Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:53]1([N:59]=[C:60]=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:38][CH3:39])[CH2:40][CH3:41])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][C:60](=[O:61])[NH:59][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OC(=O)Nc1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(OC(=O)Nc1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 25.5 h

Procedure:
(8E,12E,14E)-7-acetoxy-6,21-dihydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (100 mg, 154 μmol) was dissolved in methylene chloride (2 mL). Triethylamine (64.2 μL, 461 μmol) and phenyl isocyanate (34.0 μL, 312 μmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 25.5 hours. Then, triethylamine (200 μL, 1.43 μmol) and phenyl isocyanate (98.0 μL, 900 μmol) were further added to the reaction solution, and the reaction solution was stirred at room temperature for six hours. The reaction solution was diluted with ethyl acetate (30 mL), and the dilution was washed with saturated aqueous solution of sodium hydrogencarbonate (6 mL) twice, purified water (6 mL) twice, and brine (6 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=4:1→3:1) and thin-layer chromatography (MERCK 60 F254, 0.5 mm, toluene:acetone=5:1) to obtain the title compound (54.0 mg, 70.1 μmol, 45.6%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[CH3:17][C:18]([O-])([CH3:20])[CH3:19].[Na+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (800 mg, 3.32 mmol), DMSO (5 ml), sodium 2-methylpropan-2-olate (351 mg, 3.66 mmol). The reaction mixture was cooled to 0° C. and (bromomethyl)cyclopropane (0.372 ml, 3.66 mmol) was added in DMSO (1 mL). The reaction was removed from the ice-bath and stirred at 20° C. for 16 hours. The heterogeneous suspension was added to water (10 mL) to give a precipitate, which was collected by filtration, was successively washed with water, a small amount of ethanol and diethyl ether. The collected solid was dried in-vacuo to afford 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (746 mg, 2.53 mmol, 76% yield) as a off white solid. MS [M+H] found 295.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:14][CH2:15][CH2:16][CH2:17][N:4]1[C:3](=[O:13])[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5]1
Reactant: Cn1c(-c2ccccc2)n[nH]c1=O
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(-c2ccccc2)nn(CCCBr)c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After dissolving 4-methyl-5-phenyl-2,4-dihydro[1,2,4]triazol-3-one (CAS 50369-39-6) (500 mg) and 1,3-dibromopropane (0.87 ml) in N,N-dimethylformamide (9 ml), sodium hydride (60% in oil) (125 mg) was added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (649 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.C([Li])CCC.CCOCC.[Mg+2].[Br-].[Br-].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31]3[CH:32]=[C:33]4[C@:38]([CH:40]=[O:41])([CH2:39][C:30]=3[CH:29]=[N:28]2)[CH2:37][N:36]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH2:35][CH2:34]4)=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31]3[CH:32]=[C:33]4[C@:38]([CH:40]([C:4]5[O:3][C:2]([CH3:1])=[N:6][N:5]=5)[OH:41])([CH2:39][C:30]=3[CH:29]=[N:28]2)[CH2:37][N:36]([S:42]([C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=2)(=[O:44])=[O:43])[CH2:35][CH2:34]4)=[CH:23][CH:22]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Reactant: Cc1nnco1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nnc(C(O)[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C3)o1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
2-Methyl-[1,3,4]-oxadiazole (140 mg, 1.67 mmol) in dry tetrahydrofuran (5 mL) was cooled to −78° C. and butyl lithium (2.5 M solution in hexanes, 600 μL, 1.5 mmol) was added dropwise. The resultant reaction mixture was stirred for 10 minutes at −78° C. Magnesium bromide diethyl etherate (400 mg, 1.55 mmol) was added in one portion and the mixture was warmed to −45° C. over 1.5 hours where the temperature was maintained for 20 minutes. The reaction was re-cooled to −78° C. and a solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (100 mg, 0.4 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred whilst allowing the reaction mixture to warm to −5° C. slowly. The reaction mixture was treated with saturated ammonium chloride solution (6 mL) and sufficient water to dissolve precipitated salts. The mixture was extracted with dichloromethane (3×10 mL) and the combined organic phases were dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 50-100% ethyl acetate in cyclohexane) to afford, as a (˜2:1) mixture of diastereoisomers, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)-(R/S)-methanol as an off-white foam (50 mg). LCMS (Method A, ESI): RT 3.38 min, m+H=590.4; 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 0.5 H); 7.96 (d, J=8.2 Hz, 2 H); 7.85-7.87 (m, 3 H); 7.42-7.43 (m, 1 H); 7.30 (s, 1 H); 7.20-7.21 (m, 2H); 7.12-7.13 (m, 2.5 H); 6.43 (s, 0.4 H); 6.18 (d, J=2.3 Hz, 1 H); 5.43 (d, J=4.4 Hz, 1 H); 4.99 (s, 0.4 H); 4.30-4.32 (m, 1 H); 3.68-3.75 (m, 1 H); 3.48 (d, J=16.7 Hz, 1 H); 3.29 (d, J=16.2 Hz, 0.4 H); 3.02-3.05 (m, 1 H); 2.57 (d, J=12.0 Hz, 3 H); 2.43-2.48 (m, 2 H); 2.35-2.37 (m, 2 H); 2.20 (s, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[S:22]1C=[CH:25][CH:24]=[C:23]1[Mg]Br.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN(C)C(c1cccs1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (2.24 g, 10 mmol) in abs. THF (10 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (10 ml) and water (10 ml) were added, while cooling with ice, and extraction with diethyl ether (3×10 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[C:2]([F:1])([F:14])[F:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
64.6 g (0.25 mol) of 3-trifluoromethyl-4-methylbenzenesulphonyl chloride are taken up in 500 ml of carbon tetrachloride and, after addition of 44.5 g (0.25 mol) of N-bromosuccinimide and 0.4 g of ABN, the mixture is heated under reflux for 24 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography with petroleum ether/toluene (4:1), 50 μm particle size, gives 33.9 g (40% of theory) of the title compound. Rf : 0.41 (petroleum ether/toluene 3:1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)N(CCCl)CCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 45.2 %

