Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH2:13][C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C(O[Na])(C)=O.[CH:22]([C:24]1[N:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:34]#[N:35])=[C:27]2[O:36][CH:37]([CH3:39])[CH3:38])=O>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:22][C:24]3[N:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][C:28]([C:34]#[N:35])=[C:27]4[O:36][CH:37]([CH3:39])[CH3:38])[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)nc12
Temperature: 80 °C
Yield: 41.6 %

Procedure:
To a mixture of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (38.1 mg, 0.16 mmol) (prepared as described below), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (50.2 mg, 0.21 mmol) (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 80° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in AcOEt (20 mL) and filtered through a glass filter. The solid was washed with AcOEt and dried to give 6-{2-[2-(3-fluoro-phenyl)-ethylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a light green solid (30.7 mg, 41.6%). HR-ES (+) m/e calcd for C24H20FN5O2S (M+H)+ 462.1395. found 462.1395.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26].[C:27]([O-:30])(=[O:29])[CH3:28].[Na+]>CN(C=O)C>[C:27]([O:30][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26])(=[O:29])[CH3:28]
Reactant: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CCl)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC/C=C/Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
To a solution of 187 mg (0.5 mmol) of the compound obtained from Example 9 in 5 ml of DMF was added 410 mg (5 mmol) of sodium acetate. The reaction mixture was then stirred for about 48 hours at 100° C., and evaporated under reduced pressure to give a yellow-colored residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 140 mg (yield 70%) of the title compound as a colorless syrup.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCc1noc2cccc(Oc3ccc(N)cn3)c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-ethyl-4-[(5-nitro-2-pyridinyl)oxy]-1,2-benzisoxazole (Intermediate 32, 9 mg) was dissolved in 3.0 ml of ethanol. Then tin(II) chloride dihydrate (21.4 mg, 0.095 mmol) was added and the reaction mixture was stirred at 80° C. for 3 hours. After quenching with water and extraction with ethyl acetate, the organic phase was dried over sodium sulphate, filtered and evaporated to afford the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1>CO>[NH2:11][C@H:12]([CH2:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](N)COC(C)(C)C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
330.0 L of methanol was added and 66.0 kg of (R)-methyl 2-(benzyloxycarbonylamino)-3-t-butoxypropanoate was added to a hydrogen reactor; and then purged with nitrogen. 4.95 kg of palladium/carbon (10% water mixture) was added and hydrogen was filled to maintain at 5 bar of pressure. It was stirred for 60 minutes, filtered, washed, and then concentrated under reduced pressure. 132.0 L of ethyl acetate and 88 L of water were added to a concentrated residue; stirred for 10 minutes; an organic layer was isolated (in 6 times), dehydrated, and then concentrated under reduced pressure to obtain 27.5 kg of a title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: O=C1CCc2cc(F)c(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(F)c(F)cc2C1=O
Yield: 38 %

Procedure:
A solution of 10.6 g of 5,6-difluoro-1-indanone, 13.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 2:1). In addition to 3.6 g of educt there were obtained 5.32 g (38%) of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:23]=2[N:24]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:23]=2[N:24]=1)#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1ccc2oc(NCCCCN)nc2c1
Product: CC1CC(=O)NN=C1c1ccc2oc(NCCCCNCC(O)COc3ccccc3C#N)nc2c1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(4-aminobutylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16](O)=[O:17])=[CH:15][C:11]=2[CH:10]=1)[CH3:2].[NH3:23].C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16]([NH2:23])=[O:17])=[CH:15][C:11]=2[CH:10]=1)[CH3:2]
Reactant: N
Reactant: CCN(CC)CCOCCc1ccc2sc(C(=O)O)cc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCOCCc1ccc2sc(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 30 mL of tetrahydrofuran is dissolved 2.18 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}benzo[b]-thiophene-2-carboxylic acid, to which is added 1.98 g of N,N′-carbonyldiimidazole. The resulting mixture is stirred at ambient temperature for one hour. Then, 50 mL of 25% aqueous ammonia is added to the mixture and the resulting mixture is stirred at ambient temperature for one hour. Ethyl acetate is added to the mixture, the organic layer is separated, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol to chloroform:methanol:ammonia=5:1 to 100:10:1). Thus, 2.00 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}benzo[b]-thiophene-2-carboxamide is obtained as a colorless crystalline product.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate A1a (2 g, 11.5 mmol) in dichloromethane (0.5M, 23 mL) is treated with ethyldiisopropylamine (3 mL, 17.5 mmol) and the mixture is cooled to 0° C. Methanesulfonyl chloride (0.99 mL, 12.7 mmol) is then added dropwise and the mixture is allowed to stir at room temperature for 6 hours. The mixture is diluted with dichloromethane, washed with 1M HCl, brine, dried over sodium sulfate and concentrated in vacuo to afford tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate A1b as oil that solidifies upon standing: 1H-NMR (400 MHz, CDCl3) δ=5.25-5.19 (m, 1H), 4.30 (ddd, J=10.4, 6.4, 1.2 Hz, 2H), 4.12 (ddd, J=10.4, 4.0, 1.2 Hz, 2H), 3.09 (s, 3H), 1.46 (s, 9H); MS calcd. for C9H18NO5S ([M+H]+): 252.1, found: 252.2. The product is used without purification.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[CH3:15])([O-])=O>[Pd].C(O)C>[CH3:15][C:5]1[CH:6]=[C:7]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(C)(C)C)cc(C)c1N
Reaction time: 1 h

