Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH2:15][OH:16])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.OS([O-])(=O)=O.[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:12](=[O:14])[CH:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH2:15][OH:16])[CH2:29][CH2:30]1
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(N2CCN(C(=O)C(CO)NS(=O)(=O)c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
(RS)-2-benzenesulfonylamino-3-hydroxy-propionic acid (1.204 g) was dissolved in tetrahydrofuran (15 ml) and cooled to 0° C. 1-(2,5-Dimethylphenyl)-piperazine (1.12 g), (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP reagent, 3.26 g) and N-ethyl-diisopropylamine (1.90 g) were added. The mixture was stirred at room temperature for 18 h. Ethyl acetate and a 10% KHSO4 solution were added. The organic phase was washed with water, dried, filtered and evaporated. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:1=>ethyl acetate) to give (RS)—N-{2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide (1.45 g) as a colorless foam. MS: 418.3 ([M+H]+)
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][C:11]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:10][CH2:9]1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CO
Product: FS(F)(F)(F)(F)C1=CCC(c2ccccc2)(S(F)(F)(F)(F)F)C=C1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 98.2 %

Procedure:
(Kirsch, et al., Angew. Chem. 1999, 111, 2174; Kirsch, et al., Angew. Chem. Int. Ed. 1999, 38, 1989-1992) Palladium(II) acetate (0.3 mg, 0.001 mmol) was added to a solution of 1 (14.5 mg, 0.0384 mmol) in 0.15 g of methanol. The reaction mixture was stirred at 70° C. for 5.5 h and filtered through a pad of SiO2 with the help of hexane. Removal of the solvent gave a colorless crystalline solid which was purified by SiO2 column chromatography with hexane to give 14 (7.7 mg) as colorless crystals (99%); m.p. 196.0-197.0° C. (in sealed tube). IR (ATR): {tilde over (v)}=3007, 2992, 1599, 1481, 1391, 1277, 1260, 1101, 831, 810 cm−1. MS (GC, EI): m/z=406 [M+], 387 [M+-F], 282, 190. 1H NMR (500 MHz, CDCl3): δ=7.87 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.6 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=153.7 (C), 142.3 (C), 127.6 (2CH), 126.7 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.0 (quint, J=150 Hz, 1 F), 63.0 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:24]=[C:25]1[O:29][CH:28]([O:30][CH2:31][CH2:32]C2C=CC=CC=2)[CH:27]([NH:39][C:40]([CH:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47](=[O:61])[CH:48]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([Cl:59])[CH:53]=2)[CH3:49])=[O:41])[CH2:26]1>>[CH2:31]([O:30][CH:28]1[CH:27]([NH:39][C:40]([CH:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47](=[O:61])[CH:48]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([Cl:59])[CH:53]=2)[CH3:49])=[O:41])[CH2:26][C:25](=[O:24])[O:29]1)[CH3:32]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1
Yield: 59 %

Procedure:
Prepared from anti-(2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to afford 175 mg of title compound (59%). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.10-1.28 (m, 3H), 1.42 (d, 0.6H), 1.46 (d, 2.4H), 1.75-2.45 (m, 4H), 2.45-2.70 (m, 1H), 2.80-3.05 (m, 1H), 3.50-3.95 (m, 4H), 4.20-4.75 (m, 3H), 4.75-4.90 (m, 1H), 5.32 (s, 0.8H), 5.38 (s, 0.2H), 6.80 (d, 1H), 7.55-7.84 (m, 2H). Analytical HPLC: 10.47 min. LC-MS (ES+): m/e=467.3 (M+H+).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]([N:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:8])=[O:6].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[CH3:8][N:7]([C:5](=[O:6])[C:4]#[CH:3])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CN(C)C(=O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(=O)N(C)CC(=O)OCC
Reaction time: 0.17 h
Yield: 51.3 %

Procedure:
To a solution of ethyl 2-(3-trimethylsilyl-N-methylprop-2-ynoylamino)acetate (5.28 g, 21.9 mmol) in THF (80 mL) was added dropwise a solution of TBAF (1M in THF, 24.0 mL, 24.0 mmol). After stirring for 10 min, a saturated NH4Cl solution (150 mL) was added and the resulting mixture was extracted with EtOAc (3×100 mL). The organic layer was washed with a saturated NaCl solution (400 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (50% EtOAc/hex) to give ethyl 2-(N-methylprop-2-ynoylamino)acetate (1.9 g, 51%) as a yellow oil: TLC (50% EtOAc/hex) Rf 0.50; 1H NMR (CDCl3; a mixture of two rotomers) δ 1.26-1.33 (m, 3H), 3.03 (s, 1.2H), 3.29 (s, 1.8H), 3.09 (s, 0.43H), 3.17 (s, 0.57H), 4.16 (s, 1.1H), 4.33 (s, 0.9H), 4.17-4.28 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10]>C(Cl)(Cl)Cl>[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([Cl:3])=[O:10]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1I
Temperature: 61 °C

