Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[N:15]([C@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[O:25]1[CH2:26][CH2:27][C@H:23]([N:15]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[NH2:6])[CH2:24]1
Reactant: CC(C)(C)OC(=O)N([C@H]1CCOC1)N1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(N)[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 94.1 %

Procedure:
Methylhydrazine (3.94 mL) was added dropwise to a solution of (S)-t-butyl (1,3-dioxoisoindolin-2-yl)(tetrahydrofuran-3-yl)carbamate (12.3 g) in THF (125 mL) under ice-cooling over two minutes. The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for three days and then at 50° C. for four hours. The reaction mixture was ice-cooled, and the insoluble matter was then removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 14%) to give the title compound (7.04 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH3:16][C:17](=O)[CH2:18][CH3:19].C>>[CH:17]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)([CH2:18][CH3:19])[CH3:16]
Reactant: O=C1Nc2ccccc2C12CCCNC2
Reactant: CCC(C)=O
Agent: C
Product: CCC(C)N1CCCC2(C1)C(=O)Nc1ccccc12
Yield: 46 %

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction with spiro[indoline-3,3′-piperidin]-2-one and 2-butanone (3 equivalents). Yield: 46%. 13C NMR (CDCl3): δ 11.5, 11.6, 13.3, 13.3, 21.7, 21.9, 26.4, 26.5, 32.1, 32.1, 46.1, 48.6, 49.0, 50.9, 52.4, 56.6, 61.2, 62.5, 109.6, 121.5, 121.6, 126.4, 126.5, 127.2, 134.7, 134.9, 140.1, 140.1, 182.4, 182.5; MS (CI, CH4): m/z (rel. int.) 259 (M+1, 100).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:14]=[C:15](B(O)O)[C:16]([F:19])=[N:17][CH:18]=1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH2:31])[N:25]=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:14]=[C:15]([C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH2:31])[N:25]=2)[C:16]([F:19])=[N:17][CH:18]=1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cnc(F)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)nc(-c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cnc2F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A yellow solution of 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridin-3-ylboronic acid (177 mg, 0.541 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9; 78 mg, 0.541 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.; 19.15 mg, 0.027 mmol), and potassium acetate (159 mg, 1.622 mmol) in a mixture of dioxane (4.0 mL) and water (1.0 mL) was stirred under argon at 100° C. for 2 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (80 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic extracts were then dried over sodium sulfate and concentrated onto silica gel. Chromatographic purification (silica gel, 0 to 60% EtOAc/hexanes) provided 4-(5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (73.0 mg, 0.186 mmol, 34.5% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (dd, J=9.2, 2.5 Hz, 1H), 8.33 (d, J=1.4 Hz, 1H), 5.65 (br. s., 2H), 3.57 (s, 2H), 2.54 (s, 3H), 1.37 (s, 6H), 0.84 (s, 9H), −0.03 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −70.17 (d, J=9.2Hz, 1F). m/z (ESI, +ve) 392.3 (M+H)+.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=1[Cl:17]>CS(C)=O>[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[Cl:17]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.5 %

Procedure:
Compound (1) (0.67 g, 5.5 mmol) and EDC (1.1 g, 5. 7 mmol) was dissolved in dimethyl sulfoxide (DMSO) (10 mL). N,N-dimethyl 1,2-ethylenediamine [compound (2)] (7.5 mL, 5.7 mmol) was added and the mixture was stirred at room temperature for 5 hours, whereafter the reaction mixture was freeze dried. The residue was subjected to column chromatography [silicon dioxide (SiO2) plates chromatographed in chloroform (CHCl3)-methanol (30:1, v/v)+triethylamine (Et3N) (1:1, v/v). This procedure gave quantitative yield (1.1 g) of compound (3) as a syrup.
Reaction SMILES: [C:1]1([CH:7]2[C:14]3([CH2:18][CH2:17][C:16](=O)[NH:15]3)[CH:11]3[CH2:12][CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].[O-2].[Ca+2]>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[C:14]3([CH2:18][CH2:17][C:16](=[S:21])[NH:15]3)[CH:11]3[CH2:12][CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CCC2(N1)C1CCC(CC1)C2c1ccccc1
Agent: [Ca+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: S=C1CCC2(N1)C1CCC(CC1)C2c1ccccc1

