0.116 mmol, 1.0 eq.), the reaction mixture was stirred for five h at rt. After dilution with water, the crude product was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography yielding 37 mg (0.07 mmol, 60%) of analytically pure target compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[NH4+]>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:2][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCC(O)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
4-piperidinol (2 g, 19.8 mmol) was added to dichloromethane (20 mL), and cooled to an internal temperature of 0-5° C. Then, triethylamine (3.31 mL, 23.7 mmol) was added thereto and stirred for 30 min. Pivaloyl chloride (2.62 g, 21.8 mmol) was dropwise added thereto and heated to room temperature. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with a saturated aqueous solution of ammonium (50 mL) and extracted twice with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (3.9 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(C(C)=O)C.[I-].[K+]>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 90.3 %

Procedure:
A mixture of 4-hydroxyacetophenone (30 g), potassium carbonate (33.4 g), potassium iodide (1 g) and benzyl bromide (41.4 g) in methyl ethyl ketone (500 mL) is heated at reflux for 18 hours. The cooled reaction mixture is filtered and the filtrate evaporated. The residue is crystallised from cyclohexane to give 4-benzyloxyacetophenone (45 g, 90%).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=O)[CH2:9][CH2:10][CH3:11]>FC(F)(F)C(O)=O>[CH2:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Triethylsilane (2.3 g) was added to 2 g of 5-butanoyl-2-oxindole in 20 ml of trifluoroacetic acid at room temperature and the solution stirred for 3 hours. The reaction was poured into ice water to give a red oil which solidified after standing. The solid was collected by vacuum filtration, washed with water and hexane and dried to give 1.7 g (91% yield) of 5-butyl-2-oxindole as an off-white solid.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:4]5[CH2:5][CH2:6][CH2:7][O:1][CH2:2][CH2:3]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCOCC4)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)cc1
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 21 %

Procedure:
A solution of Intermediate 49b (90.0 mg, 0.237 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 97 mg, 0.24 mmol) in 1,4-dioxane (3 mL) and DIPEA (63 μL, 0.36 mmol) was stirred at 90° C. for 4 h, then more DIPEA (63 μL, 0.36 mmol) was added and mixture stirred at 100-110° C. for 3.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the product (31 mg, 21%). This was further purified by HPLC (C18 X-select column, 35-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying (20 mg, 13%). LCMS (Method 5): Rt 4.40 min, m/z 635.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.80-2.18 (6H, m), 2.36 (3H, s), 3.44-3.51 (4H, m), 3.78-3.85 (4H, m), 4.77-4.85 (1H, m), 5.51 (1H, t, J 4.4), 6.32 (1H, s), 7.10-7.16 (2H, m), 7.25-7.40 (8H, m), 7.60 (1H, d, J 9.6), 7.65 (1H, d, J 1.5), 8.10 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:11]=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:5][CH2:4][N:3]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[NH4+].[Cl-]>CO.O.[Zn]>[NH2:18][C:9]1[CH:10]=[N:11][N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:8]=1[N:6]1[CH2:5][CH2:4][N:3]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC1CN(c2c(N)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of (±) tert-butyl 2-methyl-4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)piperazine-1-carboxylate (370 mg, 0.94 mmol) in MeOH (15 mL) and H2O (3 mL) was added zinc (362 mg, 5.6 mmol) and NH4Cl (400 mg, 7.5 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, filtered through Celite, and evaporated under reduced pressure to afford tert-butyl (±)-4-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate as yellow solid (300 mg, 88%). MS (ESI) m/z: 364 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[CH2:5])C.[Br:25]N1C(=O)CCC1=O>O1CCCC1.O>[Br:25][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(=O)CBr)cc1
Yield: 100 %

Procedure:
To a cooled (0° C.) solution of 1,1-dimethylethyl [(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate (15 g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was added N-bromosuccinimide. The resulting solution was allowed to warn to room temperature and maintained for 90 minutes. The reaction was then concentrated and diluted with ethyl acetate (1 L). The resulting solution was washed with water (1 L) and brine (500 mL), dried (MgSO4) and concentrated to give 19.5 g (˜100%) of 1,1-dimethylethyl ((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate as a slightly yellow solid. ESMS [M+H]+: 386.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Br:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Br:25])=[C:15]([Br:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(Br)c(Br)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(Br)c(Br)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dibromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.