Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19]Cl)[N:10]=1.[CH:32]1([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(#N)C.[Ag-]=O>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[N:11]([CH2:19][O:39][C:37]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:38])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CCl)c1=O
Reactant: O=C(O)C1CCCC1
Agent: O=[Ag-]
Solvent: CC#N
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.1 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-chloromethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (0.64 mmol) in acetonitrile (18 mL) at 25° C. was treated with cyclopentanecarboxylic acid (73.4 μL, 0.67 mmol) followed by silver (I) oxide (155.4 mg, 0.67 mmol). The reaction mixture was stirred at 25° C. in the dark for 3 d. At this time, the reaction was filtered through a pad of celite® and was rinsed with a solution of 90/10 methylene chloride/methanol (1×100 mL). The filtrate was then concentrated in vacuo. Biotage flash chromatography (40S, 0.5-1.25% methanol/methylene chloride) followed by reverse phase chromatography (Pursuit C-18 column, acetonitrile gradient with trifluoroacetic acid) followed by lyophilization afforded cyclopentanecarboxylic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (75.7 mg, 21%) as an off-white solid. ES+-HRMS m/e calcd for C24H22N6O6Cl2 (M+Na+) 583.0870, found 583.0871.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH2:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([N:21]3[CH2:29][C:30]([CH3:35])([CH3:34])[C:31]3=[O:32])[CH3:20])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2ccc(CC(C)N)cc2)cc1
Reactant: CC(C)(CCl)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(C#Cc2ccc(CC(C)N3CC(C)(C)C3=O)cc2)cc1

Procedure:
To 33.5 mg (120 μmol) 2-[4-(4-ethoxy-phenylethynyl)-phenyl]-1-methyl-ethylamine (I64) in 2.0 mL ACN are added 166 mg (1.20 mmol) K2CO3, a few crystals DMAP and finally 23.5 μL (0.18 mmol) 3-chloropivaloyl chloride (in 1.0 mL ACN). The reaction mixture is stirred at reflux for 6 h. The solvent is removed in vacuo and the residue is resolved EtOAc and washed with water (1×), sat. aq. NaHCO3 solution (2×) and again with water. The organic layer is dried with Na2SO4 and the solvent is evaporated in vacuo. The residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:19])([CH3:18])[CH3:17]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)OC(C)C
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc2cc(CC(OC(C)C)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-isopropoxy-propionic acid methyl ester (preparation 8) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-isopropoxy-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:29][C:27]([F:28])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:31])=[O:3])=[CH:10][CH:11]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3ccc(C(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCCCC#Cc3ccc(C(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 e], {6-[5-(4-trifluoromethyl-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH2:13])[CH2:8][CH2:7][CH2:6]2.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[S:22])=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([NH:13][CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[S:22])=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)CCCC2N
Reactant: S=C=NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCCC2NC(=S)NCc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
The compound 32-1 (100 mg) prepared according to the same procedure as described in Step 1 was dissolved in ethyl acetate (4 ml) and to the solution were added a solution of 4-chlorobenzylisothiocyanate (123 mg) in ethyl acetate (2 ml), followed by stirring at room temperarure for 18 hours. The obtained reaction mixture was concentrated under reduced pressure and purified by column-chromatography (hexane/ethyl acetate=2/1) to yield the compound 32-2 (201 mg, 99%).
Reaction SMILES: C([N:4]1[CH:9]=[CH:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][CH:11]=2)[CH:6]=[CH:5]1)(=O)C.C(N1CCC(C2C3C(=CC=C(OC)C=3)NC=2)CC1)(=O)C>C(O)C.O=[Pt]=O.[OH-].[Na+]>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: COc1ccc2[nH]cc(C3C=CN(C(C)=O)C=C3)c2c1
Agent: O=[Pt]=O
Agent: COc1ccc2[nH]cc(C3CCN(C(C)=O)CC3)c2c1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 74.6 %

Procedure:
3-(1-Acetyl-1,4-dihydro-4-pyridyl)-5-methoxyindole (3.0 g) was dissolved in hot ethanol (150 ml) and hydrogenation was carried out with Adams catalyst (0.25 g). The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue containing 3-(1-acetyl-4-piperidyl)-5-methoxyindole. This residue was diluted with 2N aqueous sodium hydroxide solution (22 ml) and ethanol (30 ml) and refluxed for 18 hours. Ethanol was then distilled off and the residue was cooled. The precipitate was collected by filtration and recrystallized from a mixture of ethanol and water to give 5-methoxy-3-(4piperidyl)indole (1.92 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19].C(O[C:26](=[O:28])[CH3:27])(=O)C>N1C=CC=CC=1>[C:18]([C:1]([C:26](=[O:28])[CH3:27])([C:16](=[O:21])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19])(=[O:19])[CH3:17]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)C(CCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO)(C(C)=O)C(C)=O