Procedure:
33 mmoles of 3-phenyl-spiro[bicyclo[2.2.2]-octane-2,2'-pyrrolidin]-5'-one are dispersed in 200 ml of toluene, and a mixture of 7.3 g of phosphorus pentasulfide and 7 g of calcium oxide is added, whilst stirring, and the mixture is stirred at 50° C. for 21/2 hours. The hot reaction solution is filtered into a saturated sodium carbonate solution. The residues are dissolved in concentrated hydrochloric acid and the solution is diluted with water and carefully combined with the toluene/sodium carbonate mixture. The aqueous phase is extracted several times with toluene and the extracts are combined, dried and concentrated in vacuo. Recrystallization of the residue from a little ethyl acetate gives colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])=[C:10]([N:39]([CH3:41])[CH3:40])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:32]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=1[C:11]1[C:10]([N:39]([CH3:41])[CH3:40])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:30])[NH:14][C:13]=2[CH:12]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1cccc(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1-c1cccc(F)c1F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {2-dimethylamino-2′,3′-difluoro-5-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example M8) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (47 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br>C(O)(=O)C.C(#N)C.C(OCC)C>[CH3:13][O:12][C:10]1[CH:11]=[C:3]2[C:4](=[CH:8][C:9]=1[O:14][CH3:15])[C:5](=[O:6])[O:7][CH:1]2[PH2:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)c(C(=O)O)cc1OC
Agent: Br
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C([PH2](c1ccccc1)(c1ccccc1)c1ccccc1)OC2=O
Temperature: 90 °C
Yield: 97.1 %

Procedure:
A suspension of 2-formyl-4,5-dimethoxy-benzoic acid (6.43 g, 30.62 mmoles), obtained as described in example 2, triphenyl-phosphine (8.3 g, 30.62 mmoles), 30% HBr in acetic acid (8.26 ml, 30.62 mmoles) and glacial acetic acid (20 ml) under N2 was heated at 90° C. for 4.5 hours. The mixture was brought to dryness, re-dissolved in acetonitrile (50 ml) and diluted with ethyl ether up to turbidity, then cooled and filtered, and the filtrate was washed with ethyl ether and dried under vacuum to give 13.6 g of the title compound (yield: 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:6].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].CN(C=O)C>C1C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)=C(C(=O)OC)C(=O)OC
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C=CN(C)C)=C(C(=O)OC)C(=O)OC
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 3-ethoxycarbonyl-2-methoxycarbonyl-but-2-enoic acid methyl ester (10 g, 43.5 mmol), dimethylformamide dimethyl acetal (6.1 mL, 45.7 mmol) and DMF (8 mL) was heated at 80° C. for 3 h. The slightly cooled solution was poured into 100 mL of benzene, and the resulting mixture was washed several times with water. The organic layer was dried over MgSO4 and concentrated to give a dark yellow solid, which was recrystallized from CCl4 to give 10.6 g of the title compound as a bright yellow solid. 1H NMR (CDCl3, 200 MHz): δ=6.77 (d, 1H, J=12.8 Hz), 5.74 (d, 1H, J=13.2 Hz), 4.34 (q, 2H, J=7.0 Hz), 3.80 (s, 3H), 3.71 (s, 3H), 2.97 (br s, 6H), 1.36 (t, 3H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)=[O:29])=[CH:24][CH:23]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:28]([C:25]4[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=4)([C:30]4[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=4)[OH:29])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: Cc1ccc(C(=O)c2cncn2C)cn1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(C)nc3)c3cncn3C)ccc2n1
Yield: 48 %

