Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][C:15]3[O:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:18][N:19]=3)=[CH:6][CH:7]=2)=[CH:35][CH:34]=1)[CH3:27]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3Nc3nnc(-c4ccccc4)o3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH2:40][NH2:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:41][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=1)=[O:21]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.072 g, 0.190 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol) followed by (3-(trifluoromethyl)phenyl)methanamine (0.030 mL, 0.207 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (SF15-12, Analogix®, Burlington, Wis.), and the title compound was eluted with a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.50-7.55 (m, 1H), 7.37-7.44 (m, 2H), 7.17-7.34 (m, 11H), 6.30 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 4.07 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [Cl:1][C:2]([Cl:51])([Cl:50])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:49])[C@@H:14]([NH:34][C:35](=[O:48])[C@@H:36]([NH:40]C(OC(C)(C)C)=O)[CH:37]([CH3:39])[CH3:38])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:51][C:2]([Cl:1])([Cl:50])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:49])[C@@H:14]([NH:34][C:35](=[O:48])[C@@H:36]([NH2:40])[CH:37]([CH3:39])[CH3:38])[CH2:15][O:16][Si:17]([C:30]([CH3:32])([CH3:33])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (450 mg, 0.57 mmol) in anhydrous dichloromethane (10 mL) at 0° C. and under an atmosphere of nitrogen, was added trimethylsilyl trifluoromethanesulfonate (156 μL, 0.86 mmol). The reaction mixture was stirred at 0° C. for 2 h before adding N,N-diisopropylethylamine (410 μL, 2.30 mmol) and then concentrated in vacuo to afford (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH2:20][CH3:21])=[O:9])=[O:5]
Reactant: Nc1ccccc1C(=O)CCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(=O)c1ccccc1N

