Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH2:20][CH2:21][OH:22]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:19]([CH3:18])[CH2:20][CH2:21][OH:22]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(CCO)c1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 554 μL (5.0 mmol) of 3,4-difluoronitrobenzene in 10 mL of dimethyl sulfoxide were added 1.38 mg (10.0 mmol) of potassium carbonate and 803 μL (10.0 mmol) of 2-methylaminoethanol, and the mixture was stirred for 1.5 hours at 100° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, then, the extract was washed with water and saturated saline solution. After dried over with anhydrous sodium sulfate, the solvent was removed under reduced pressure ant the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 1.06 g (99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)CCC1>[CH2:23]([NH:30][C:7]1[CH:6]=[C:5]2[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]3[C:4]2=[CH:3][C:2]([Cl:1])=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(NCc3ccccc3)ccc21
Yield: 43.4 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (400 mg, 1.19 mmol), benzyl amine (510 mg, 4.7 mmol) and NMP (2 ml) gave title compound (218 mg, 42%) after purification by column chromatography using DCM/MeOH (95:5) as the eluent.
Reaction SMILES: O.[OH-].[Li+].CC([Si](C)(C)[O:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:23]=1)[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14])(C)C>C1COCC1>[CH3:32][C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][C@@H:25]([O:24][C:22]1[CH:21]=[C:12]([CH:11]=[C:10]([OH:9])[CH:23]=1)[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14])[CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O[Si](C)(C)C(C)(C)C)cc(C(=O)Nc2nccs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
An aqueous solution of lithium hydroxide monohydrate (0.304 g, 7.25 mmol) was added to a solution of 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide (1.552 g, 2.90 mmol) in THF (40 mL) and stirred at RT overnight. The THF was removed in vacuo and the residual solution adjusted to pH 7 by addition of 1N hydrochloric acid (7.25 mL). A gum formed, and the solution was filtered and the gum dissolved in methanol. The filtrate was partitioned with ethyl acetate (75 mL) and the organics washed with brine, dried (MgSO4), combined with the methanol solution and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give the required product (0.865 g)
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]2[N:20]([CH:21]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[CH2:19][CH2:18][S:17][C:16]=2[CH:33]=1>CCO>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:20]([CH:21]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22]3)[CH2:19][CH2:18][S:17][C:16]=2[CH:33]=1
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(N)ccc32)C1
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(NC(=N)c4cccs4)ccc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (0.53 g, 1.874 mmol) was added to a mixture of tert-butyl 3-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.31 g, 0.937 mmol) in EtOH (20 mL). The mixture was stirred under room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution (50 mL). The solution was then transferred to a separatory funnel, diluted with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The crude material was subjected to flash chromatography on silica gel (50-90% EtOAc/hexanes). The concentrated fractions afforded a yellow oil (0.29 g, 69%). 1H NMR (CDCl3) δ 7.41 (dd, J=0.9, 5.1 Hz, 1H), 7.38 (d, J=3.6 Hz, 1H), 7.06 (dd, J=3.9, 4.9 Hz, 1H), 6.79-6.76 (m, 2H), 6.68-6.66 (m, 1H), 4.84 (brs, 2H), 4.35-4.23 (m, 1H), 3.74-3.22 (m, 6H), 3.12-3.07 (m, 2H), 2.19-1.99 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 447, 445 (MH+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[O:11]=[C:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=2)[NH:13]1>>[OH:21][C:20]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=2)[NH:13][C:12]1=[O:11]
Reactant: COc1ccc(C)cc1Br
Reactant: N#Cc1ccc2c(c1)C(=O)C(=O)N2
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(C#N)cc21
Yield: 50.8 %

Procedure:
With 7.06 g of 2-bromo-1-methoxy-4-methyl benzene and 4.03 g of 2,3-dioxo indoline-5-carbonitrile as starting materials, 3.50 g of the title compound (brown amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[S:7][C:6]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)s2)cs1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)s2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.9 %

Procedure:
In a water bath at about 20° C., to a suspension of N-(4-{2-[5-(hydroxymethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (500.0 mg, 1.771 mmol) in anhydrous chloroform (2.5 ml) was added dropwise thionyl chloride (0.77 ml, 10.6 mmol). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. Anhydrous chloroform (5 ml) was added to the residue and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove thionyl chloride azeotropically. The residue was dried under reduced pressure to give N-(4-{2-[5-(chloromethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (633.2 mg) as a pale-brown solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[C:4]([OH:6])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[CH:20][CH:19]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cccc([N+](=O)[O-])c1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc([N+](=O)[O-])c1

Procedure:
(RS)-Methoxy-(3-nitro-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(3-nitro-phenyl)-acetamide. Light yellow gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=[N:9][OH:10])[C:6](=[O:8])[CH3:7])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:10][N:9]=[C:5]([C:6](=[O:8])[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11])=[CH:15][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCc1ccc(F)cc1)C(C)=O
Yield: 95.9 %