Procedure:
To a 1 liter stirred autoclave were charged 62 g. (0.3 mole) of 2-nitro-1,3-dimethyl-5-tertiary-butyl-benzene, 300 ml. of ethanol and 1.0 g. of 5% palladium on charcoal. The autoclave was purged with hydrogen and then pressure to 1000 psig at 90° C. to 95° C. After 1 hour, the reaction was stopped. A total of 500 psig were taken up. The reaction mixture was filtered through Celite and the ethanol was evaporated. The final product was distilled at 93° C. to 98° C./7 to 10 torr to yield 47.2 g. of a very pale yellow liquid. An 89% isolated yield of 99+% pure 2,6-dimethyl-4-tertiary-butylaniline was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[H-].[Na+].[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:64][CH3:65])=[C:26]([CH2:35][NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][C:49]4[CH:50]=[C:51]([C:56]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:62]I)[CH:57]=5)[C:52]([F:55])=[CH:53][CH:54]=4)=[O:46])[CH:40]=3)=[O:38])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]>CN(C=O)C>[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:64][CH3:65])=[C:26]([CH2:35][NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][C:49]4[CH:50]=[C:51]([C:56]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:62][N:7]6[CH2:6][CH2:5][NH:4][CH2:3][C:2]6=[O:1])[CH:57]=5)[C:52]([F:55])=[CH:53][CH:54]=4)=[O:46])[CH:40]=3)=[O:38])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CI)c3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4=O)c3)c2)c1
Reaction time: 15 h
Yield: 13 %

Procedure:
To a solution of 1,1-dimethylethyl 3-oxo-1-piperazinecarboxylate (0.027 g, 0.135 mmol) in DMF (0.25 mL) was added NaH (0.0033 g, 0.135 mmol). This mixture was stirred at room temperature for 5 min whereupon a solution of the above N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[6-fluoro-3′-(iodomethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide in DMF (0.25 mL) was added. The resulting mixture was stirred for 15 h and purified with a Gilson HPLC (with TFA). The relevant HPLC fractions collected and treated with TFA (0.10 mL), the solvent concentrated on GeneVav EZ-2 evaporator, purified again with Gilson HPLC (with TFA), solvent concentrated on GeneVav EZ-2 evaporator, and the residue basified with an amine cartridge to afford 0.0143 g (13%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.81-1.93 (m, 2 H) 2.09 (d, J=12.55 Hz, 2 H) 3.16 (q, J=7.53 Hz, 2 H) 3.48-3.55 (m, 2 H) 3.55-3.61 (m, 2 H) 3.62-3.72 (m, 2 H) 3.93 (s, 2 H) 3.99-4.08 (m, 2 H) 4.30-4.40 (m, 1 H) 4.47 (q, J=7.11 Hz, 2 H) 4.60 (s, 2 H) 4.72 (d, J=4.77 Hz, 4 H) 7.15 (dd, J=10.67, 8.41 Hz, 1 H) 7.32-7.41 (m, 2 H) 7.44 (t, J=7.53 Hz, 1 H) 7.47-7.54 (m, 3 H) 7.60 (t, J=7.91 Hz, 1 H) 8.00-8.08 (m, 2 H) 8.29 (s, 1 H) 8.38 (t, J=1.63 Hz, 1 H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:7]([N:14]1[CH2:15][CH:16]2[C:24](=[CH2:1])[C:23]3[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[CH:19][C:18]=3[CH:17]2[CH2:28]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1c2ccc(OC)cc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%−two steps) of the subtitle compound. MS calculated for C20H21NO+H: 292, observed: 292.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[C:1]1([C:7]#[C:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1ccc(C#Cc2ccccc2)cc1
Yield: 70 %