Procedure:
Thionyl chloride (8.2 ml, 112.5 mmol) was added to a mixture of 3-iodo-4-methylbenzoic acid (18.5 g, 75 mmol) in chloroform (100 ml) and heated at 61° C. for 16 hours. The solvent was removed in vacuo and excess thionyl chloride removed by azeotroping with toluene (3×30 ml). The desired product was formed as a beige solid (19.5 g 93%) and used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[OH:31][CH2:32][CH2:33][C:34](O)=[O:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl-].[NH4+]>CN(C)C=O>[OH:35][CH2:34][CH2:33][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:31]
Reactant: O=C(O)CCO
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(CCO)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol) and 3-hydroxypropanoic acid (131 mg, 0.435 mmol) in N,N-dimethylformamide (5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (160 mg, 0.544 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) and precipitated from ethanol to give the title compound (30 mg, 17%) as a pale-green powder.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reaction time: 1.2 h

Procedure:
To 906.4 mg (3.58 mmol) of 1-benzyl-5-nitro-1H-indazole (Step 1) in 20 mL of MeOH and 5 mL of EtOAc at RT was added a slurry of 150 mg of 10% Pd—C in 5 mL of MeOH. The resulting slurry was then stirred under a balloon of H2 for 1.2 h, filtered through Celite®, and rinsed with MeOH and EtOAc. Concentration of the filtrate gave (1-benzyl-1H-indazol-5-yl)amine as a pinkish solid: MS m/z=224 [M+H]+. Calc'd for C14H13N3: 223.11.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:23])[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoroacetamide (1.0 g, 3.49 mmol) was added to a suspension of 60%-sodium hydride (147 mg, 3.67 mmol) in tetrahydrofuran (20 ml) at room temperature and stirred for 30 minutes. Then, methyl iodide (0.239 ml, 3.84 mmol) was added thereto and stirred for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/1) to obtain N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide (731 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O.CC(O)=O.CC(O)=O.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCCN(Cc2cccc(I)c2)C1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCCN(Cc2cccc(Nc3ccccc3)c2)C1=O
Temperature: 80 °C
Reaction time: 0.02 h

Procedure:
In a 100 ml round bottomed flask Binap, (S)-(−)2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl, (0.210 g, 0.3375 mmol) dissolved in 15 mL toluene was stirred at 80° C. for 1 minute . To the flask cooled to room temperature under inert atmosphere Pd(OAC)2 (0.050 g, 0.225 mmol) was added and the solution was stirred at room temperature for 2 minutes. To the reaction mixture [1-(3-Iodo-benzyl)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (1.0 g, 2.25 mmol) dissolved in 15mL toluene , aniline (1.047 g, 11.25 mmol) and Sodium tert-butoxide (0.259 g, 2.70 mmol) were added and the solution was stirred at 80° C. for 18 h. The reaction was cooled to room temperature, diluted with 200 mL of water, and extracted twice with 100 mL of ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to an oil. The oil was purified on flash silica gel column using 10-30% ethyl acetate in hexanes as eluent to yield 0.562 g (61%). MS (ESI) M+H=432.5.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N:4]1([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][C:14]3[C:15](Cl)=[N:16][C:17]4[C:22]([C:23]=3[Cl:24])=[CH:21][C:20]([I:25])=[CH:19][CH:18]=4)=[CH:11][CH:10]=2)[CH:8]=[N:7][CH:6]=[N:5]1.ClCCl>C1(C)C=CC=CC=1>[N:4]1([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][C:14]3[C:15]([O:2][CH3:1])=[N:16][C:17]4[C:22]([C:23]=3[Cl:24])=[CH:21][C:20]([I:25])=[CH:19][CH:18]=4)=[CH:11][CH:10]=2)[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: Clc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
Sodium methoxide (741 mg, 13.7 mmol) was added to a solution of 3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2,4-dichloro-6-iodoquinoline (1.1 g, 2.3 mmol, Intermediate 20: step b) in toluene (11 mL) with stirring. The mixture was heated to 105° C. After 2 hours, additional sodium methoxide (250 mg, 4.6 mmol) was added. After 3 hours, the flask was allowed to cool to 23° C. Dichloromethane (50 mL) was added and then the mixture was filtered through Celite®. The filter cake was washed with dichloromethane. The filtrate was concentrated to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6](C(=O)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14]Br)[CH:8]=2)=[O:4].C[Si](C)(C)[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.N>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14][C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(CBr)cc2n1C(C)=O
Reactant: C[Si](C)(C)n1ccnc1
Agent: N
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2[nH]1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A solution of 1-acetyl-6-bromomethylindole-2-carboxylic acid methyl ester (3.1 g.) in toluene (25 ml.) was added dropwise with stirring to a solution of 1-trimethylsilylimidazole (5.60 g.) in toluene (25 ml.) at 80° C. The mixture was stirred at 80° for 2 hours and then evaporated. Water was added and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated to give an oil which was dissovled in a concentrated solution of ammonia in ethanol (40 ml.). The solution was allowed to stand at room temperature for 2.5 hours and then evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from ethyl acetate to give 6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester (1.49 g.), m.p. 204°-205° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46](I)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:46]3[CH:47]=[C:42]4[N:41]=[C:40]([CH2:39][CH2:38][C:34]5[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][N:35]=5)[NH:49][C:43]4=[N:44][CH:45]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: Cc1ccc(N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(c6ccc(C)cc6C)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 47.5 %