Procedure:
Ethyl2-hydroxyimino-3-oxobutyrate (syn isomer, 40.0 g.), 4-fluorobenzyl chloride (43.6 g.), N,N-dimethylformamide (60.0 ml), potassium carbonate (52.0 g.) and ethyl acetate (60.0 ml.) were treated in a conventional manner to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 64.4 g.).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Na].[CH:23]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:28][CH2:29][O:30][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OCCC1CCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Agent: [Na]
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(OCCC2CCCC2)c2[nH]c(C(F)(F)F)nc12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the sodium salt of 2-cyclopentylethanol to obtain 4-(2-cyclopentylethoxy) -7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 397.3.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](CO)[C:12](O)=[C:11](C)[C:10]=1[CH3:19])C1C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]([O:30][CH3:31])([O:28][CH3:29])[CH3:27])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]1([CH3:27])[O:28][CH2:29][C:13]2[CH:14]=[C:9]([OH:8])[C:10]([CH3:19])=[C:11]([CH3:12])[C:31]=2[O:30]1)[CH3:21]
Reactant: Cc1c(OCc2ccccc2)cc(CO)c(O)c1C
Reactant: CCOC(=O)CCC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1(C)OCc2cc(O)c(C)c(C)c2O1
Reaction time: 48 h

Procedure:
To a solution of 4-benzyloxy-6-hydroxymethyl-2,3-dimethyl-phenol (52 mg, 0.20 mmol), prepared as in Example 29, in 0.5 mL of dry DMF was added the above dimethyl ketal, 4,4-dimethoxy-pentanoic acid ethyl ester (420 mg, 2.2 mmol) and 5 mg of pyridinium p-toluene sulfonate (PPTS). The mixture was stirred for 48 h and concentrated. The crude product was purified on silica gel column chromatography (8:1 hexane/EtOAc) to afford a clear oil containing the desired product and starting ketal material. This mixture was then dissolved in EtOH (5 mL) and hydrogenated in the presence of 10 mg of Pd/C for 1.5 h at atmosphere pressure. After filtration the solution was concentrated and purified by chromatography (5:1 hexane/EtOAc) to afford 3-(6-hydroxy-2,7,8-trimethyl-4H-benzo[1,3]dioxin-2-yl)-propionic acid ethyl ester as a light brown sticky oil (38 mg). 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.29 (s, 1H), 4.77 (s, 1H), 4.72 (q, J=14.9, 2H), 4.13 (q, J=7.2, 2H), 2.57-2.52 (m, 2H), 2.22-2.16 (m, 2H), 2.16 (s, 3H), 2.10 (s, 3H), 1.47 (s, 3H), 1.27 (t, J=7.2, 3H); 13C-NMR δ (ppm): 173.8, 147.2, 142.5, 126.0, 122.8, 116.5, 107.5, 99.5, 60.5, 33.9, 28.6, 21.8, 14.2, 11.9, 11.5.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C:10]3=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:10]3=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CNCCC2
Reaction time: 2 h
Yield: 141.5 %

Procedure:
Intermediate 39A (1.22 g, 3.17 mmol) was dissolved in DCM (10 mL) and TFA (5 mL) was added. The resulting mixture was stirred for 2 hours. The mixture was concentrated, toluene was added and the mixture was concentrated again and dried under vacuum to give 1.28 g of intermediate 64A which was used in the next step without purification. LCMS (+ESI) m/z 286.1 [M+H]+
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1cccc2ccccc12
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Upon boiling a solution of 7.8 g 1-naphthaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(naphth-1-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 162°-163° C (ethanol) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COCCN(C)CCOc1ccc(CCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 45.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:2])=[O:22]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: OCCCCCCCCCBr
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)CCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
Pyridinium chlorochromate (38.7 g, 180 mmol) and silica 60A (39 g, particle size 35-70 micron) suspended in DCM (250 mL) were stirred at RT for 45 minutes. 9-Bromononanol (26.7 g, 120 mmol) was added, in one portion, and the suspension was stirred at RT for 18 hours. The reaction mixture was filtered through a celite plug, and the resulting filtrate concentrated under vacuum affording the title compound (28.0 g, >100%). The material was used without further purification in the next step.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:5]1)(=O)C.[OH-].[K+]>CCO.O>[C:24]([CH2:23][CH2:22][CH:6]1[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[C:10]([CH3:20])=[CH:9][C:8]=2[CH3:21])[NH:4][CH2:5]1)([OH:26])=[O:25]
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCC(=O)O
Yield: 70.4 %