Procedure:
In a Schlenk tube, a solution of 5 g (20 mmol) of methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.3 g (20 mmol) of N,N-bis(2-chloroethyl)methanesulfonamide in 65 ml of N,N-diisopropylethylamine is heated at 127° C. with vigorous stirring for 18 h. After the addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 3.3 g (46%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:26]([O:28]C)=[O:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:26]([OH:28])=[O:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(CNC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 50 °C

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-((benzyloxycarbonylamino)methyl)piperidine-1,4-dicarboxylate from step A in methanol (5 mL) was added 1 N aq. NaOH (0.615 mL, 0.615 mmol). The reaction was heated at 50° C. overnight, acidified to pH 5 with 1 N aq. HCl, and extracted 3× with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under vacuum to give the title compound, which was carried on crude. MS (ES+) [M+H]+=393.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: NC(=O)c1ccc(Oc2ncc(C=O)cc2Cl)cc1
Reactant: NCCc1cccs1
Product: NC(=O)c1ccc(Oc2ncc(CNCCc3cccs3)cc2Cl)cc1
Yield: 35.7 %

Procedure:
Using a method similar to Example 460, using 4-(3-chloro-5-formyl-pyridin-2-yloxy)-benzamide (114 mg, 0.412 mmol) and 2-thiophen-2-yl-ethylamine (0.048 mL, 0.412 mmol) gives the title compound (57 mg, 36%). Mass spectrum (ion spray): m/z=387.9 (M+1); 1H NMR (DMSO-d6): 8.37 (bs, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.99 (bs, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.39 (dd, J=1.2 Hz, 5.0 Hz, 1H), 7.36 (bs, 1H), 7.21 (d, J=8.9 Hz, 2H), 6.99-6.94 (m, 2H), 4.16 (s, 2H), 3.26-3.11 (m, 4H).
Reaction SMILES: N[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21]>O>[OH:21][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)CCc1ccc2c(c1)Cc1cc(N)ccc1-2
Solvent: O
Product: CC(=O)CCc1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
Diazonium salt was prepared by the same way as in Example 6 using 6.47 grams of 4-(7-amino-2-fluorenyl)-butan-2-one. The diazonium salt was dropped into a refluxing and stirring mixture of 9 ml of concentrated sulphuric acid and 150 ml of water. After being stirred for 2 hours, the mixture was cooled and crystals separated out therefrom were collected by filtration. They were washed until the washing became neutral and dried with air. The resulting crystals were subjected to a silica gel column chromatography, eluted with a 4:1 mixture of n-hexane and ethyl acetate, and the resulting crystals were recrystallized from methanol to give 4.96 grams of 4-(7-hydroxy-2-fluorenyl)-butan-2one, pale yellow crystals, m.p. 170°-170.5° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:25][O:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[O:26][CH3:25])[CH2:32]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 13 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 39 (13% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.99 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.68-3.82 (4s, 6H), 4.43 and 4.94 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.81 and 7.08 (2d, 1H), 7.82-7.85 (m, 1H), 7.93-8.04 (m, 3H), 8.12-8.24 (m, 2H), 8.70-8.76 (m, 2H); MS (ESI) m/z 494 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].CCN(C(C)C)C(C)C.[CH2:32]([O:34][CH2:35]Cl)[CH3:33].O>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[O:14][CH2:35][O:34][CH2:32][CH3:33]
Reactant: CCOCCl
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(C)ccc1C)=C2O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOC1=C(c2cc(C)ccc2C)C(=O)NC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 250 mg of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound C1, preparation example P1, step P1.5) in 2.5 ml of tetrahydrofuran were added 160 μl of Hünig's base and 85 μl of chloromethyl ethyl ether. After stirring for 20 hours at room temperature, water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate, the combined organic phases dried with sodium sulfate, filtered and concentrated. Chromatography (heptane/acetone 4:1) yielded 72 mg of 3-(2,5-dimethyl-phenyl)-4-ethoxymethoxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound A61) as a solid, mp: 150-152° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH:2]([NH:1][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(N)Cc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(F)cc1)NS(=O)(=O)c1ccc(C)cc1
Yield: 80.7 %

