Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][CH:49]([CH:76]([CH3:78])[CH3:77])[C:50]([N:52]1[CH2:56][CH2:55][CH:54]2[N:57]([C:70]3[N:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:58][CH:59]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:53]12)=[O:51]>CN1C(=O)CCC1.C(OCC)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]([C:11](=[O:13])[NH:48][CH:49]([C:50]([N:52]1[CH2:56][CH2:55][CH:54]2[N:57]([C:70]3[N:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:58][CH:59]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:53]12)=[O:51])[CH:76]([CH3:77])[CH3:78])[CH3:10])[CH3:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution containing Boc-N(Me)Ala-OH (75 mg, 0.37 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (140 mg, 0.37 mmol) and DIPEA (52 mg, 0.42 mmol) were added followed by the addition of 73 (148 mg, 0.35 mmol) in anhydrous NMP (3 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with diethyl ether and washed successively with water, aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 202 mg of crude 74 which was used without further purification. Mass spectrum, m/z [608] (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:6]=O)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.[Cl:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[N:22][N:21]2[C:27]=1[S:28]([NH2:31])(=[O:30])=[O:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[N:22][N:21]2[C:27]=1[S:28]([N:31]=[CH:6][N:5]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Reactant: CC(C)CN(C=O)CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12)CC(C)C
Reaction time: 0.5 h

Procedure:
N,N-Diisobutylformamide (5.44 g, 34.5 mmol) was dissolved in chloroform (25.0 mL) and cooled in an ice-sodium chloride bath, and phosphorus oxychloride (3.22 mL, 34.5 mmol) was added dropwise thereto at −2° C. or less. After the mixture was stirred at −2° C. or less for 30 minutes, 2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (6.15 g, 23.0 mmol) was added thereto. After the mixture was stirred at −10° C. for 10 minutes, triethylamine (19.3 mL, 138 mmol) was added dropwise over 20 minutes to the solution at 5° C. or less. The mixture was stirred for 1 hour at 0° C. or less and for 1 hour at room temperature, then poured into an aqueous saturated sodium bicarbonate and extracted 5 times with chloroform. The extracts were combined, dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound as pale yellow crystals. The yield was 5.58 g (59.6%).
Reaction SMILES: Cl.O.C([NH:6][C:7]1[CH:24]=[CH:23][C:10]2[N:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[C:12]3[S:13][C:9]=2[CH:8]=1)(=O)C>COCCO>[NH2:6][C:7]1[CH:24]=[CH:23][C:10]2[N:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[C:12]3[S:13][C:9]=2[CH:8]=1
Reactant: CC(=O)Nc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Agent: Cl
Solvent: O
Solvent: COCCO
Product: Nc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Reaction time: 4 h
Yield: 83.1 %

Procedure:
To a mixture of 100 ml of concentrated hydrochloric acid solution and 300 ml of methylcellosolve was added 8.5 g of 7-acetamido-2-phenylimidazo[2,1-b]benzothiazole mono-hydrate and the mixture was stirred for 4 hours at 100°-110° C. The reaction mixture was cooled to form crystals, which were recovered by filtration. The crystals were suspended in 200 ml of methylcellosolve and after alkalifying the suspension by adding concentrated aqueous ammonia, 80 ml of water was added to the mixture followed by cooling, thereby crystals precipitated. The crystals precipitated were recovered by filtration and dried to provide 5.76 g of 7-amino-2-phenylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]([F:30])([F:29])[F:28])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)=O.[CH3:31][NH:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CN(C=O)C>[CH3:31][N:32]([CH2:1][C:3]1[C:4]([C:27]([F:29])([F:28])[F:30])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)[CH3:33]
Reactant: CNC
Reactant: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
2-(2-(4-Formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (30 mg, 0.068 mmol), Dimethylamine (2M solution in THF, 0.169 mL, 0.34 mmol) and DMF (1 mL) were treated with acetic acid (5 drops) and sodium triacetoxyborohydride (57.2 mg, 0.270 mmol) and the mixture stirred at RT overnight. The sample was filtered and purified by preparative reverse phase HPLC followed by additional purification by SCX ion exchange chromatography to yield the title compound (13.5 mg, 0.029 mmol, 42%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].[H-].[Na+].[CH3:14]I.O>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH3:14]
Reactant: Cc1cccc(CCO)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCc1cccc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-(2-bromo-3-methylphenyl)ethanol (1.6 g, 7.4 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (50% in oil) (0.46 g, 9.6 mmol). After stirring the mixture for 15 min methyl iodide (1.6 g, 11.3 mmol) was added and the reaction mixture was stirred for 3 h. at room temperature. Water (0.2 g) was added and then acetic acid (0.2 g). The solvents were evaporated under reduced pressure and purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 1.5 g (89%) of the desired product as an oil.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]1>C(O)(=O)C>[CH2:1]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C(CC1CCNCC1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(CC1CCN(Cc2ccccc2)CC1)C(=O)OCC
Temperature: 62.5 °C
Reaction time: 12 h

