Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([C:11]2([O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]2[O:14]C(=O)C)[OH:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH:35]1([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([C@:11]2([O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]2[OH:14])[OH:12])=[CH:10][C:3]=1[CH2:2][C:41]1[CH:42]=[CH:43][C:38]([CH:35]2[CH2:37][CH2:36]2)=[CH:39][CH:40]=1)#[N:6]
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
An Ar filled flask is charged with 2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile (1.60 g), 4-cyclopropyl-phenylboronic acid (1.0 g), potassium carbonate (1.85 g) and a degassed 3:1 mixture of acetone and water (22 mL). The mixture is stirred at room temperature for 5 min, before it is cooled in an ice-bath. Then palladium dichloride (30 mg) is added and the reaction mixture is stirred for 16 h at ambient temperature. The mixture is then diluted with brine and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in methanol (20 mL) and treated with 4 M aqueous potassium hydroxide solution (4 mL). The resulting solution is stirred at ambient temperature for 1 h and then neutralized with 1M hydrochloric acid. The methanol is evaporated, and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts collected are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[C:4]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:3]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[C:4]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:3]=1
Reactant: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1-n1cncn1)c(OCc1ccccc1)c2=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1-n1cncn1)c(O)c2=O
Yield: 81 %

Procedure:
Hydrogenolysis of N-(4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.40 mmol) as described for example 1 gave 0.134 g (82% yield) of the title compound white crystals (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (6H, d, J=6.5 Hz, 2×CH3), 3.60 (2H, t, J=8.5 Hz, CH2), 4.12 (2H, t, J=8.5 Hz, CH2), 4.25 (1H, m, CH), 4.48 (2H, d, J=6.8 Hz, NCH2), 7.13 (1H, dd, J=2.5 Hz and J=8.4 Hz, aromatic), 7.24 (1H, m, aromatic), 7.69 (1H, dd, J=5.8 Hz and J=8.6 Hz, aromatic), 8.18 (1H, s, CH), 8.46 (1H, s, CH), 8.66 (1H, broad t, NH), 11.41 (1H, broad, OH). HRMS (ESI+) calculated for C19H21FN7O3 [M+H+]: 414.1690. found: 414.1677.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([Br:22])[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[CH:25]1([CH2:28]O)[CH2:27][CH2:26]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:28][CH:25]3[CH2:27][CH2:26]3)[CH:18]=[C:17]([Br:22])[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: OCC1CC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC3CC3)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (1.0 g; 2.43 mmol), cyclopropylcarbinol (175 mg; 2.43 mmol) and tributylphosphine (1.07 mL; 4.38 mmol) was dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (1.1 g; 4.38 mmol) dissolved in THF (20 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane 1:9→2:3). Yield: 980 mg; 86%; HPLC-MS: m/z: 465.0 (M)+; Rt: 2.74 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:5]([N:7]([CH3:34])[C@@H:8]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6].Cl.[CH3:40]OC(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:5]([N:7]([CH3:34])[C@@H:8]([C:17]([NH:19][C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:40])=[CH:12][CH:11]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Agent: Cl
Product: COc1ccc(C[C@H](C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)N(C)C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-O-methyl-(D)-tyrosine (prepared by O-methylation of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (example 64)) with (L)-tryptophan methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-O-methyl-(D)-tyrosyl-(L)-tryptophan; FAB-MS m/e 528 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]=[O:21])=[CH:7]2.O.[CH2:23]1COCC1>>[OH:21][CH:20]([C:8]1[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:10](=[O:12])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH3:23]
Reactant: C1CCOC1
Reactant: Cc1ccccc1-n1c(C=O)cc2cccc(C)c2c1=O
Solvent: O
Product: Cc1ccccc1-n1c(C(C)O)cc2cccc(C)c2c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
8-Methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carbaldehyde 4161 (2.4 g, 8.6 mmol) was dissolved in anhydrous THF (280 mL) and cooled to −78° C. under a nitrogen atmosphere. Methyl MgBr (2 M, 5 mL, 10 mmol) was added slowly, and the resulting mixture was stirred at −78° C. for 2 h. H2O (5 mL) was added and then the solution was poured into ice-water (200 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue product was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, 3-(1-hydroxyethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 4102 (1.8 g, 71% yield) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[S:14])[O:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>CCO.O>[S:14]=[C:12]1[NH:11][C:10]2[CH:15]=[CH:16][C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])=[CH:8][C:9]=2[O:13]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=S)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(2-Thioxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid ethyl ester (76 mg) in 90% aq. EtOH was added NaOH (48 mg) at room temperature. After stirred for 16 h at room temperature, the reaction mixture was cooled to room temperature, diluted with water. The resulting aqueous layer was acidified with acetic acid and then extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (58 mg, 86.0%, brown solid)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:21][O:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:24][CH2:23][O:22][CH3:21])=[CH:9][CH:10]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: COCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of (RS)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid methyl ester (500 mg, CAS 143323-49-3) in DMF (4 ml) was treated under an argon atmosphere with 2-bromoethyl methyl ether (0.34 ml), cesium carbonate (695 mg) and tetrabutylammonium iodide (66 mg) and stirred at r.t. overnight. Then it was quenched with H2O and extracted with EtOAc. The organics were washed with water, dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane ->cyclohexane/EtOAc 4:1) to give (RS)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid methyl ester (434 mg, 72%) as viscous colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s 1H), 4.80 (d, J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4, 122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS (ES+) m/z 313.7 (M+1), 315.7 (M+1).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([O:23][CH3:24])[C:15]([O:21][CH3:22])=[CH:16][CH:17]=3)[CH:12]2[CH3:25])=[CH:7][CH:6]=1)([O-])=O>CO.O.[Pd].C(O)C>[ClH:1].[NH2:2][C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17](=[CH:16][C:15]([O:21][CH3:22])=[C:14]([O:23][CH3:24])[CH:13]=3)[CH:12]2[CH3:25])=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1OC)C(C)N(CCc1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Reaction time: 20 h
Yield: 72.3 %

