Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH3:58])[C:52](O)=[O:53])(=[O:50])[CH3:49]>>[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH3:58])[C:52]([NH:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:53])(=[O:50])[CH3:49]
Reactant: CCCCC(C(C)=O)C(=O)O
Reactant: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The amount of 2-acetylhexanoic acid in dichloromethane from Example 15A is treated with 2.3 g (17.0 mmol) of 1-hydroxy-1H-benzotriazole and 3.44 g (34 mmol) of 4-methylmorpholine and cooled to −20° C. After addition of 3.26 g (17.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, the mixture is stirred for 30 min. The cooling bath is removed in the course of this. 1.60 g (6.55 mmol) of 6-(1-aminoethyl)-3-(4-methylbenzyl)-1,2,4-triazin-5(4H)-one (Example 8A) are then added after fresh cooling to −20° C. and the mixture is stirred overnight while warming to room temperature. For work-up, the dichloromethane phase is washed with 1 N potassium hydrogensulphate solution and then with saturated sodium hydrogencarbonate solution. The dried organic phase is concentrated and chromatographed using the eluent dichloromethane/methanol 100/1 to 30/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1>[CH3:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:17](=[O:18])[O:11][C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(O)cc1C
Solvent: C1CCOC1
Product: COc1cc2[nH]c(=O)oc2cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 2-amino-5-methyl-4-(methyloxy)phenol (1.54 g, 10 mmol) in THF (60 mL) was added carbodiimidazole (1.94 g, 12 mmol). The reaction mixture was stirred for 3 hours at room temperature, concentrated, diluted with EtOAc (100 mL), washed with 1N HCl, H2O, brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (1.76 g, 98%) as a white solid. MS (ES) m/e 180 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:29]([C:25]([CH2:24][C:8]1[N:7]([CH2:6][C:5]2[CH:33]=[CH:34][C:2]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[CH:14]=[CH:15][C:10]=2[N:9]=1)([CH2:31][CH3:32])[C:26]([OH:28])=[O:27])[CH3:30]
Reactant: C1CCNCC1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1)C(=O)O
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCCCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from 2-({1-(4-Bromobenzyl)-6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1H-benzimidazol-2-yl}methyl)-2-ethylbutanoic acid using piperidine in the conditions for Example 152. MS (ESI): mass calcd. for C31H39N5O3, 529.31; m/z found, 530.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.70 (d, J=9.0, 1H), 7.55 (d, J=2.2, 1H), 7.35-7.27 (m, 5H), 7.25 (dd, J=9.0, 2.3, 1H), 6.31 (d, J=2.3, 1H), 5.75 (s, 2H), 5.05 (s, 2H), 3.86 (s, 3H), 3.45-3.33 (m, 6H), 1.91-1.64 (m, 10H), 0.87 (t, J=7.5, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:17].[CH2:18]1COC[CH2:19]1>>[Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([C@H:9]([NH:10][S@@:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH2:18][CH3:19])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Reactant: C1CCOC1
Product: CC[C@@H](N[S@](=O)C(C)(C)C)c1cc(C)c(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a separate flask a solution of INT 36 (3.5 g, 12.88 mmol) in THF (100 mL) was cooled in a dry ice bath under argon to −78° C. At this temperature the organozincate solution from above was added dropwise over a period of about 30 minutes. Stirring was continued for another 90 minutes before the resulting mixture was first quenched carefully with 10% ammonium chloride solution (40 mL), then water (50 mL). The reaction mixture was allowed to warm up to room temperature and was then extracted with Et2O (200 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:15])[CH:4]=1)#[N:2].[NH2:16][OH:17]>CO>[NH2:2][C:1](=[N:16][OH:17])[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: NO
Reactant: COC(=O)c1cc(OC)c(C#N)cc1F
Solvent: CO
Product: COC(=O)c1cc(OC)c(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-cyano-2-fluoro-5-methoxybenzoate (64 mg; 0.31 mmol; 1 eq.) was dissolved in MeOH. Hydroxylamine (90.23 μl; 1.53 mmol; 5 eq.) was added and the mixture was stirred at RT overnight. As the reaction was not complete, it was heated at 50° C. for one more day. The solvents were then evaporated, affording the title product as an orange oil, which was used without further purification (74 mg; 100%). LC/MS (Method B): 243.1 (M+H)+. HPLC (Method A) Rt 1.24 min (Purity: 80.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:15]=[C:14](Br)[CH:13]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=1)=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: CCCNC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1cc(C(=O)OC)cc(-c2ccccc2)c1