Procedure:
Benzyl chloride (54.4 g) and sodium carbonate (149.4 g) were added to the solution of the acetic acid salt of diethyl (4-piperidylmethyl)malonate [XXIXb] from the previous step. The obtained slurry was stirred for 12 hours at 60-65° C. and evaporated under reduced pressure. Water was added to the residue and the obtained mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, passed through short silica gel column and evaporated under reduced pressure. The obtained residue was washed with hexanes and dried under reduced pressure to give diethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIb].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(Cl)C=1C(C1C2C(=NC=C([C:41]3[CH:42]=[N:43][N:44]([CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:45]=3)C=2)NC=1)C>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:41]3[CH:42]=[N:43][N:44]([CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:45]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Reactant: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12

Procedure:
Prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine according to typical Suzuki coupling procedure described for synthesis of 3-[1-(2,6-Dichlorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in example 1. MS (ES+): m/z 458.01, 460.03 [MH+]. HPLC: tR=2.34 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=[O:13])[CH:8]([N:10]=[N+]=[N-])[CH3:9])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12>C(OCC)(=O)C.[Pd]>[C:4]1(=[O:14])[N:5]([CH2:6][C:7](=[O:13])[CH:8]([NH2:10])[CH3:9])[C:1](=[O:19])[C:2]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:3]12
Reactant: CC(N=[N+]=[N-])C(=O)CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(N)C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 4, 1-phthalimido-3-azido-2-butanone, ethylene ketal in ethyl acetate is reduced with molecular hydrogen and palladium on charcoal to give 1-phthalimido-3-amino-2-butanone, ethylene ketal.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N+:12]([O-])([O-:14])=[O:13].[Na+]>>[N+:12]([C:6]1[CH:7]=[C:8]2[C:3]([CH2:2][CH2:1][CH2:11][C:9]2=[O:10])=[CH:4][CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCCc2ccccc21
Agent: [Na+]
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
10.0 g (68 mmol) of α-tetralone were dissolved in 80 ml of conc. sulftric acid with ice-cooling. After addition of 6.4 g (75 mmol) of sodium nitrate in portions, the mixture was additionally stirred at 0° C. for 1 h and then poured onto 350 ml of ice water. The precipitated product was filtered off with suction, washed with water until neutral, dried in vacuo and recrystallized from isopropanol. 6.5 g of 7-nitro-3,4-dihydro-2H-naphthalen-1-one were obtained, m.p. 104-106° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5](OS(C)(=O)=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 33.1 %

Procedure:
Methanesulfonyloxy-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester (I102) (594 mg, 1.82 mmol), aniline (0.25 mL, 2.73 mmol), and DIPEA (0.48 mL, 2.73 mmol) are dissolved in acetonitrile (4 mL). The reaction is heated under microwave irradiation at 100° C. for 1 hour and 30 minutes. Aniline (0.17 mL, 1.820 mmol) is added again and the reaction is heated under microwave irradiation at 100° C. for 3 hours. Acetonitrile is removed under vacuum and the residue is purified by flash chromatography (Petroleum ether/DCM=75/25) to afford intermediate I151 as a yellow oil (195 mg, 60% yield).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=453.8 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoate (700 mg, 1.87 mmol) was dissolved in 45 mL MeOH/H2O (8:1) and treated with NaOH (2 M, 10.8 mmol, 5.4 mL). The reaction was complete in 2 hours and was acidified with 1 M HCl and extracted 3×EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give pure 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (620 mg, 92%) as a clear oil. MS found: (M+H)+=361
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:27])=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)[CH:2]=[CH2:3].F[B-](F)(F)F.[CH3:34][O+](C)C.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:27][CH3:34])=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC1(c2ccc(C(O)=C3C(=O)Oc4ccccc43)cc2)CC1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)NC1(c2ccc(C(OC)=C3C(=O)Oc4ccccc43)cc2)CC1

Procedure:
1 g of allyl(1-{4-[hydroxy-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)-carbamate, 0.78 g of trimethyloxonium tetrafluoroborate (Meerwein salt), and 1 mL of diisopropylethylamine (Hünig base) were refluxed in 20 mL of dichloromethane for 2 hours, then another 1 mL of Hünig base and 0.5 g of Meerwein salt were added and the mixture was refluxed again for 2 hours. After cooling, the mixture was extracted 3× with water, and the organic phase was dried over MgSO4 and evaporated down to the residue. Yield: 1.05 g of crude.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[CH2:31][C:32](O)=[O:33].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH:23]1[CH2:31][C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:33]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CC1Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CC1Cc2ccccc2C1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 77.1 %