Procedure:
A solution of N-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7,8-dimethoxy-1-methylisoquinoline hydrochloride (66.3 g, 0.17 m) in methanol (1 liter) and water (10 ml) was placed in an 1100 ml pressure bottle and 5% Pd/C catalyst (5.0 g) added under nitrogen. The mixture was hydrogenated at 40 psi in a Parr apparatus for 20 hr. The catalyst was removed by filtration and the solvent evaporated leaving an oily residue. The residue was dissolved in 95% ethanol (300 ml) and after 24 hr a solid had crystallized out which was collected by filtration and air dried giving 44.3 g (82%) of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline monohydrochloride. The free base could be obtained by basifying a solution of this salt with NaOH and extracting with CHCl3. Evaporation of the solvent and crystallization of the resulting oil from cyclohexane gives the base in 80% efficiency as a white solid. Melting point after drying at 60° for 26 hr under high vacuum 102°-103°.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:6]=1[NH:23][CH:24]([CH3:29])[C:25](OC)=[O:26])([O-:4])=[O:3]>CO>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:6]=1[NH:23][CH:24]([CH3:29])[C:25]([NH2:1])=[O:26])([O-:4])=[O:3]
Reactant: COC(=O)C(C)Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: CC(Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(N)=O

Procedure:
Ammonia was led at room temperature for 28 hours into a solution of 11.7 g of the methyl 2-[N-{2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl}amino]propionate, obtained according to Example I, in 100 ml of methanol. After evaporating to dryness under reduced pressure and recrystallizing from acetonitrile, an orange crystalline substance was obtained having a melting-point of 187° C. Elementary analysis: 47.67% C (calculated 47.60), 3.24% H (calculated 3.25) and 10.24% N (calculated 10.41).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=1)(=[O:9])=[O:8].O.NN>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)(=[O:9])=[O:8]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c(N)c2)c(OC)c1
Yield: 48 %

Procedure:
2,4,6-trimethoxystyryl-N-(4-methoxy-3-nitrophenyl)sulfonamide (7 mmol) was dissolved in ethanol (55 mL) in a round bottomed flask. Palladium catalyst (5% Pd/C, 275 mg) was added. Hydrazine hydrate (182 mmol) was then added in one porion. The resulting misture was refluxed for 5 h and the reaction prgress was monitored by TLC. When the reaction was complete, the palladium catalyst was removed by filtration and the filtrate was poured into a beaker containing ice cold water. The solution was stirred and a solid precipitate formed. The precipitated material was separated by filtration and dried in vacuum. (m.p. 143–145; yield 48%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[C:4]2[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]4)=[N:3][C:4]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCC(O)CC1
Reactant: FC(F)(F)c1cccc(-c2cnn3ccc(Cl)nc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CC[C@H](Nc2ccn3ncc(-c4cccc(C(F)(F)F)c4)c3n2)CC1

Procedure:
A mixture of 5-chloro-3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.336 mmol), 4-aminocyclohexanol (58.0 mg, 0.504 mmol), and DIEA (0.117 ml, 0.672 mmol) in 2-propanol (3 ml) was irradiated to 135° C. for 14 h in a Biotage microwave. After cooling, the mixture was diluted with saturated aqueous NaHCO3, and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. After absorbing on celite, the compound was purified by Isco (12 g silica, 1/5/4 MeOH/EtOAc/hex) to give trans-4-((3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)cyclohexanol (101 mg, 80% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[CH:25]=[CH:24][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[N+:26]([O-])=O)=[CH:4][CH:3]=1.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH2:26][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:8]=1[O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=1)[C:12]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: CC(C)CN1CCN(C(=O)c2ccc(OCc3ccc(F)cc3)c([N+](=O)[O-])c2)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CN1CCN(C(=O)c2ccc(OCc3ccc(F)cc3)c(N)c2)CC1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 89.3 %