Procedure:
Using Preparation Method 2, 68C (247 mg, 0.82 mmol) was reacted with phenyl boronic acid (109 mg, 0.9 mmol) in the presence of 5 mol % Pd(PPh3)4, 0.82 mL of 2N Na2CO3, 0.43 mL of Ethanol and 1.8 mL of toluene. The resulting reaction mixture was purified using SiO2 with CH2Cl2/AcOEt 98:2 to 90:10 to give a greenish oil (284 g, quant.). NMR 1H (ppm, CDCl3): 8.37 (t, J4=1.64 Hz, 1H), 8.27 (d. t., J3=6.03 Hz, J4=1.75 Hz, 1H), 7.63 (d, J3=6.97 Hz, 1H), 7.49-7.36 (m, 5H), 6.27 (br. s., 1H), 3.49-3.42 (m, 2H), 1.64 (sext., J3=7.25 Hz, 2H), 1.00 (t., J3=7.37 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 120 °C
Yield: 96.8 %

Procedure:
To a suspension of NaH (4.2 g) in 100 mL of dry DMF under nitrogen was slowly added 14.02 g of 4-methoxythiophenol. The reaction mix was stirred until no further gas evolution occurred (circa 20 minutes). To this solution was added 15.76 g of 4-chloronitrobenzene dissolved in 100 ml of dry DMF, after which the mixture was heated to 120° C. for one hour. The reaction mix became red in colour during this time. The mixture was then cooled to room temperature and poured over 1000 g of crushed ice. The resulting yellow solid was filtered, washed several times with water, and dried to afford 25.29 g (96%) of 4-(4-methoxy-phenylsulfanyl)-nitrobenzene as a yellow solid. MS M+H; 264.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([NH:18][CH3:19])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].Cl[CH2:23][C:24]1[C:25]([CH3:40])=[N:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([N:18]([CH3:19])[CH2:23][C:24]2[C:25]([CH3:40])=[N:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(NC)c2c1CCCC2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2

Procedure:
In analogy to the procedures described in example 5C] and 5D], 2-methyl-2-(4-methylamino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 4G]) to give 2-methyl-2-(4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:26])[C:10]=2[CH:27]=1.[OH-].[Na+]>>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2([C:11](=[O:26])[C:10]3[CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=[CH:8][C:9]=3[O:25]2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccc(/C=C/C(=O)O)cc1C2=O
Yield: 98.6 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H),4′-piperidin]-5-yl}-acrylic acid methyl ester (100 mg, 0.258 mmol, Intermediate 4, Step E) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H),4′-piperidin]-5-yl}-acrylic acid as a white solid (95 mg, 98%). The product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H),4′-piperidin]-5-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (89 mg, 74%). Finally, removal of the protecting groups following the procedure described in Example 1, Step C gave (E)-3-{3-oxo-spiro[benzofuran-2(3H),4′-piperidin]-5-yl}-N-hydroxy-acrylamide (14 mg, 23%) as its hydrochloride salt.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(Cc3cccnc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(Cc2cccnc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carbaldehyde (0.17 g), tetraethyl methylenediphosphonate (0.11 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.015 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]ethenylphosphonate as a colorless oil (0.19 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Br:11][C:12]1[CH:13]=[C:14]2[CH:20]=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C[C:22](O)=[O:23]>O>[Br:11][C:12]1[CH:13]=[C:14]2[C:20]([CH:22]=[O:23])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc(Br)cc12
Temperature: 100 °C
Yield: 33 %

Procedure:
Hexamethylenetetramine (1.08 g, 7.61 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5 mol) in HOAc (6.34 mL). The mixture was heated at 100° Celsius for 6 hours. The reaction mixture was then cooled to rt and diluted with water. The mixture was extracted with EtOAc, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to provide the title compound (379 mg, 33%). 1H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.77 (d, J=2.2, 1H), 8.48 (d, J=2.2, 1H), 7.99 (d, J=2.7, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:21]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CC=O
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCNc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.1 %

Procedure:
A mixture of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol), acetaldehyde (10.0 mg, 0.227 mmol), and sodium triacetoxyborohydride (52.1 mg, 0.246 mmol) was stirred at room temperature for 2.5 h. The reaction was then partitioned between EtOAc and H2O. The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue recrystallized from EtOAc/hexanes to afford the title compound (21.6 mg, 39%) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O.O>[CH2:32]([O:31][C:29]([N:17]1[CH2:18][CH2:19][N:14]([C:13]2[CH:12]=[CH:11][C:10]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:9][C:8]=2[F:7])[CH2:15][CH2:16]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
1.2 g (8.6 mmol) of potassium carbonate are added to a solution of 1.0 g (3.4 mmol) of 6-[3-fluoro-4-(piperazin-1-yl)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 10 ml of acetone and 10 ml of water. When the suspension has cooled down to 0° C., 0.42 ml (4.4 mmol) of ethyl chloroformate are added and stirring is continued for 30 minutes. The precipitated solid is suction filtered, washed with 10 ml of acetone-water mixture and recrystallized from 40 ml of acetonitrile. 0.73 g (60%) of a colourless solid, m.p. 193°-194° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC(c1ccccc1)c1ccccc1Cl
Yield: 76 %