Procedure:
N-[1-Acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (2.6 g) was dissolved in EtOH (40 ml), and a solution of KOH (1.3 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. EtOH was evaporated under reduced pressure, and the mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with CHCl3 (100 ml). The CHCl3 layer was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure to give 1.5 g of N-[3-(2-carboxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][N:21]4[CH:27]=3)[O:17][C:13]=2[CH:12]=[C:11]([O:28][CH3:29])[CH:10]=1)C1C=CC=CC=1.[H][H]>ClCCl.CO.[Pd]>[CH3:29][O:28][C:11]1[CH:12]=[C:13]2[O:17][C:16]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][N:21]4[CH:27]=3)=[CH:15][C:14]2=[C:9]([OH:8])[CH:10]=1
Reactant: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A solution of 2-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine (Example 39A, 1.00 g, 2.59 mmol) in a mixture of dichloromethane (420 mL) and methanol (150 mL) in a 1 L flask was hydrogenated over 10% Palladium over carbon (0.30 g, i.e., 30 mg Pd) and under 1 atm of hydrogen for 6 h. The reaction mixture was maintained under vacuum for 2 min and then flushed with nitrogen. The catalyst was filtered and washed with warm dichloromethane-methanol (8:2, 100 mL) and the combined filtrate was concentrated under reduced pressure. The yellow residue was boiled with 1,2-dichloroethane (30 mL) and allowed to stand at room temperature for 18 h. The solid was filtered (contains methanol by NMR) and dried in vacuo at 120° C. for 12 h to give the title material (0.760 g, 99% yield) of a yellow solid. LC (Method A): 1.844 min. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 2.54 (s, 3H), 3.77 (s, 3H), 6.28 (d, J=1.96 Hz, 1H), 6.70 (dd, J=1.96, 1.17 Hz, 1H), 7.20 (d, J=9.39 Hz, 1H), 7.24 (d, J=0.78 Hz, 1H), 8.03 (d, J=9.78 Hz, 1H), 8.50 (s, 1H), 10.10 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl>[CH2:12]([O:11][C:10]1[C:6]2[C:5](=[O:25])[N:4]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[C:7]=2[N:8]2[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-amino-2-(4-fluorobenzyl)-10-benzyloxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (21 mg, 47 μmol) and diisopropylethylamine (10 μL, 56 μmol) in anhydrous chloroform (2 mL), acetyl chloride (8 μL, 104 μmol) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The intermediate bisacetylated product was dissolved in methanol, stirred at room temperature overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title monoacetylated product.
Reaction SMILES: CS[C:3](=[S:10])[NH:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1.[NH2:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1>CN(C)C=O>[NH:14]1[CH:15]=[N:16][C:12]([NH:11][C:3]([NH:4][C:5]2[N:9]=[CH:8][NH:7][N:6]=2)=[S:10])=[N:13]1
Reactant: CSC(=S)Nc1nc[nH]n1
Reactant: Nc1nc[nH]n1
Solvent: CN(C)C=O
Product: S=C(Nc1nc[nH]n1)Nc1nc[nH]n1
Yield: 58 %

Procedure:
A 3,000 ml multinecked flask provided with a reflux condenser and placed on a water bath was filled with 156.2 g (0.8964 mole) of N-1,2,4-triazolyl-dithiocarbamic acid methyl ester, prepared as described in U.S. Pat. No. 3,686,201, 1,700 ml of dimethylformamide, 75.37 g (0.8964 mole) of 3-amino-1,2,4-triazole. The reaction mixture was heated for 24 hours thus obtaining first a solution and then the formation of a precipitate. The suspension was filtered, the product thus obtained washed with methanol and then dried thus obtaining 109.3 g of a white product (Yield 57%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.S(O)(=O)(=O)C.O[CH2:39][CH:40]1[O:44][N:43]=[C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:39][C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:41]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: OCC1CC(c2ccccc2)=NO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CS(=O)(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3cc(-c4ccccc4)no3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(oo) In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 61(c)] with 5-hydroxymethyl-3-phenyl-4,5-dihydro-isoxazole mesylate, prepared according to a generally known procedure, there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-phenyl-isoxazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 591 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=[O:26])[C:16]([C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[N:17]O)=[CH:14][C:9]=3[N:8]([CH3:27])[C:7]2=[O:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29].[H][H]>C(O)C.C(OCC)C.[Pd]>[ClH:29].[NH2:17][CH:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[CH:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7](=[O:28])[N:8]([CH3:27])[C:9]=2[CH:14]=1)[OH:26]
Reactant: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1cccc(C(N)C(O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Reaction time: 3 h
Yield: 92.4 %

Procedure:
1-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-m-tolyl-ethane-1,2-dione 2-oxime (5 gm, 13.2 mmol) was dissolved in ethanol (300 mL) in a Parr bottle. Concentrated HCl (3.3 mL, 40 mmol) was added, followed by 10% Pd on carbon (approximately 0.5 gm). The resulting mixture was placed on a Parr hydrogenation apparatus and hydrogenated at a hydrogen pressure of 40 psi. Hydrogen consumption slowed considerably after 3 hours, with the amino ketone being formed initially. Hydrogenation was continued overnight, after which time the reaction was determined to be complete. The mixture was filtered through a celite plug and the filtrate was concentrated in vacuo to afford a viscous yellow oil, which was triturated/repulped in diethyl ether to afford 4.90 gm of a white solid.