Procedure:
To 85 ml of an ethanol solution containing 1-[4-(4-fluorobenzyloxy)-3-nitrobenzoyl]-4-isobutylpiperazine (HCl free form of Example 8) (17.5g) was added tin (II) chloride monohydrate (47.4 g) and the resulting mixture was stirred at 70° C. for 40 minutes. The mixture was poured into ice water, neutralized with sodium hydrogencarbonate, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 to 1:0), thereby yielding 14.5 g of 1-[3-amino-4-(4-fluorobenzyloxy)benzoyl]-4-isobutylpiperazine as a crystal. This compound (1.30 g) was converted into the corresponding hydrochloride salt as in the case of Example 8 which will be explained later, thereby yielding 1.51 g of the aimed compound. This compound is a crystal with a high hygroscopicity.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:20])[C:12]3[N:13]([CH2:16][CH2:17][CH2:18][N:19]=3)[C:14]=2[CH:15]=1>>[Cl:6][C:7]1[C:8]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][C:10]2[C:11](=[O:20])[C:12]3[N:13]([CH2:16][CH2:17][CH2:18][N:19]=3)[C:14]=2[CH:15]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Product: O=C1C2=NCCCN2c2cc(Cl)c(S(=O)(=O)Cl)cc21
Temperature: 71.5 °C
Yield: 6 %

Procedure:
Chlorosulfonic acid (6 mL, 90.3 mmol, 12.2 eq) was added slowly to solid 7-chloro-3,4-dihydropyrimido(1,2-a)indol-10-(2H)-one (1.64 g, 7.43 mmol) with cooling in an ice bath. The ice bath was removed and the reaction mixture was heated to 65-78° C. for 2 hours. After cooling to room temperature the reaction was added drop-wise via pipette onto ice keeping the temperature cold with an external ice bath. The reaction mixture was extracted with CHCl3 (3×) and CH2Cl2 (2×). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified on Biotage KP silica gel eluting with EtOAc to give the title compound as a bright yellow solid (0.142 g, 6% yield). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:35][C@H:36]([CH:55]([CH3:57])[CH3:56])[C:37]([N:39]1[CH2:44][CH2:43][C@@:42]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)([OH:45])[C:41]([CH3:54])([CH3:53])[CH2:40]1)=[O:38]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:35][C@H:36]([CH:55]([CH3:57])[CH3:56])[C:37]([N:39]2[CH2:44][CH2:43][C@@:42]([C:46]3[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=3)([OH:45])[C:41]([CH3:53])([CH3:54])[CH2:40]2)=[O:38])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@@H](NC(=O)c1cccc(N)n1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a suspension of 6-aminopicolinic acid (33 mg, 0.24 mmol) in DMF (2 mL) was added EDC (45.9 mg, 0.24 mmol), HOBt (32.3 mg, 0.24 mmol). The mixture was stirred at rt for 0.5 h, then was added DIPEA (0.083 mL, 0.48 mmol) and (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (90 mg, 0.239 mmol). The mixture was stirred at rt overnight. The reaction was quenched with NaHCO3 (aq) and stirred at rt for 1 h, extracted by EtOAc, washed with brine and dried over Na2SO4. After concentrating in vacuo, the residue was triturated with CH2Cl2 and filtered to give a yellow solid as 6-amino-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)picolinamide (86 mg, 0.187 mmol, 78% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1(CNCC2CCCCC2)CCCCC1.[F:28][C:29]1[CH:50]=[CH:49][C:32]([NH:33][C:34]2[CH:46]=[C:45]([CH:47]=[CH2:48])[CH:44]=[CH:43][C:35]=2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][CH:30]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:28][C:29]1[CH:50]=[CH:49][C:32]([NH:33][C:34]2[CH:46]=[C:45](/[CH:47]=[CH:48]/[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=3)[CH:44]=[CH:43][C:35]=2[C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)Nc1cccc(Br)c1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccc(NS(C)(=O)=O)c2)cc1Nc1ccc(F)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
N-(3-Bromophenyl)methanesulfonamide 0.36 g, N,N-dicyclohexylmethylamine 0.41 mL and palladium acetate 5.4 mg were added to N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g at room temperature, and it was stirred at 130° C. for 4 hours. N-(3-bromophenyl)methanesulfonamide 0.12 g, N,N-dicyclohexylmethylamine 0.10 mL and (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 5.4 mg were added to it, and it was stirred at 130° C. for 2 hours. (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 11 mg and tri-tert-butylphosphine tetrafluoroborate 6.9 mg were added to it, and it was stirred at 130° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, and the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=1:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-(methanesulfonamido)phenyl)vinyl)benzoate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[N:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)nc1

Procedure:
15.4 g (98.7 mmol) of 5-acetyl-2-chloro-pyridine are stirred for 1 h at 110° with 100 ml of dimethylformamide diethylacetal. After cooling to 0° filtering and drying at 60°, under HV, 3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is obtained; 1H-NMR (DMSO): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.6 (1H,d), 7.8 (1H,d), 8.3 (1H, m), 8.9 (1H,m).