Procedure:
Following the same procedure as that described in Example 1E, 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (0.200 g, 0.574 mmol) and (6-methyl-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (0.105 g, 0.522 mmol) generated 0.118 g (48% yield) of [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-methyl-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1F)[C:6]([OH:8])=[O:7])#[N:2].O.[NH2:14][NH2:15]>C(O)C>[NH2:2][C:1]1[C:3]2[C:11](=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[NH:15][N:14]=1
Reactant: NN
Reactant: N#Cc1cc(C(=O)O)ccc1F
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 3-cyano-4-fluorobenzoic acid (980.0 mg, 5.94 mmol) in ethanol (6 mL), was added hydrazine hydrate (0.89 mL, 17.8 mmol). The reaction was heated at reflux for 3 hours. The reaction was cooled to room temperature and ethanol was removed under reduced pressure. The resultant yellow oil was taken up in water (50 mL) and basified with 1 N aqueous sodium hydroxide (5 mL). The solution was washed once with ethyl acetate (25 mL). The aqueous phase was acidified to pH=3 with 6 N aqueous hydrochloric acid and was allowed to stir at room temperature for 1 hour. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (612 mg, 48%) as a pink solid. +ESI (M+H) 178.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.42-8.47 (m, 1H), 7.76 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][NH2:27])[CH3:23]>>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][NH:27][C:9](=[O:10])[C:8]([C:3]1[NH:4][C:5]([CH3:7])=[CH:6][C:2]=1[CH3:1])=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)C(=C1C(=O)Nc2ccccc21)c1[nH]c(C)cc1C
Yield: 30.5 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with N,N-diethylethylenediamine (48 mg) using method B to give 37 mg (46%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([N:19]1[CH2:23][C:22](=O)[N:21]=[CH:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc(N)n(-c2ccc(Cl)cc2C)n1
Reactant: CC(=O)N1C=NC(=O)C1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(Cl)cc1C

Procedure:
5-Amino-3-methyl-1-(4-chloro-2-methylphenyl) pyrazole (22.16 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 13.1 g. of product, mp 195°-195°.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[N:8]1([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 189 %

Procedure:
In a dichloromethane solution containing 5.1 g of N-Boc-hydroxyproline (Boc-Hyp-OH), 0.35 g of tert-butylamine, 7.4 g of HOBt and 6.0 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 144 (Process 2) to give 2.59 g of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(OCC)C>CN(C)C=O.O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
In an argon stream, 2.2 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide. The suspension was added dropwise to a solution of 9.6 g of the 3-(1-piperidinomethyl)phenol obtained in Reference Example 1 in 30 ml of N,N-dimethylformamide, followed by stirring at room temperature for 30 minutes. Next, a solution of 14.7 g of N-(3-bromopropyl)phthalimide in 50 ml of N,N-dimethylformamide was added dropwise to the mixture, and the resulting mixture was stirred at 65° C. for 8 hours. After cooling the mixture, a mixture of diethyl ether and water (1:1) was added thereto for extraction, and the organic layer was concentrated under reduced pressure. To the concentrate was added 6N hydrochloric acid for extraction into the aqueous layer, which was then made alkaline with potassium hydroxide, followed by extraction with diethyl ether. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent, giving 16.3 g of transparent oily N-[3-[3-(piperidinomethyl)-phenoxy]propyl]phthalimide (yield 86% ).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=O.[NH:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[CH:1]=[C:27]1[NH:21][C:22](=[O:23])[NH:24][C:25]1=[O:26])([O-:20])=[O:19]
Reactant: O=C1CNC(=O)N1
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)CCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
A mixture of ethyl 4-[3-formyl-4-nitrophenoxy]butanoate (2.00 g, 7.1 mmol), hydantoin (0.71 g, 7.1 mmol), and anhydrous sodium acetate (0.58 g, 7.1 mmol) and acetic anhydride (20 mL) was heated at reflux for 1 hour. Upon cooling, H2O was added and the mixture extracted with dichloromethane. The organic portion was washed with water, evaporated, and the residue dissolved in a solution of methanol (20 mL) and 4N NaOH (30 mL). After stirring for 1 hour, the mixture was acidified to pH=2 by addition of 2N HCl. The precipitate was collected and triturated with MeOH/CH2Cl2 to afford 4-[[4-nitro-3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]phenyl]oxy]butanoic acid (0.88 g, 37%). An analytical sample was prepared by crystallization from DMF/H2O to give gold plates, m.p. 181°-184° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>C(O)C>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[NH2:3][C:2]([NH2:4])=[NH2+:1]
Reactant: N=C(N)N
Agent: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: CCO
Product: NC(N)=[NH2+]
Reaction time: 0.25 h

