Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].O.Cl.Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20](=[O:28])[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20]([CH2:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:26][CH2:27]1)=[O:28]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Ethyl bromoacetate (12.12 g, 0.073 mol) in dry acetonitrile (30 mL) was added dropwise to a mixture of N-(2,6-dimethylphenyl)-1-piperazineacetamide dihydrochloride hydrate (18.0 g, 0.073 mol) and potassium carbonate (18.0 g, 0.13 mol) in dry acetonitrile (200 mL). The mixture was stirred at room temperature for 16 h before it was filtered and evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was separated, washed with brine dried and concentrated. There was isolated 21 g (86%) of the XI compound as a colorless oil which was used without further purification; 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.06 (s, 3H), 4.11 (q, J=3.6 Hz, 2H), 3.22 (s, 2H), 3.13 (s, 2H), 2.68 (br s, 8H), 2.14 (s, 6H), 1.19 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 171.65 (0), 169.63 (0), 166.02 (0), 136.72 (0), 136.67 (0), 129.36 (+), 128.09 (+), 63.07 (-), 61.54 (-), 60.24 (-), 54.67 (-), 53.59 (-), 19.7 (+), 15.88 (+); IR (KBr) 3242, 3020, 2988, 2964, 2936, 2914, 2878, 2824, 1744, 1662, 1530, 1478, 1466, 1444, 1428, 1390, 1380, 1306, 1278, 1224, 1198, 1166, 1136, 1042, 1020, 836, 762, 718 cm-1 ; MS (DCI) m/e 334.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:35])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:30]1([O:29][C:20]2[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]3[N:24]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:7][C:6]([OH:36])=[O:5])=[C:10]([CH3:35])[CH:11]=4)[O:17][C:18]=3[N:19]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCCOc1nc(OC2CCCC2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(OC2CCCC2)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 108.2 %

Procedure:
25 mg of [4-(5-cyclopentyloxy-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester were dissolved in 2 ml of dichloromethane and treated with 1 nil of trifluoroacetic acid. After 16 h the mixture was concentrated and freeze-dried. 24 mg of the title compound were obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](=[O:30])(=[O:29])[NH2:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34](Cl)(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:28][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:29])=[O:30])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
In a stream of nitrogen and at 0° C., 117 mg (1.04 mmol) of potassium t-butoxide was added to an anhydrous tetrahydrofuran (10 ml) solution containing 200 mg (0.52 mmol) of 3-benzyloxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 1, and the mixture was stirred for 1 hour. Next, this solution was mixed with 0.16 ml (0.78 mmol) of decanoyl chloride and stirred at room temperature for 3 hours. After completion of the reaction, this was neutralized by adding an ammonium chloride aqueous solution and then the solvent was evaporated. The resulting residue was extracted with ethyl acetate, washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 150 mg (yield: 50.0%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=O)[C:5]#[N:6].Cl.[NH2:14][OH:15].C([O-])(=O)C.[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[N:14][OH:15])[C:5]#[N:6]
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: N#Cc1cc(F)c(C=NO)c(F)c1
Temperature: 60 °C
Yield: 23.3 %

Procedure:
A mixture of 3,5-difluoro-4-formylbenzonitrile (500 mg, 3.0 mmol), hydroxylamine hydrochloride (207 mg, 3.0 mmol) and potassium acetate (586 mg, 6.0 mmol) in methanol (10 mL) was heated to 60° C. for 1 h then concentrated in vacuo and purified by column chromatography (eluent: DCM) to afford 3,5-difluoro-4-((hydroxyimino)methyl)benzonitrile (130 mg, 0.7 mmol) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12]C#N)[C:9]([CH3:15])=[CH:8][C:7]=1O.COC(=O)CC1CCC2C(=CC(C)=C(S)C=2)O1>>[SH:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][C:9]=1[CH3:15])[O:17][CH:3]([OH:2])[CH2:4][CH2:5]2
Reactant: COC(=O)CCc1cc(SC#N)c(C)cc1O
Agent: COC(=O)CC1CCc2cc(S)c(C)cc2O1
Product: Cc1cc2c(cc1S)CCC(O)O2