Procedure:
3-(2-Aminobenzoyl)propionic acid (26.7 g) and concentrated sulphuric acid (25 cc) in absolute ethanol (250 cc) are stirred for 17 hours at room temperature (approximately 20° C.). The ethanol is evaporated off under reduced pressure, water (200 cc) and ethyl acetate (200 cc) are added and potassium carbonate is added until the pH is 8. The mixture is filtered, and the aqueous phase decanted and re-extracted with ethyl acetate (2×100 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl 3-(2-aminobenzoyl)propionate (24.8 g) is obtained in the form of an oil. The proton NMR spectrum in deuterated chloroform shows the following characteristics:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-].[Na+].[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([O:15][C:16]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
To a solution of 108 g of o-phenylenediamine (1.0 mol) in 1000 mL of dioxane was added. 500 mL of 1N sodium hydroxide aq., and then 218 g of tert-butyldicarbonate (1.1 mol) in 500 mL of dioxane under ice-cooling. After stirring for 6 hours at room temperature, the mixture was left overnight. The mixture was concentrated to ½ volume by evaporation, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography (eluent: chloroform) to give a solid, which was then washed with diethyl ether to give 68.4 g of N-tertbutoxycarbonyl-o-phenylenediamine (Yield: 32.8%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH3:14][S:15]SC>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15][CH3:14])=[N:3][CH:4]=1
Reactant: CSSC
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CSc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a stirred solution of 2,5-dibromopyridine (5.00 g, 21.11 mmol) in anhydrous toluene (300 mL) at −78° C. under nitrogen was slowly added a solution of n-BuLi (10.13 mL, 25.33 mmol, 2.5M in hexanes). After 2 h at −78° C., methyl disulfide (2.47 mL, 27.44 mmol) was added. The reaction mixture was stirred for 1 h at −78° C. and was allowed to warm to room temperature, quenched with saturated NH4Cl to form a two-phase system. The organic layer was separated, washed with sat NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/hexane, 5/95) to afford the title compound 50 (2.74 g, 13.43 mmol, 64% yield) as a pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) δ(ppm): 8.49 (dd, J=2.3, 0.6 Hz, 1H), 7.60 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (dd, J=8.6, 0.8 Hz, 1H), 2.57 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>O1CCOCC1.C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:10][C:9](=[O:11])[C@@H:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:46]2
Reactant: O=C(O)C(Cc1ccccc1)Nc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@H](Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3-phenyl-2-(phenylamino)propanoic acid (I21) (1.21 g, 5.01 mmol) in dioxane, a 4M solution of HCl in dioxane (5 mL) is added and the reaction is allowed to stir at RT for 1 hour; the solvent is evaporated under reduced pressure to obtain a white solid which is dissolved in dry THF (70 mL). DCC (1.22 g, 6.01 mmol), HOBt (0.8 g, 6.0 mmol) and 3(R)-quinuclidinol (1.31 g, 10.1 mmol) are added to the resulting solution and the mixture stirred for 24 hours at RT under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated. 1N HCl (20 mL) is added to the resulting crude and the aqueous layer is washed with EtOAc (2×50 mL); NaHCO3 is added to the aqueous layer (pH=7-8) and the product is extracted with DCM and dried over Na2SO4, to obtain 530 mg (35% yield) of diastereoisomer 1 of C22, which is further purified by preparative LC-MS to get the titled product as a brown oil (mixture of diastereoisomers that contains 20% of diastereoisomer 2 of C22, TFA salt).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]([F:25])([F:24])C(OC)=O.O>CN(C=O)C>[F:24][CH:19]([F:25])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OC(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (6 g), Cs2CO3 (25.7 g) and methyl 2-chloro-2,2-difluoroacetate (5 ml) in DMF (50 ml) was stirred at 90° C. for 1 h. At room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed twice with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1:1 (v/v)] as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Hydroxyphenyl)cyclohexanone (4.98 g, 26.18 mmol), benzyl bromide (4.92 g, 28.79 mmol), K2CO3 (5.06 g, 36.65 mmol) and 75 mL of acetone were mixed in a reaction flask equipped with a reflux condenser. The mixture was heated to reflux and stirred overnight. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting solid was recrystallized in ethyl acetate to provide the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.80-2.00 (m, 2 H), 2.13-2.26 (m, 2 H), 2.43-2.55 (m, 4 H), 2.91-3.05 (m, 1 H), 5.05 (s, 2 H), 6.94 (d, J=8.82 Hz, 2 H), 7.16 (d, J=8.82 Hz, 2 H), 7.28-7.48 (m, 5 H); MS (DCI) m/z 298 (M−NH4)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:30]=[C:31]([O:35][CH3:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cnc(OC)nc4OC)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12m and 3-bromoanisole
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[C:51](O)=[O:52])=[O:44])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([O:14][C:51](=[O:52])[CH:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])[CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:43]([O:42][CH2:41][C:38]2[CH:37]=[CH:36][CH:35]=[CH:40][CH:39]=2)=[O:44])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 96 mg of 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (MW: 481.52, 0.2 mmol), 195 mg of Z-Lys (Z)—OH (MW: 414.46, 0.4 mmol) and 49 mg of 4-dimethylaminopyridine (MW: 122.17, 0.4 mmol) in 2 ml dichloromethane was treated under stirring at room temperature with 115 mg N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid hydrochloride (MW: 191.70, 0.6 mmol). The reaction mixture was stirred over night. The mixture was diluted with 20 ml ethyl acetate and the organic layer washed successively with 10 ml N aqueous hydrochloric acid, 20 ml water and 20 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography on silica, using a 9/1 dichloromethane/methanol mixture as eluent to leave a colorless sticky oil. Yield: 150 mg, 88%. MS: 878.8 (M+H)+, Method ESI+.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][C:4]([O-:6])=[O:5].[Li+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=C([O-])CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of lithium 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (2.0 g, 7.9 mmol) (Example 2A) in water (15 ml) is added a solution of Aliquat 336® (3.1 g) and benzyl bromide (1.35 g, 7.5 mmol) in dichloromethane (15 ml). The reaction mixture is stirred for two days at room temperature, then extracted with dichloromethane (500 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[OH:12][C:13]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[CH3:20][C:13]1([OH:12])[CH2:19][CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC1(O)CCCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(O)CC1
Temperature: 130 °C
Yield: 67.2 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (390 mg, 2.4 mmol) and 4-hydroxy-4-methylazepane hydrochloride (0.48 g, 2.9 mmol) in EtOH (9.5 mL) was added DIPEA (1.9 ml, 10.9 mmol). The reaction mixture was heated at 130° C. in a microwave for 1 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (0-5% MeOH/DCM) to give 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a colorless oil (410 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.77 (s, 3H), 3.56-3.47 (m, 1H), 3.28-3.20 (m, 2H), 3.08-3.04 (m, 1H), 2.17-2.03 (m, 1H), 1.95-1.81 (m, 4H), 1.78-1.67 (m, 1H), 1.56 (br s, 1H), 1.25 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([N:13]([CH3:25])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a solution of the compound (12.1 g) obtained in step 1 in DMF (55 mL) was added sodium hydride (1.82 g) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, methyl iodide (11.4 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10% ethyl acetate/hexane) to give tert-butyl [3,5-bis(trifluoromethyl)phenyl](methyl)carbamate (12.5 g, 99%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
To a solution of compound 1 (600 mg, 1.36 mmol) in dry DMF (10 mL) was added NaH (60%, 60 mg, 1.50 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. Ethyl 2-bromoacetate (225 mg, 1.36 mmol) was added and then this mixture was stirred at rt for 5 h. Water was added for quench and the solution was extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=5/1) to give compound 42 (150 mg, 21%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCN1CCOCC1

Procedure:
5.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.9 ml of 4-(2-aminoethyl)morpholine are boiled under reflux for 18 h in 50 ml of tetrahydrofuran. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-morpholin-4yl-ethyl)acetamide remains as colorless crystals of m.p. 180-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][N:8]2[CH2:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1n[nH]c2cc(Cl)ccc12
Reactant: Fc1cccnc1CCl
Product: N#Cc1nn(Cc2ncccc2F)c2cc(Cl)ccc12
Yield: 92.7 %

Procedure:
2.3 g (12.95 mmol) of 6-chloro-1H-indazole-3-carbonitrile (WO 2011/149921, Expl. 58C) were reacted in analogy to Example 53A with 2.07 g (14.25 mmol) of 2-(chloromethyl)-3-fluoropyridine. 3.44 g of the title compound were obtained (93% of theory).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][CH2:26][C:27]([O-])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:24]([O:31][CH3:32])=[O:30])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)OC
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), mono-methyl succinate (156 mg, 1.18 mmol), HBTU (536 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature over the weekend. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 70% ethyl acetate in hexane. The product fractions were combined and concentrated to give methyl 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoate as an oil (520 mg, 105%). LC-MS m/z 418 (M+H)+.