Procedure:
In a procedure similar to Grode and Cardellina,93 D-erythro-sphingosine (4, 2 mg, 6.7 μmol, Sigma) in acetic anhydride (1 mL) and pyridine (2 mL) was stirred at 25° C. for 4.5 h, at which time no starting material could be observed by TLC. The solvent was removed by a stream of nitrogen to give 133: white solid; silica TLC Rf 0.86 (3:12:2:2 CHCl3/1-BuOH/AcOH/H2O, phosphomolybdic acid), 0.65 (9:1 CHCI3/MeOH, phosphomolybidic acid); FABMS m/z 580, 426, 366, 306, 264; CIMS m/z 468, 454, 426, 424, 394, 366, 364, 306, 264, 144, 85, 84, 83, 61.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([C:17](=[CH2:21])[C:18](O)=[O:19])[CH:14]([CH3:16])[CH3:15]>O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:21][CH:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:18]2=[O:19])=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C(C)(C)C
Reactant: C=C(CC(C)C)C(=O)O
Solvent: O
Product: COc1cc2c(cc1C(C)(C)C)C(=O)C(CC(C)C)C2
Temperature: 60 °C

Procedure:
To Iton reagent (obtained from 110 g of P4O10 and 560 ml of methanesulfonic acid at 110° C.) a mixture of 59.4 g (0.362 mol) of 1-tert-butyl-2-methoxybenzene and 51.5 g (0.402 mol) of 2-isobutylacrylic acid was added dropwise at vigorous stirring in such a rate to maintain temperature at 60±1° C. (for ca. 40 min). The resulting mixture was stirred for 40 min at 65° C., cooled to room temperature, and then poured on 1000 cm3 of ice with 1000 cm3 of water. The product was extracted by 3×500 ml of dichloromethane. The combined organic extract was washed by aqueous K2CO3, dried over Na2SO4 and then evaporated to dryness. Fractional rectification of the residue gave dark red oil, b.p. 165-174° C./5 mm Hg. This oil was recrystallized from 100 ml of hexanes. White crystals precipitated at 5° C. were collected, washed by 20 ml of cold hexanes, and dried in vacuum. Yield 24.9 g (25%) of the title product.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:84])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:84][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CCN(Cc2ccnc(Cl)c2C)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(Cc2ccnc(N)c2C)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1-[4-(2-Chloro-3-methyl-pyridin-4-ylmethyl)-piperazin-1-yl]-ethanone (free base, 0.040 g, 0.15 mmol), NaOtBu (0.020 g, 0.21 mmol), BINAP (0.014 g, 0.020 mmol), and Pd2dba3 (0.0068 g, 0.0103 mmol) were stirred in 1 mL anhydrous toluene under N2. Benzophenone imine (0.030 mL, 0.18 mmol) was added and the reaction was heated to 80° C. After 3 h the reaction was cooled to RT, diluted with Et2O, filtered through celite, and concentrated in vacuo. To the residue was added 1:1 THF/1M HCl. The mixture was stirred for 2 h, then washed 2× w/EtOAc. The aqueous phase was adjusted to pH 10 with Na2CO3 (solid). The solution was extracted 3× with DCM/nBuOH (95:5), and the combined organic extracts were dried over Na2SO4, filtered, concentrated. The residue was purified by flash column chromatography (95:5-90:10 DCM/MeOH) to afford the pure titled compound. 1H NMR (CDCl3) δ7.89 (d, 1H, J=5.1 Hz), 6.65 (d, 1H, J=5.1 Hz), 4.45 (bs, 2H), 3.61 (t, 2H, J=4.9 Hz), 3.43 (m, 4H), 2.41 (t, 4H, J=5.2 Hz), 2.12 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH:31][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC2CCC(F)(F)CC2)cn1
Yield: 27 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using 4,4-difluorocyclohexylamine instead of aminomethylcyclopropane to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 37 mg, 27%) which was obtained as a white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C=O)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(CO)cnc21