Procedure:
A mixture containing 15.0 g (0.0692 mole) of 2-chlorobenzophenone, 4.1 g (0.1094 mole) of sodium borohydride, and 200 ml of anhydrous isopropanol is heated to reflux and maintained at reflux until the reaction is complete (2.0 hours), as indicated by vpc techniques. The solvent is removed in vacuo, whereupon the residue is diluted with ether, washed with a dilute hydrochloric acid solution and with water until neutral, dried (magnesium sulfate), and concentrated in vacuo. Recrystallization of the resulting residue from petroleum ether affords 11.5 g (0.0526 mole) of 2-chlorobenzhydrol, m.p. 61°-63°.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:9]([CH2:23][CH2:24][C:25]([O-:27])=[O:26])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[O:7]([C:9]1([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[CH2:23][CH2:24][C:25](=[O:26])[O:27]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1CCC(Oc2ccccc2)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
Phenol (941 mg), 1-(4-nitrobenzyl) 2-oxoglutarate (3.09 g) and DCC (2.27 g) were dissolved in 100 ml of dichloromethane and stirred for 3 hours at room temperature. The precipitated crystals were filtered off and the filtrate was subjected to silica gel column chromatography eluting with dichloromethane-ethyl acetate (3:1) to obtain 1.55 g of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:34]([N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 53.9 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (2.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then morpholinocarbonyl chloride (6.8 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and diluted with diethyl ether (2 ml). The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=2/1) to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-oxiranyl ]-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (9.7 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:30])[C:16](=[O:29])[NH:17][C:18]3[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[C:21]([N+:22]([O-])=O)=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C.[Pd]>[CH2:6]([O:5][P:4]([CH:9]1[N:14]2[C:15](=[O:30])[C:16](=[O:29])[NH:17][C:18]3[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[C:21]([NH2:22])=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C1CCc2c([N+](=O)[O-])c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(OCC)C1CCc2c(N)c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Yield: 69.2 %

Procedure:
226 mg of 8-nitro-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester is dissolved in 20 ml of ethanol, mixed with 50 mg of 10% palladium on activated carbon and hydrogenated at room temperature and under normal pressure. After suctioning off the catalyst, it is concentrated by evaporation and recrystallized from ethanol. 146 mg of 8-amino-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester of melting point 242° C. (with decomposition) is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].C=O.[C:23]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:23][NH:6][C:5]1[CH:7]=[CH:8][C:9]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:3]([CH3:2])[CH:4]=1
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CNc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
To a stirred solution of 1.4 g of the product aniline of Example 31 and 2.5 ml of 37% aqueous formaldehyde in 19 ml of acetonitrile was added in portions 0.62 g of sodium cyanoborohydride. After twenty minutes the solution was adjusted to pH 7 with glacial acetic acid and stirred for another hour. Ice was added, acetonitrile was removed in vacuo, and the mixture was partitioned between water and dichloromethane. The organic layer was dried over potassium carbonate, filtered, and concentrated to an oil which was chromatographed on a silica gel column using dichloromethane as eluent. Fractions containing the title compound were concentrated to give a solid, m.p. 159°-161°. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [C:1]1([C:7]2([C:10](O)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[CH2:14][N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN>CN(C=O)C.CO>[CH3:14][NH:15][CH2:10][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:8]1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CNCC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
1-Phenylcyclopropanecarboxylic acid (2.95 g) was dissolved in DMF (120 mL). To the solution, EDC.HCl (5.2 g), HOBt (3.2 g), and a solution of methylamine in methanol (40%, 1.94 mL) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate/hexane). An aliquot (1.1 g) of the obtained amide compound (2.9 g) was dissolved in THF (60 mL). To the solution, a solution of LAH in THF (2.4 M, 7.9 mL) was added dropwise at 0° C., and the mixture was heated to reflux at 80° C. for 12 hours. To the reaction mixture, water (4.0 mL) was gradually added dropwise at 0° C. The precipitate was removed by filtration and washed with THF (60 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (1.0 g) as a colorless oil.