Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(C(C)C)CC)(C)C.[F:14][C:15]([F:44])([F:43])[C:16]1[CH:17]=[C:18]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:19][N:20]([CH:24]1[CH2:30][CH2:29][CH2:28][NH:27][C:26]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:25]1=2)[C:21](=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([N:20]([CH2:19][C:18]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:16]([C:15]([F:14])([F:44])[F:43])[CH:17]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:1]([Cl:4])=[O:2])[C:26]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:25]1=2)(=[O:23])[CH3:22]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Add phosgene (1.1 mmol, 1.93 M solution in toluene) followed by diisopropyl ethylamine (1.1 mmol) to a toluene (15 mL) solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.50 g, 1.1 mmol) under nitrogen. After stirring at room temperature for 1 h, remove solvent under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30%) to elute. This provides the title compound (0.55 g, 96%) as an oil which solidifies upon standing: MS (ES+): 527 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2 diethylamino-ethyl) amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl-]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (86.2 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:7]2.[CH:52](=O)[CH3:53].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:52]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:7]2)[CH3:53]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cccc(N)c4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1cccc2c1C(=O)N(c1c[nH]c3ncc(-c4ccc(S(=O)(=O)C(C)C)cc4)nc13)C2
Reaction time: 48 h

Procedure:
7-amino-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (63 mg, 0.09133 mmol) dissolved in DCE (5 mL) and acetaldehyde (5.6 μL, 0.10 mmol) then Na(OAc)3BH (38.72 mg, 0.1827 mmol) added at RT under N2. Reaction mixture stirred for 48 h then quenched by the addition of water. DCM added and layers separated. Organic phase dried and concentrated. Residue taken up in DCM (2 mL) under N2 and treated with triethylsilane (73 μL, 0.4566 mmol) then TFA (300 μL). Reaction mixture stirred overnight then concentrated. Residue purified by hplc to give the title compound; 1H NMR (400 MHz, DMSO) δ 1.20-1.26 (9H, m), 3.50 (1H, partly obsc sep), 5.38 (2H, s), 6.64-6.68 (2H, m), 6.85 (1H, d), 7.42 (1H, d), 8.00 (2H, d), 8.44 (1H, d), 8.51 (2H, d), 9.08 (1H, s), 12.31 (1H, s) ppm; MS (ES+) 476.0.
Reaction SMILES: [CH:1]1([C:5]2[C:13](I)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>CCOCC>[CH:1]1([C:5]2[C:13]([CH:17]=[O:16])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Temperature: -78 °C
Yield: 41 %

Procedure:
Into a three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 62.1, 5.00 g, 80%, 12.7 mmol) in a solvent mixture of tetrahydrofuran and Et2O (50 mL/50 mL). The solution was cooled to −78° C. then n-butyllithium (15 mL, 2.5 M in hexanes) was added drop-wise with stirring. N,N-Dimethylformamide (2.64 mL, 34.2 mmol) was added and the resulting mixture was stirred for 1 h at −78° C., then carefully quenched by slow addition of aqueous NH4Cl (sat., 50 mL). The pH was adjusted to 1-2 with aqueous hydrogen chloride (6 M), then diluted with ethyl acetate (100 mL) and washed with brine (4×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as the eluent to furnish 1.62 g (41%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 70.8 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and hexylbromide (702 μL, 825 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetyl-octanoic-acid-tert-butylester (250k) (1063 mg, 3.54 mmol, 71%) as a slightly yellow oil. Then, 250k (2.19 g, 7.29 mmol) and 139 mg (0.73 mmol) p-TsOH.H2O were stirred in 22.0 mL benzene according to decarboxylation method A. Kugelrohr distillation at 0.8 mbar and 80° C. and subsequent flash-chromatography (column dimensions: 2.0×20.0 cm, diethylether/petroleum ether=1:6) gave 251k (419 mg 2.10 mmol, 29%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(C(F)(F)F)ccc1C#N
Temperature: 50 °C
Yield: 82 %

Procedure:
The 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq) in isopropanol (20 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give e as a yellow solid (0.45 g, 82% Yield, 1.96 mmol). 1HNMR (DMSO, 200 MHz) δ 1.35 (s, 3H), 1.38 (s, 3H), 5.33 (m, 1H), 7.55 (d, 1H, J=6), 8.26 (d, 1H, J=6).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)C(=O)C2)[CH2:10][CH2:9]1.[OH-].[K+]>CO.O>[O:4]=[C:3]1[CH2:2][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][NH:5]1
Reactant: NC(=O)C(F)(F)F
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CC2(CCN1)CCNc1ccccc12
Yield: 91.1 %

