Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[CH:12]=[C:11](C(C)(C)C)[CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:17])(C)(C)C.[C:18]([C:22]1[CH:27]=[C:26](C(C)(C)C)[CH:25]=[CH:24][C:23]=1[OH:32])(C)(C)C.[NH2:33][C@H:34]1CCCC[C@@H:35]1[NH2:40].O>C(O)C>[CH:11]1[CH:12]=[CH:5][C:6](=[O:17])/[C:7](=[CH:8]\[NH:33][CH2:34][CH2:35][NH:40]/[CH:18]=[C:22]2\[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]\2)=[O:32])/[CH:10]=1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CCO
Product: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O

Procedure:
3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected by filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand 2 obtained in this manner was 90-97%.
Reaction SMILES: Br.[O:2]([CH2:4][CH2:5][Br:6])[NH2:3].C(O)(=O)C.N1C=CC=CC=1.[CH3:17][CH:18]1[C:25]2[N:24]3[CH:26]=[CH:27][CH:28]=[C:23]3[CH2:22][C:21]=2[S:20][C:19]1=O>C(O)C>[CH3:17][C:18]1[C:25]2[N:24]3[CH:26]=[CH:27][CH:28]=[C:23]3/[C:22](=[N:3]/[O:2][CH2:4][CH2:5][Br:6])/[C:21]=2[S:20][CH:19]=1
Reactant: CC1C(=O)SC2=C1n1cccc1C2
Reactant: NOCCBr
Agent: Br
Solvent: CCO
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCBr
Yield: 23 %

Procedure:
Add 5 g of 2-aminoxy-1-bromoethane hydrobromide, 1.5 mol of glacial acetic acid and 1.6 ml of pyridine in succession to a suspension of 1.43 g of 3-methyl-8H-thieno[2,3-d]pyrrolo[1,2-a]pyrrol-2-one (Preparation 29) in 70 ml of ethanol. The reaction mixture is heated at reflux for 3 hours, then the ethanol is removed under reduced pressure and the residue is extracted with 100 ml of diethyl ether. After washing with water, drying, concentrating to dryness and working up again in a diethyl ether/petroleum ether mixture, 1:1, the title compound is obtained in the form of a powder.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:17]([Cl:18])=[C:16](I)[CH:15]=[CH:14][C:13]=1[NH:20][C:21](=[O:29])[C@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24].CCOC(C)=O>CN(C=O)C.[Cu-]=O>[CH3:11][C:12]1[C:17]([Cl:18])=[C:16]([S:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[NH:20][C:21](=[O:29])[C@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:24])[F:25]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: Cc1c(NC(=O)[C@@](C)(O)C(F)(F)F)ccc(I)c1Cl
Agent: O=[Cu-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)[C@@](C)(O)C(F)(F)F)ccc(Sc2ccc(C(=O)O)cc2)c1Cl
Temperature: 150 °C
Yield: 89.3 %

Procedure:
4-Mercaptobenzoic acid (308 mg) was added to a suspension of Copper(I) oxide (93 mg) and (R)-N-(2-methyl-3-chloro-4-iodo-phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 46) (530 mg) in DMF (5 ml). The mixture was heated under Argon to 150° C. for 4.5 hours. The mixture was allowed to cool to ambient temperature and EtOAc (100 ml) was added and the resulting suspension was filtered through diatomaceous earth, and volatile material was removed by evaporation. The residue was purified by chromatography, eluting with 5-10% MeOH in DCM to give the title compound (504 mg). NMR: 1.58 (s, 3H), 2.26 (s, 3H), 7.34 (m, 4H), 7.51 (brs, 1H), 7.92 (brs, 2H), 9.94 (s, 1H), 13.00 (brs, 1H); m/z 432.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:18])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([F:17])[CH:8]=3.[CH3:19][OH:20]>>[F:16][C:11]1[CH:10]=[C:9]([F:17])[CH:8]=[C:7]2[C:12]=1[N:13]=[C:14]([CH3:15])[C:5]1[N:6]2[C:2]([O:20][CH3:19])=[N:3][C:4]=1[CH3:18].[Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:18])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([F:17])[CH:8]=3
Reactant: CO
Agent: Cc1nc(Br)n2c1c(C)nc1c(F)cc(F)cc12
Product: COc1nc(C)c2c(C)nc3c(F)cc(F)cc3n12

Procedure:
Examples 70-73 were prepared according to the general Suzuki coupling procedure Example 19 using 1-bromo-6,8-difluoro-3,4-dimethylimidazo[1,5-a]quinoxaline (8A). Example 73 6,8-difluoro-1-methoxy-3,4-dimethylimidazo[1,5-a]quinoxaline was obtained from 1-bromo-6,8-difluoro-3,4-dimethylimidazo[1,5-a]quinoxaline (8A) and methanol (stirred for 2 hours at room temperature).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1
Reactant: COc1ccc(CO)nc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=O)nc1