Procedure:
Methyl 2-amino-3-(4-fluorophenyl)propionate (2.01 g), p-toluenesulfonyl chloride (2.25 g) and 4-dimethylaminopyridine (309 mg) were dissolved in chloroform (30 ml), and pyridine (3.0 ml) was added to heat the mixture under reflux for 4.5 hours. P-Toluenesulfonyl chloride (2.20 g) was additionally added, and the mixture was heated under reflux for 3.5 hours. The reaction mixture was poured into ice and 1N hydrochloric acid (17 ml) to conduct liquid separation. The resultant organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatagraphy on silica gel (hexane:ethyl acetate=9:1→2:1) to obtain the title compound (2.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:16]1(Br)[CH2:19][CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: BrC1CCC1
Product: CCc1nn(C2CCC2)c2cc(C(=O)OC)ccc12
Yield: 32.4 %

Procedure:
This compound was prepared according to the method of Preparation 3, using 750 mg (3.67 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 0.38 mL (4.04 mmol, 1.1 equiv) cyclobutyl bromide as starting materials to give 307 mg (32%) of a clear oil: HRMS calcd for C15H18N2O2+H: 259.1447. Found: 259.14550.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:14][C:13]1=[O:29])[C:5]([O:7][CH3:8])=[O:6].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][C:14]1[C:13](=[O:29])[N:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[Cl:1])[C:17]([CH3:18])=[CH:16][C:15]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
Methyl 3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 2) (2.60 g, 6.21 mmol) was taken up in CH2Cl2 (20 ml). N-bromosuccinimide (1.11 g, 6.21 mmol) was added and the mixture stirred at room temperature for 4 hours. The CH2Cl2 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.75 g, 24%). 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=1.88 Hz, 1H), 8.06 (dd, J=8.19, 1.75 Hz, 1H), 7.59 (app q, J=8.46 Hz, 1H), 7.33 (d, J=8.19, 1H), 6.96 (dt, J=8.06, 1.21 Hz, 1H), 6.89-6.84 (m, 1H), 6.13 (s, 1H), 5.26 (s, 2H), 3.95 (s, 3H), 1.95 (s, 3H); ES-MS m/z 478 (M+H). ES-HRMS m/z 497.9892 (M+H calcd for C22H16BrClF2NO4 requires 497.9914).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:13][CH:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:12])([O-])=O>C(O)C.[Pd]>[N:18]1[CH:19]=[CH:20][C:15]([CH:14]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[O:13][C:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])OC(c1ccncc1)C1CCNCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NC(=O)OC(c1ccncc1)C1CCNCC1
Yield: 95.1 %

Procedure:
A solution of 2-nitro-N-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)benzeneamine (7.55 g, 21.2 mmol) and 5% palladium-on-carbon (4.00 g) in ethanol (250 mL) was placed under an atmosphere of hydrogen (1 bar). After consumption of the starting material (16-20 h), the mixture was filtered through diatomaceous earth. Hot ethyl acetate was used to wash the filter cake. Concentration of the filtrate in vacuo yielded 6.58 g (96%) of the title compound.