Procedure:
4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (104 mg, 0.279 mmol) in methanol (3 mL) was stirred with sodium borohydride (15.8 mg, 0.418 mmol) at room temperature for 2 hours, after addition of water, the reaction mixture was extracted with chloroform twice, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting pale yellow oil containing the title compound was used for the next step without further purification.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(thiazol-2-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ12.7 (s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (t, 3H), 7.6 (d, 2H), 7.3 (d, 1H), 7.2 (d, 1H), 6.8 (d, 1H); APCI−MS m/z 456 (M+H)+ and 454 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([O:17]CC)=[O:16])[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Li+]>O1CCCC1.CO.O.O>[CH2:6]([NH:5][C:4]([NH:3][N:2]([CH2:14][C:15]([OH:17])=[O:16])[CH3:1])=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CN(C)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(=O)O)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 2-(1-methyl-2-(benzylcarbamoyl)hydrazinyl)acetate (Compound XXXII-1) 1.33 g (5.0 mmol) in tetrahydrofuran/methanol/water (2:3:1) 24 ml, lithium hydroxide monohydrate 420 mg (10.0 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water 25 ml and washed with ether 25 ml. The aqueous phase was acidified with 10%-citric acid 25 ml and extracted with chloroform 30 ml. The organic phase was washed with brine 25 ml and dried with magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the title compound 1.05 g (88%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ncccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cccnc3C)c2cc1OC
Temperature: 135 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (245 mg), 2-methyl-3-pyridinol (227 mg), and 4-dimethylaminopyridine (420 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 135° C. for 2 days. The reaction solution was cooled to room temperature. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give the title compound (324 mg, yield 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][C:4]=1[O:12][CH3:13].[OH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH:25]=[O:26])[CH2:21][O:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][CH3:11])[CH:7]=[CH:8][C:3]=1[CH2:2][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH:25]=[O:26])[CH2:21][O:22]2)=[CH:17][CH:16]=1
Reactant: O=CC1=Cc2ccc(O)cc2OC1
Reactant: CCCc1ccc(CCl)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(COc2ccc3c(c2)OCC(C=O)=C3)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
1-(chloromethyl)-2-methoxy-4-propylbenzene (1.1 g) was dissolved in DMF (20 mL), and 7-hydroxy-2H-chromene-3-carbaldehyde (975 mg) and K2CO3 (1.15 g) were added thereto, followed by stirring at 80° C. for 1 hour. Further, sodium iodide (416 mg) was added thereto, followed by stirring at 80° C. for 1 hour. After confirming completion of the reaction, to the reaction liquid was added water to stop the reaction, followed by extraction with EtOAc three times. The organic layer was combined, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 80:20) to obtain 7-[(2-methoxy-4-propylbenzyl)oxy]-2H-chromene-3-carbaldehyde (1.21 g) as a yellow powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[NH:10][C:9]2[C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[NH2:15][C:11]1[C:9]2[NH:10][C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][O:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CNC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h
Yield: 22 %

Procedure:
N-Methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (25 mg, 0.080 mmol) was dissolved in methanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (5 mg, 0.05 mmol). The reaction vessel was charged to 50 PSI hydrogen and shaken for 2 h. The reaction mixture was filtered and concentrated in vacuo to give crude 5-amino-N-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (0.005 g. 100%). LCMS calculated for C15H17N4O2 (M+H)+: m/z=285.1. found: 285.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH2:8][S:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([OH:25])=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:7]2[CH2:8][S:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([O:25][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCSC1
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCSC1

Procedure:
The benzopyran of Example 21 is reacted with γ-piperidinobutyric acid hydrochloride and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][CH:31]=[CH2:32])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][CH2:31][CH3:32])=[O:22])=[CH:34][CH:35]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=CCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-allylphenyl)benzamide (100 g) and 10% palladium on carbon (20 mg) in methanol (15 ml) was stirred under an atmospheric pressure of hydrogen at ambient temperature. After 3 hours, the reaction mixture was filtered through a bed of Celite, concentrated and then triturated from diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-propylphenyl)benzamide (70 mg).
Reaction SMILES: CN(C)[C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:15][Li].[Cl-].[NH4+]>C1COCC1>[C:8]1([C:5]2([C:3](=[O:4])[CH3:15])[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]C
Reactant: CN(C)C(=O)C1(c2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1(c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
4.34 g of 27 is dissolved in 189 ml of THF, cooled to −10° C., and 21.5 ml of methyllithium solution (1.6 M in diethyl ether) is added in drops under nitrogen. It is stirred for 2 hours at this temperature, and the reaction mixture is then poured into saturated ammonium chloride solution. After extraction with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.7 g of title compound 28 is obtained as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:33]([O:37][C:38](=[O:49])[NH:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH2:48])=[CH:43][CH:42]=1)([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1>CN(C)C=O>[C:33]([O:37][C:38](=[O:49])[NH:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][NH:48][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:6])=[CH:45][CH:46]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
2-Chloro-nicotinic acid (2.86 g, 18.2 mmol), 1-hydroxybenzotriazole (3.0 g, 21.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.18 g, 21.8 mmol) were dissolved in N,N-dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (4.29 g, 18.2 mmol) (see Preparation 1) added followed by addition of N-methyl morpholine (4 ml, 36.3 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was then triturated with diethylether (2-fold 10 ml) to give (4-{[(2-chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (6.71 g) as a white solid.