Procedure:
By the method of example 53(A), but using bis(triphenylphosphine)palladium(II) acetate as catalyst (3 mol %), phenylacetylene and 4-bromobenzaldehyde are coupled to give 4-(2-phenylethynyl)benzaldehyde in 70% yield after distillation. By the methods of example 1, this is converted into the title compound, obtained as a colorless solid, mp 190°-191° after recrystallization from hexane-ethyl acetate.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CCC(O)[C@@H](N)CC
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(O)[C@H](CC)Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4S)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 10 mg (37%).(57% de 4S,3R: 43% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.85-1.06 (m, 6H, —NHCH(CH2CH3)CH(CH2CH3)OH, 1.57 (d, 6H, J=6.79 Hz, & —CH(CH2)2), 1.43-1.64 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J=6.16 Hz, OH) 3.56-3.70 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.91-4.02 (m, 1H, —NHCH(CH2CH3) CH(CH2CH3) OH), 4.58-4.71 (m, 1H, —CH(CH3)2), 4.86-4.98 (m, 2H, —HNCH2-Pyr), 5.21-5.32 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 6.76-6.94 (m, 1H, —HNCH2-Pyr), 7.16-7.26 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.74 Hz, Pyr-H), 7.58 (s, 1H, —N═CH—N—), 7.64-7.70 (m, 1H, Pyr-H), 8.60 (d, 1H, J=4.45 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (35), 307 (37), 297 (25), 289 (20). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2523.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd].[C]>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1
Reactant: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(C3CCCNC3)c[nH]c2c1
Reaction time: 16 h

Procedure:
3-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-indole (430 mg, 1.48 mmole) was dissolved in methanol (30 ml) under argon. Pd/carbon (43 mg, 10%) was added and the reaction mixture was hydrogenated for 16 hours at 2 bar. The reaction mixture was worked up by filtering the solution through silica gel and washing with methanol (10×10 ml). The filtrate was concentrated by evaporation and dried. 3-piperidine-3-yl-1H-indole was obtained as a yellow oil in a yield of 233 g (79%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1>CC(N(C)C)=O>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:31][C:32]=1[C:40]([F:41])([F:42])[F:43])([CH3:39])[CH3:38]
Reactant: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol) and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered through Celite®. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=504.2 [M+H]+; 1H NMR (400 MHz, DMSO-db) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H).
Reaction SMILES: ClC1C=CC(C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-:15].[Cs+].[Cs+].[CH:20]1([P:26]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=2[O:41][CH3:42])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O.NN>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.CO.O1CCOCC1>[CH:43]1([P:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=2[O:41][CH3:42])=[O:15])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Clc1ccc(-c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(OC)c1-c1ccccc1P(=O)(C1CCCCC1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To the mixture of 4-chlorobiphenyl (15 mg, 0.079 mmol) and 1,4-dioxane (1 ml), water (0.1 ml), cesium carbonate (0.16 g, 0.48 mmol), sodium 1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl trifluoroborate (40 mg, 0.16 mmol), palladium(II) acetate (1.8 mg, 0.0079 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.5 mg, 0.016 mmol) were added at room temperature, and then the obtained reaction mixture was stirred at 100° C. (an outer temperature) overnight. The reaction mixture was cooled to room temperature, and then hydrazine hydrate (40 mg, 0.79 mmol) and methanol (2 ml) were added thereto, followed by heating to reflux for 30 min. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto, followed by filtration with celite. The organic layer of the filtrate was separated and washed with saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with NH-silica gel column chromatography (ethyl acetate), thereby obtaining the entitled compound (7.7 mg, 53%) as the mixture with 2′-(dicyclohexyl-phosphinoyl)-2,6-dimethoxy-biphenyl (3.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]2=[O:38])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[O:42]1[CH:43]=[CH:44][C:40]([NH:39][S:23]([C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:13]([C:4]2[C:3]([O:2][CH3:1])=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=2)[C:14](=[O:38])[CH:15]=[CH:16]3)(=[O:24])=[O:25])=[N:41]1
Reactant: COc1cc2ccccc2cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ccccc2cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of perfluorophenyl 1-(3-methoxynaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.250 g, 0.457 mmol), 3-aminoisoxazole (0.037 ml, 0.502 mmol) and THF (4.57 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.959 ml, 0.959 mmol) was added dropwise. After 60 min, the mixture was diluted with 1N aq. HCl and EtOAc. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was concentrated and then triturated with in Et2O. The resulting suspension was sonicated, then filtered. The collected solid was washed with Et2O (2×), dried under a stream of N2 (g), then dried under vacuum to give N-(isoxazol-3-yl)-1-(3-methoxynaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.175 g, 0.391 mmol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.49-11.79 (m, 1H), 8.68-8.78 (m, 1H), 8.38-8.42 (m, 1H), 8.24-8.29 (m, 1H), 7.96-8.01 (m, 2H), 7.86-7.91 (m, 1H), 7.78-7.84 (m, 1H), 7.66 (s, 1H), 7.56-7.64 (m, 1H), 7.42-7.50 (m, 1H), 6.75-6.86 (m, 2H), 6.42-6.47 (m, 1H), 3.72-3.81 (m, 3H). m/z (ESI) 447.9 (M+H)+.