Procedure:
To a solution of 5.7 g (41 mmol) (5-methoxypyridin-2-yl)methanol in 100 mL CHCl3 was added 15 g MnO2 and the mixture heated to reflux for 2 hours, filtered, and washed with boiling CHCl3. The filtrate was washed with brine, dried over MgSO4, and concentrated in vacuo to afford 5-methoxypyridine-2-carbaldehyde as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.3 (dd, J=8.4, 2.4 Hz, 1H), 3.95 (s, 2H).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[CH3:7].ClC(Cl)C.Cl>C1COCC1>[C:16]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=2)[CH2:2][CH2:1]1)#[N:17]
Reactant: [Li]CCCC
Reactant: CCOc1ccc(CC#N)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: CCOc1ccc(C2(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6M n-Butyllithium (680 ml) is added over 5 min to a stirred solution of 4-ethoxyphenyl acetonitrile (56 g) in anhydrous THF (600 ml) at 25° C. under an atmosphere of nitrogen. After 1 h, a solution of 1.2 dichloroethane (111 g) in anhydrous THF (300 ml) is added dropwise over 2 h and the mixture stirred at 25° C. for 16 h. The mixture is then poured onto 3N HCl (1 l ), concentrated under reduced pressure, extracted with diethyl ether (x3), washed with water, dried over anhydrous sodium sulphate, the solvent removed under reduced pressure and the residue distilled to give the product, b.p. 116°-120° C., yield 40 g. nD 1.5320.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C=CC(=O)c2ccc(C)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(CCCc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 99.4 %