Procedure:
A solution of guanidine (0.0029 mol) [prepared from guanidinium nitrate and KOH] in ethanol (50 ml) was added to a solution of omeprazole (1.0 g, 0.0029 mol) and the resulting solution was stirred for 15 min. The solvent was evaporated giving omeprazole guanidinium salt, mp 110°-112° C. (soluble in water).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][C:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:25][C:16]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:15])[CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH2:23][CH2:24]1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: CC(C)(CCN1CCNCC1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CCN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 2-(3-pyridyl)thiazolidin-4-carboxylic acid (0.81 g), 1-(3-methyl-3-phenylbutyl)-piperazine (0.73 g), 1-hydroxybenzotriazole (0.50 g) and dicyclohexylcarbodiimide (0.76 g) in N,N-dimethylformamide (7 ml) was stirred under room temperature for 12 hours. To the reaction solution was added ethyl acetate (10 ml) and the insoluble matter was filtered off. To the filtrate was added 0.5N sodium hydroxide and the solution was extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N hydrochloric acid. The aqueous layer was made basic with potassium carbonate and extracted with ethyl acetate. The resultant ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and elution with an ethyl acetate-methanol (10:1) mixture gave 1.32 g of 1-(3-methyl-3-phenylbutyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][C:11](=O)[NH:10][CH2:9]2)[N:7]=1.[BH4-].[Na+].C(O)(=O)C>O1CCCC1>[F:15][C:2]([F:1])([F:16])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[N:7]=1
Reactant: O=C1COC(c2csc(C(F)(F)F)n2)CN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: FC(F)(F)c1nc(C2CNCCO2)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.9 g (0.036 mol) of 2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one in 40 ml of tetrahydrofuran at 3° C. is mixed with 1.35 g (0.036 mol) of sodium borohydride. Then, at 5°-8° C., very slowly and with vigorous stirring 2.43 g (0.036 mol) of glacial acetic acid dissolved in 20 ml of tetrahydrofuran are added dropwise. The cooling is removed after 2 hours, and the mixture is stirred at room temperature for 16 hours. After evaporation to dryness, the resulting residue is mixed with 15 ml of 20% strength hydrochloric acid, and the mixture is heated at 90° C. for 30 minutes. It is then evaporated to dryness, the resulting product is taken up in water, and the solution is made alkaline with sodium carbonate solution. The mixture is then extracted several times with methylene chloride, the organic phase is dried over sodium sulphate and concentrated, and the residue is purified on a silica gel column using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=O)[CH:16]([NH:24][C:25](=O)[CH2:26][CH2:27][O:28][CH3:29])[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[NH4+:41].CO>C(OCC)(=O)C>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[NH:41][C:25]([CH2:26][CH2:27][O:28][CH3:29])=[N:24][C:16]=4[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: COCCC(=O)NC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCCC1)c1cccc(C)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCc1nc(-c2cccc(C)c2)c(-c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)[nH]1
Yield: 85.8 %

Procedure:
N-[2-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-oxo-1-m-toly-ethyl]-3-methoxy-propionamide (294 mg, 0.65 mmol) was stirred with ammonium trifluoroacetate (857 mg, 6.5 mmol) and the mixture was heated to 150 deg C. in an oil bath. Occasionally, the sides of the flask were rinced down with methanol to insure all reactants were heated uniformly. A TLC (ethyl acetate) of the reaction mixture after 1 hour of heating showed complete reaction. The oil bath was removed, and hot water was added to the reaction mixture as it cooled. When the mixture reached room temperature, no precipitate formed, so the aqueous mixture was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with water and dried over anhydrous sodium sulfate to afford 240 mg of a tan solid. MS (M+1)=431.3.