Procedure:
A solution of 49 mg (0.157 mmol) of the high RF material from Step B in methanol/water 4:1 with excess potassium hydroxide was stirred over night. The solution was concentrated and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 31 mg (0.143 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:24]([NH:23][S:20]([C:15]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:1]([S:20]([CH3:15])(=[O:22])=[O:21])[S:39]([CH3:38])(=[O:41])=[O:40])=[CH:7][N:6]=3)=[C:9]([F:28])[CH:10]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:22])=[O:21])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 17.25 h

Procedure:
To a 20 mL vial were added a stir-bar, 4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (49 mg, 0.12 mmol), dry DCM (2.0 mL), DIPEA, (0.10 mL, 0.58 mmol), and methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirred at rt for 17.25 h before subjecting it to FCC to give impure title compound. The product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:9](OC)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=[O:2].[NH2:12][NH2:13].O>CN(C=O)C>[CH:7]1[CH:6]=[N:5][C:4]2[N:1]([OH:2])[N:12]=[N:13][C:9]=2[CH:8]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: On1nnc2cccnc21
Reaction time: 24 h
Yield: 52.1 %

Procedure:
To 13.58 g of 2-nitro-3-methoxypyridine was added 26.4 mL of 95% hydrazine, 10.4 mL of water and 15.3 mL of DMF. The mixture was carefully warmed to about 70° on a hot plate. Spontaneous warming then set in, the temperature rising to about 80° as the solid dissolved. The solution was set aside for 24 hr and then evaporated from a water bath with the aid of a water aspirator to remove excess hydrazine and water. The dark green residue was cooled in an ice bath, diluted with 50 mL of water and acidified to Congo Red with concentrated hydrochloric acid (ca. 17 ml). A yellow-straw-colored solid separated and was filtered and washed with a little cold water to give 6.25 g (52.1%) of HOAt upon recrystallization from 75 mL of water gave 5.46 g (45.5%) of nearly colorless crystals, mp 216°-217° 1H NMR (CDCl3-DMSO-d6): δ 7.35 (dd, 1, β-H), 8.3 (dd, 1, γ-H), 8.66 (dd, 1, α-H); Jα,β=4.2 Hz, Jβ,γ=8.2 Hz, Jα,γ=1.6 Hz. Evaporation of the filtrate gave an additional 0.14 g of the pure hydroxy compound so the total yield was 5.6 g (46.7%).
Reaction SMILES: [F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:22][C@@H:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=3)[CH:16]=2)[CH2:22][C@@H:23]([OH:28])[C:24]([F:26])([F:27])[F:25])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Oc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)C[C@@H](O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O[C@H](CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(OCc2cccc(C(F)(F)F)c2)c1)C(F)(F)F
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol) from EX-20B and 3-trifluoromethylbenzyl bromide (70.0 mg, 0.27 mmol) in 2.5 mL of acetone was added cesium carbonate (100 mg, 0.31 mmol). The reaction mixture was heated at 60° C. for 18 h then cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 63.3 mg (45%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H21F10NO3: 586.1440 [M+H]+, found: 586.1419. 1H NMR (acetone-d6) δ 7.61-7.82 (m, 4H), 7.41 (t, 1H), 7.25 (d, 1H), 7.10-7.21 (m, 3H), 6.34-6.67 (m, 4H), 5.73 (d, 1H), 5.19 (s, 2H), 4.82 (s, 2H), 4.34-4.48 (m, 1H), 3.99 (dd, 1H), 3.68 (dd, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][NH2:35])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][NH:35][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Reactant: C=CC(=O)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Product: CCOC(=O)CCNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
Ethyl acrylate (100 mg) and Sc(OTf)3 (5 mg) were added to the solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (530 mg) in dichloromethane (3 mL). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by Mass Directed Auto Prep to afford ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}-β-alaninate (D85) (186 mg) as a yellow solid. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1C(O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>C(OC(=O)C)(=O)C>[CH3:26][O:25][C:23]([C:22]1[C:21]([C:27]([O:29][CH3:30])=[O:28])=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11][C:10]=12)=[O:24]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=C(O)C1Cc2ccccc2N1C(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccccc2)n2c1Cc1ccccc1-2
Temperature: 120 °C