Procedure:
Preparation of example 121 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131 mmol), indan-2-yl-acetic acid (28 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. When the reaction was judged complete, the mixture was filtered to collect the solids, which were then washed with methanol. After drying under vacuum, the title compound (45 mg, 0.101 mmol) was obtained as a yellow powder in 77% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[C:16]12[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:21]C(=O)O[C:17]2=[O:18].C([O-])(O)=O.[Na+]>CS(C)=O>[C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:17](=[O:18])[C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH2:21])[CH:10]=2)[C:6]([CH3:15])([CH3:14])[CH2:7]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3ccccc3N)cc21
Temperature: 150 °C

Procedure:
A mixture of 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (1.02 g, 5 mmol) and isatoic anhydride (0.85 g, 5.2 mmol) in DMSO (5 mL) was heated to 150° C. for 6 h. After cooling to RT, the mixture was suspended in a NaHCO3 solution (40 mL) and extracted with CH2Cl2 (20 mL×3). The organic solution was combined and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (EtOAc:hexanes 9:2) to give the desired compound as an off-white solid.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[CH:20]N(C)C)[CH:18]=O>CO>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:20]=[C:6]([C:4]#[N:5])[C:7](=[O:8])[NH:9][CH:18]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C=O)c1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(-c2ccccc2Cl)c[nH]c1=O

Procedure:
In the manner described in Example 6, a solution of 48.6 g. of sodium methoxide and 42.0 g. of cyanoacetamide in 1000 ml. of methanol and 93.6 g. of 2-(2-chlorophenyl)-3-(dimethylamino)-2-propenal is refluxed for 16 hours to yield 30.0 g. of a tan solid. The solid is recrystallized from ethanol to yield the product of the Example as white needles, m.p. 252°-254° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[C:17]([CH3:29])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:25][C:24]([F:26])([F:27])[C:23]([NH:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:16][C:17]=1[CH3:29])=[O:28]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2)cc(C)c1NC(=O)C(F)(F)F
Reaction time: 4.5 h
Yield: 74 %

Procedure:
A two-neck 100 ml round bottom flask equipped with a reflux condenser capped with a three-way stopcock was charged with 4-tert-butylphenylboronic acid (0.841 g, 4.724 mmol), N-(4-bromo-2,6-dimethylphenyl)-2,2,2-trifluoroacetamide (1.3346 g, 4.73 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), and Na2CO3 (1.009 g, 3.53 mmol). The reactor was purged of air (three vacuum/argon cycles) before degassed methanol (50 ml) was added. The reaction flask was placed in an ultrasound bath for 4.5 h. The solution was filtered on celite and evaporated. The residue was dissolved in 20 ml of CHCl3 and washed twice with water. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was recrystallized from a CHCl3/hexane mixture to afford 2,2,2-trifluoro-N-(4′-tert-butyl-3,5-dimethyl-biphenyl-4-yl)-acetamide as a white grey solid in 74% yield. 1H NMR (CDCl3): δ=1.36 (s, 9H, C(CH3)3); 2.28 (s, 6H, ortho-CH3); 7.30-7.31 (d, 2H, CHar); 7.44-7.50 (m, 4H, CHar).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)=[O:11]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 7-chloro-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione (prepared by cyclization of N-benzyloxycarbonyl-4-chloroanthranilic acid with phosphorus tribromide) (1.0 g, 5.06 mmol) in DMF (18 ml) was added 4-dimethylaminopyridine (62 mg). After 5 mins of agitation at room temperature, 4-aminomethyl-1-diphenylmethylpiperidine (1.56 g, 5.56 mmol) was added to the solution and stirred for 5 hours. The reaction mixture was diluted with AcOEt, washed twice with H2O, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel to give 2-amino-4-chloro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 892 mg (41%): mp 161°-162° C.
Reaction SMILES: [O:1]=[C:2]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[NH:9][N:8]=1)=[O:6].CO>[Pd].C1COCC1>[O:1]=[C:2]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:37])[F:36])[CH2:25][CH2:26]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[NH:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2[N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1-c1cc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)n[nH]1
Yield: 26.8 %

Procedure:
10% Pd/c (30 mg) was added to a stirred solution of 5-(2-Nitro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (160 mg, 0.3 mmol) in mixture of MeOH (60 mL) and THF (10 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 1.5 hrs at room temperature. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure. The crude was washed with ethyl acetate, filtered and dried to afford 40.3 mg (27% yield) of 5-(2-Amino-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.73%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.6 (m, 1H), 7.6 (m, 4H), 7.5 (m, 1H), 7.4 (d, 1H), 7.3 (s, 1H), 7.0 (s, 1H), 6.5 (m, 4H), 6.2 (m, 2H), 5.1 (m, 1H), 4.2 (m, 3H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).