Procedure:
A mixture of 0.614 g of 1-(4-bromo-benzene-sulfonyl)-4-(2,4-dimethylphenyl)-piperazine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 8 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 7 hours. To the resulting mixture 10 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 10 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 23 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-20:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.27 g of the title compound as a solid of m.p. 208-209° C. The mass spectrum shows the molecular peak MH+ at 583.5 Da.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2].[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]3[CH:30]=[CH:31][C:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27][CH:28]=3)=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc(N)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1

Procedure:
Acylation of 1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 μl) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:15][N:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:36]1[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:36]3[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=3)=[CH:20][CH:19]=2)=[N:15][N:14]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cc(C(F)(F)F)ccc4Cl)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
4-(5-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 30 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as an off-white solid (131.1 mg). Yield 56.5%.
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[C:7]([C:2]1([NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3]1)#[N:8]
Reactant: CCCCC(=O)Cl
Reactant: N#CC1(N)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1(C#N)CCCC1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
To 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane dissolved in 100 ml of dichloromethane, 15 ml 10.9 g (0.1 mol) of triethylamine was added, then dropwise 13 ml, 13 g (0.1 mol) of valeroyl chloride, while keeping the temperature at 25-35° C. The reaction mixture was stirred at 30-35° C. for 2 hours, then it was washed with water. The phases were separated, the organic phase was evaporated to obtain the pure title compound as an oil. The compound was identified by elementary analysis, IR, NMR and GC-MS spectomety.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([CH3:36])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[C:14]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:27][N:18]([C:15]1[C:14]([C:28]#[C:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:13][C:12]([NH:11][C:9](=[O:10])[CH:8]([NH:7][CH3:6])[CH3:36])=[CH:17][CH:16]=1)[C:19]([CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:20]
Reactant: CC(C(=O)Nc1ccc(N(C)C(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1ccc(N(C)C(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
A mixture of tert-butyl-N-methyl-N-[1-[[5-[methyl(oxane-4-carbonyl)amino]-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate F5b (5 mg) and DCM:TFA (9:1, 1 ml) is stirred at RT for 100 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 7 mg. HPLC-MS: M+H=421; tR=1.33 min (*Method—1).
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:18][OH:19]>CCO.CCOC(C)=O>[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)/[C:9](=[N:18]/[OH:19])/[CH2:8][CH2:7]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O/N=C1\CCOc2ccccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium acetate (503.852 mg, 6.14 mmol) was added to a stirred solution of 4-chromanone ([CAS491-37-2], 700 mg, 4.73 mmol) and hydroxylamine hydrochloride ([CAS5470-11-1], 426.808 mg, 6.14 mmol) in EtOH (31 mL). The mixture was stirred at 80° C. for 16 h. The mixture was cooled to RT, diluted with EtOAc, and washed with water. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to yield I-36 (727.7 mg, 93%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][S:13](=[O:17])(=[O:16])[CH2:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[O:16]=[S:13]1(=[O:17])[CH2:14][CH2:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(C2=CCS(=O)(=O)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 4-(4-nitro-phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (as prepared in the previous step, 502 mg, 1.98 mmol) and 10% Pd/C (250 mg, 50 wt %) in 15 mL of MeOH was stirred at RT under H2 (balloon pressure) for 2 h. The Pd catalyst was removed by filtration on Celite, and the filtrate was concentrated to give 314 mg (70%) of the title compound as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 7.03 (d, 2H, J=8.3 Hz), 6.67 (d, 2H, J=8.3 Hz), 3.51-3.79 (br s, 2H), 3.11-3.17 (m, 4H), 2.70 (dddd, 1H, J=12.3, 12.3, 2.9, 2.9 Hz), 2.31-2.43 (m, 2H), 2.15-2.23 (m, 2H).