Procedure:
A mixture of 1-benzoyl-2,3-dihydro-1H-indole-2-carboxylic acid (7.48 g, 28 mmol) and dimethyl acetylenedicarboxylate (4.55 g, 32 mmol) in acetic anhydride (40 mL) was heated for 4.5 h at 120° C. until no gas was eliminated. The dark solution was concentrated in vacuo to dryness and the solid residue was recrystallized from methanol to yield 3-phenyl-8H-3a-azacyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester, 7.5 g (77%): mp 149-151° C.; 1H NMR (DMSO-d6) δ 3.62 (3H, s, OMe), 3.79 (3H, s, OMe), 4.15 (2H, s, CH2), 6.60-6.67 (1H, m, ArH), 7.18-7.23 (2H, m, 2×ArH), 7.51-7.67 (6H, m, 6×ArH). Anal. Calcd for C21H17NO4: C, 69.40; H, 5.21; N, 3.85. Found: C, 69.42; H, 4.65; N, 3.83.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[N+:9]([C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23]>>[N+:9]([C:12]1[S:16][C:15]([CH:17]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])s1)C(C)=O

Procedure:
The procedure described in Example 12 was repeated by using 2.59 g of 5-nitro-2-thiophenecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione. Yield 0.5 g, yellow viscous oil.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([F:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([F:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-5-fluoro-2-methylbenzoate (269 mg, 0.701 mmol) in dichloromethane (5 mL) and acetic acid (500 uL) was added acetaldehyde (124 mg, 2.80 mmol) and sodium triacetoxyborohydride (469 mg, 2.10 mmol) at 0° C. The reaction mixture was stirred at rt for 12 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (277 mg, 96% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.19-7.36 (m, 6H), 6.97 (dd, J=2.4, 10.4 Hz, 1H), 3.89 (s, 3H), 3.86 (d, J=10.4 Hz, 1H), 3.39 (d, J=10.4 Hz, 1H), 3.02-3.10 (m, 4H), 2.74-2.80 (m, 1H), 2.43 (s, 3H), 1.74-1.82 (m, 1H), 1.51-1.63 (m, 2H), 1.32-1.40 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.93 (d, J=7.2 Hz, 3H), 0.86 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 413.0.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]N3CCN(C)CC3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.C1(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)CC1.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>>[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][N:65]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH:8]=2)[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Yield: 97.6 %

Procedure:
The general procedure of Example 1 (6) was repeated by use of 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl-1-piperazine carboxylate, to thereby yield the title compound as a yellow oil (yield: 97.6%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:14](=[O:16])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O[I:27](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>ClCCl>[I:27][C:15]1[C:14](=[O:16])[C:13]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[O:12][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C2=CC(=O)C3(CCOCC3)O2)cc1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C2=C(I)C(=O)C3(CCOCC3)O2)cc1
Yield: 77.5 %

Procedure:
A mixed solution of 2-{4-(methylsulfonyl)phenyl}-1,8-dioxa-spiro[4,5]dec-2-en-4-one (0.55 g), [bis(trifluoroacetoxy)iodo]benzene (0.84 g) and iodine (0.45 g) in 50 ml dichloromethane was stirred for 6 hours at room temperature. Then the reaction was quenched by adding 10 ml aqueous saturated sodium thiosulfate. The organic layer was washed with brine and was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (hexane/ethylacetate) to afford 0.6 g of 3-iodo-2-{4-(methylsulfonyl)phenyl}-1,8-dioxa-spiro[4,5]dec-2-en-4-one. mp: 210-213° C. NMR: δ1.60-1.72 (m, 2H), 2.11-2.44 (m, 2H), 3.12 (s, 3H), 3.80-3.90 (m, 2H), 4.04-4.14 (m, 2H), 8.21 (d, J=9 Hz, 2H), 8.41 (d, J=9 Hz, 2H). IR (cm−1): 1690, 1580, 1146, 912, 744.
Reaction SMILES: [CH:1]1(CCCCCCCCCCCCN)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:25]([N:43]=[C:44]=[O:45])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH:1]1([N:43]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:44]([NH:43][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:45])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 42, starting from 7.0 g of the compound of Example 1 and 5.9 g of octadecyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.Br.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:15].[CH3:12][C:10]1[CH:11]=[C:2]([N:1]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: Cc1cc(N)cc2c1NC(=O)CC2
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N2CCNCC2)cc2c1NC(=O)CC2
Temperature: 64 °C
Reaction time: 13 h
Yield: 60.1 %

Procedure:
A mixture of 6-amino-8-methyl-3,4-dihydro-2(1H)-quinolinone (19.4 g), bis(2-bromoethyl)amine hydrobromide (41 g) and methanol (140 ml) was stirred for 13 hours at 64° C. After cooling, sodium carbonate (5.83 g) was added thereto and the mixture was stirred for 9 hours at 70° C. After cooling, the resulting precipitate was collected by filtration and the residue was washed with methanol to give 3,4-dihydro-8-methyl-6-(1-piperazinyl)-2(1H)-quinolinone hydrobromide (21.6 g).