Procedure:
To a suspension of 2.14 g of 4,4'-dimethylchalcone in 40 ml of acetic acid was added 0.2 g of 5% palladium on carbon. The reaction vessel was purged with hydrogen gas, and the mixture was vigorously stirred at room temperature for 8.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give 2.02 g of the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C@H:17]2[C@H:22]([CH2:23][OH:24])[CH2:21][CH2:20][N:19]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]1([C@H:17]2[C@H:22]([CH:23]=[O:24])[CH2:21][CH2:20][N:19]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(N1CC[C@@H](CO)[C@H](c2ccccc2)C1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@@H]1CCN(C(=O)C(F)(F)F)C[C@H]1c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, to a solution of 1.62 mL of DMSO in 40 mL of dichloromethane cooled in a dry ice-acetone bath was added dropwise 0.996 mL of oxalyl chloride, while keeping the inner temperature at −70° C. or lower. After stirring for 10 minutes, a solution of 1.64 g of rel-[(3R,4R)-3-phenyl-1-(trifluoroacetyl)piperidin-4-yl]methanol in 25 mL of dichloromethane was added dropwise thereto over 20 minutes. After stirring over 10 min while keeping it at −70° C. or lower, 4.77 mL of triethylamine was added dropwise thereto over 15 min, and the reaction system was warmed to −30° C., followed by stirring for 15 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by warming to room temperature. After extraction with chloroform, the organic layer was washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain rel-(3R,4R)-3-phenyl-1-(trifluoroacetyl)piperidine-4-carbaldehyde as a crude product (as a pale yellow oily substance, 1.78 g).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][C:11]=2[NH:22][C:23]([C:25]2[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=2)[CH2:28][S:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH:5]=1)=[O:3].[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1.CCN(C(C)C)C(C)C.CN>O1CCCC1.O>[O:42]1[CH2:43][CH2:44][N:45]([C:48]2[CH:49]=[CH:50][C:51]([CH2:54][NH:55][C:2]([C:4]3[CH:9]=[CH:8][N:7]=[C:6]([C:10]4[CH:15]=[C:14]([N:16]5[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]5)[CH:13]=[CH:12][C:11]=4[NH:22][C:23]([C:25]4[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=4)[CH2:28][S:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH:5]=3)=[O:3])=[CH:52][CH:53]=2)[CH2:46][CH2:47]1
Reactant: NCc1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)Cl)ccn2)c1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(N4CCOCC4)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.3 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(3-(2-(4-(chlorocarbonyl)pyridin-2-yl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)-propanoate (120 mg, 0.20 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), (4-morpholinophenyl)methanamine (68 mg, 0.35 mmol, 1.50 equiv), and DIPEA (32 mg, 0.25 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at room temperature. An additional 68 mg of 4-morpholinophenyl)methanamine was added. The resulting solution was stirred for an additional 2 h at room temperature. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 200 mg of crude product as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[C:10](=[O:15])[O:11]2)=O)(C)(C)C.[CH3:16][S:17]([OH:20])(=[O:19])=[O:18]>C(OCC)(=O)C>[CH3:16][S:17]([O-:20])(=[O:19])=[O:18].[O:15]=[C:10]1[C@@H:9]2[CH2:14][C@@H:12]([CH2:13][NH2+:8]2)[O:11]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C(=O)O2
Reactant: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)[O-]
Product: O=C1O[C@@H]2C[NH2+][C@H]1C2
Temperature: 45 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
(1S,4S)-3-Oxo-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (100.0 g, 469 mmol) was dissolved in ethyl acetate (970 mL) and methanesulfonic acid (43.5 mL, 659 mmol) was added at 45° C. The mixture was stirred for 16 h at 45° C. The suspension was cooled to room temperature, filtered, and the precipitate was washed with ethyl acetate (240 mL) and dried in vacuo to yield the title compound as a white crystalline solid (94.2 g, 96%). MS (EI, neg): m/z=113 [cation-H]+, 69 [cation-H—CO2]+, 68 [cation-H—HCO2]+. 1H NMR (DMSO-d6, 600 MHz): δ 2.12 (dd, J=1.2 Hz, 12.0 Hz, 1H), 2.33 (s, 3H), 2.59 (d, J=12.0 Hz, 1H), 3.33 and 3.50 (ABX, JAB=12.0 Hz, JAX=1.9 Hz, JBX=0 Hz, each 1H), 4.58 (s, 1H), 5.41 (s, 1H), 9.74 (br s, 2H).
Reaction SMILES: C([O:4][CH:5]1[CH2:8][CH:7]([C:9](=[O:41])[NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:30]([CH3:33])[C:31]=4[CH3:32])=[O:26])=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)[CH2:6]1)(=O)C.[OH-].[Na+]>CO>[OH:4][CH:5]1[CH2:6][CH:7]([C:9]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:30]([CH3:33])[C:31]=4[CH3:32])=[O:26])=[N:20][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[O:41])[CH2:8]1
Reactant: CC(=O)OC1CC(C(=O)Nc2cc(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)nc3)ccn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC(O)C4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
A solution of 3-((4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutyl acetate (40 mg, 0.072 mmol) in MeOH (2.5 mL) was cooled to 0° C., then NaOH (6 mg, 0.144 mmol) was added to the mixture. The reaction was stirred at rt for 1 hour, then concentrated in vacuo. The residue was washed with water (5 mL) and ether (5 mL), then filtered to give the title compound as a white solid (17 mg, 42%).
Reaction SMILES: [Cl:1]Cl.[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26](SC(C)(C)C)[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26]([Cl:1])[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CN=[N+]=[N-]
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CN=[N+]=[N-])C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
286 μl of a solution of chlorine in carbon tetrachloride containing 1.14 g/10 ml is added at -60° C. to a solution of 110 mg of p-nitrobenzyl 5-azido-2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 9 ml of methylene chloride. The reaction solution is evaporated in a rotary evaporator, 119 mg of yellow oil being obtained. IR spectrum in CH2Cl2 : 2930, 2860, 2105, 1780, 1755, 1720, 1610, 1530, 1350, 1190 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]([CH:22]=O)[N:11](CC3C=CC(OC)=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:35](I)=[CH:34][N:33]([Si](C(C)C)(C(C)C)C(C)C)[C:30]2=[N:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:35]([CH2:22][C:10]3[NH:11][N:12]=[C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=4)[CH:9]=3)=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C=O)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Product: Fc1ccc(CNc2cc(Cc3c[nH]c4ncc(Cl)cc34)[nH]n2)cc1

Procedure:
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine P-2016 was prepared in three steps from 5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazole-3-carbaldehyde 113 and 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4 as shown in Scheme 19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17](=[O:20])[CH2:18]Cl)[CH2:15][CH2:14][NH:13][C:12]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17](=[O:20])[CH2:18][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:15][CH2:14][NH:13][C:12]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COc1ccc(C2C(=O)NCCN2C(=O)CCl)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(=O)NCCN2C(=O)CN2CCOCC2)cc1OC

Procedure:
7.8 g of the 3-(3,4-dimethoxyphenyl)-4-chloroacetylpiperazin-2-one prepared in accordance with Example 7, 50 ml of toluene and 4.5 g (0.05 mol) of morpholine are boiled under reflux for 3 hours. The reaction mixture is then concentrated in vacuo, an aqueous solution of potassium carbonate is added to the residue and the mixture is extracted by shaking with methylene chloride. The organic phase is separated off and the methylene chloride is removed by evaporation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br>>[Br:10][CH2:11][CH2:12][O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrCCBr
Reactant: Cc1cccc(C)c1O
Product: Cc1cccc(C)c1OCCBr

Procedure:
2,6 Dimethylphenol (2 mmol) was reacted with 1,2-dibromoethane (10 eq) as described in Step 2A to yield the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[C@:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)([OH:12])[CH2:10][C@H:9]2[CH2:20][C@@H:6]1[CH2:7][CH2:8]2)[CH3:3].CCN([CH2:26][CH3:27])CC.O.[C:29]([O-:32])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:5]1([C@H:26]([CH3:27])[C:29]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C@@:11]3([OH:12])[CH2:10][C@H:9]4[CH2:20][C@H:6]([CH2:7][CH2:8]4)[C@@H:5]3[CH2:4][N:2]([CH3:1])[CH3:3])[CH:14]=2)=[O:32])[CH:11]=[CH:10][CH:9]=[CH:20][CH:6]=1
Reactant: CN(C)C[C@H]1[C@H]2CC[C@H](C2)C[C@]1(O)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CC
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](C(=O)Oc1cccc([C@@]2(O)C[C@@H]3CC[C@@H](C3)[C@@H]2CN(C)C)c1)c1ccccc1
Yield: 84.7 %

Procedure:
Stir a solution of (S)-2-phenylpropanoic acid (300 mg, 2.0 mmol) in 5 mL of oxalyl chloride for 3 hours at room temperature. After removal of solvent under vacuum, (S)-2-phenylpropanoyl chloride is obtained as pole yellow oil. Dissolve the oil in 10 mL of CH2Cl2. Add (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (400 mg, 1.45 mmol) and Et3N (293 mg, 2.9 mmol) to the solution. Stir the resultant mixture at room temperature for additional 3 hours. After addition of 20 mL of water, basify the mixture with K2CO3 to pH=10, and extract the aqueous mixture with EtOAc (20 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (500 mg, 84.7%; MS (m/z): 408 (M+1)) as yellow oil. Stir (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (250 mg, 0.61 mmol) with H2O (11 mg, 0.61 mmol) and TMSCl (66 mg, 0.61 mmol) in 2-butanone (5 mL) for 3 hours. Collect the precipitate by filtration to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochlorid (215 mg, Yield: 79.3%) as white solid. The absolute configuration of its hydrochloride salt form was confirmed by x-ray analysis. 1H NMR (400 MHz, DMSO) δ 9.81 (br, 1H), 7.31-7.41 (m, 7H), 7.14 (s, 1H), 6.87-6.90 (m, 1H), 5.01 (s, 1H), 4.08-4.10 (m, 1H), 3.02-3.08 (m, 1H), 2.42-2.58 (m, 4H), 2.12-2.26 (m, 6H), 1.90-1.99 (m, 2H), 1.75-1.80 (m, 2H), 1.51-1.59 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.[C:12]1(OC)C=CC=CC=1.[F:20][C:21]([F:28])([F:27])[S:22]([O:25]C)(=[O:24])=[O:23]>C(OCC)(=O)C>[F:20][C:21]([F:28])([F:27])[S:22]([O-:25])(=[O:24])=[O:23].[Cl:1][CH:2]1[NH+:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]1[CH3:12]
Reactant: COc1ccccc1
Reactant: Clc1nc2cccccc-2n1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CN1C2=CC=CC=CC2=[NH+]C1Cl
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2-Chlorocycloheptimidazole (0.78 g) was added to 4 ml of anisole, 0.93 g of methyl trifluoromethanesulfonate was added dropwise thereto, and the mixture was stirred at room temperature for 40 minutes. Then, 50 ml of ethyl acetate was added to the reaction solution, and deposited crystals were collected by filtration and dried.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)[N:17]([C:32]3[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[CH:33]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][CH:12]=4)=[CH:16][N:17]3[C:32]3[CH:33]=[C:34]([NH:38][CH3:39])[N:35]=[CH:36][N:37]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CNc1cc(-n2cc(-c3cccc(N)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1cc(-n2cc(-c3cccc(NC(C)=O)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
Acetic anhydride (20.3 μL, 0.214 mmol) was added to a mixture solution of 6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (30 mg, 0.071 mmol) and pyridine (28.7 μL, 0.355 mmol) in methylene chloride (2 mL) at room temperature. After stirring for 1 hour at room temperature, the reaction solution was added to saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([CH2:27][S:28]C(=O)C)[CH:6]([C:13]1[CH:14]=[N:15][C:16]([NH:19]C(OC(C)(C)C)=O)=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>Cl>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]([CH2:27][SH:28])[C:4]([OH:32])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(CSC(C)=O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: Cl
Product: Nc1ccc(C(c2ccccc2)C(CS)C(=O)O)cn1

Procedure:
2-Acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl )-3-phenyl-propionic acid ethyl ester (58 mg, 0.125 mmol) was dissolved in conc. HCl (3.0 mL). The solution was heated to reflux for 130 min under argon. Concentration under reduced pressure gave the title compound as the hydrochloride salt (41 mg, 100%).