Procedure:
Compound 15C was prepared according to the method of example 1C utilizing compound 15B. MS: 195 (M−1)+. Preparation of 6-Mercapto-7-methyl-chroman-2-yl-acetic acid methyl ester (Compound 15D)
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:49]([NH:51][C:52]1[S:53][C:54]([Br:64])=[C:55]([C:57](=[N:61][O:62][CH3:63])[C:58](O)=[O:59])[N:56]=1)=[O:50]>C(OCC)(=O)C.C(OCC)C.C(O)(C)C.CN(C)C=O>[CH:49]([NH:51][C:52]1[S:53][C:54]([Br:64])=[C:55]([C:57](=[N:61][O:62][CH3:63])[C:58]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=4)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:59])[N:56]=1)=[O:50]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nc(NC=O)sc1Br
Yield: 43.1 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.3 g.), trimethylsilylacetamide (6.4 g.) and bis(trimethylsilyl)acetamide (6.0 g.) in dry ethyl acetate (100 ml.) and a solution of dimethylformamide (0.9 ml.), phosphoryl chloride (1.1 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 5.1 g.) in dry ethyl acetate (5 ml.) were treated in a similar manner to that of Example 1-(1) (isopropyl alcohol was used for pulverization instead of diethyl ether) to give 4-nitrobenzyl 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.65 g.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: COc1ccccc1O
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COc1ccccc1OCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 48.3 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 2-(methyloxy)phenol (124 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (23.0 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16](F)[C:15]([F:19])=[CH:14][C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[C:29]([OH:37])[CH:30]=[N:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35]>CS(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([O:37][C:16]2[C:15]([F:19])=[CH:14][C:3]([C:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)=[O:5])=[C:2]([F:1])[CH:17]=2)[CH:30]=[N:31][C:32]=1[O:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)Oc1ncc(O)cc1Cl
Reactant: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(OC(C)C)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.1 %

Procedure:
4-Methylphenyl 2,4,5-trifluorobenzoate (Preparation 12, 1.00 g, 3.54 mmol) and potassium carbonate (1.66 g, 12.04 mmol) were suspended in DMSO (24 mL). 5-chloro-6-isopropoxypyridin-3-ol (Preparation 15, 651 mg, 3.47 mmol) was added portionwise over 5 minutes. The mixture was stirred at room temperature for 60 minutes, then partitioned between water (100 mL) and EtOAc (2×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford a green oil (2.5 g) which crystallised on standing. The solid was triturated with heptane to afford the title compound as a colourless solid (1.01 g, 65%):
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[IH:12].CS[C:15](=[NH:17])[NH2:16]>C(O)C>[IH:12].[C:1]([N:8]([CH2:9][CH2:10][NH2:11])[C:15]([NH2:17])=[NH:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CSC(=N)N
Reactant: CC(C)(C)OC(=O)NCCN
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCN)C(=N)N
Yield: 72.8 %

Procedure:
A solution of commercial N-BOC-ethylendiamine (1 g) in dry ethanol (100 ml) and 2-methyl-2-thiopseudourea hydroiodide (1.5 g) was refluxed for 8 hours. The solvent was removed at reduced pressure and the crude residue purified by flash chromatography (methylene chloride/methanol: 9/1) to yield 1.5 g of N-BOC-2-aminoethylguanidine hydroiodide as a yellow oil which was dissolved in methanolic hydrochloric acid solution 5N (20 ml) and stirred at room temperature for 3 hours. The white precipitate was collected, washed with dry ethanol, affording 700 mg of the intermediate.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:40])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=3)[N:21]=[CH:20][C:19]=2Cl)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(OCC)(=O)C>O.O1CCCC1>[C:3]([O:7][C:8](=[O:40])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH2:31][N:32]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]3[CH:20]=[N:21][C:22]4[C:27]([C:18]=3[CH:17]=2)=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc2ncc(Cl)c(C=C(CNCc3ccccc3)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc3c(c2n1)C=C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CN3Cc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of sodium hydroxide (500 mg, 12.5 mmol, 33.6 eq) in water (6 mL) is added at room temperature to a stirred solution of {trans-4-[1-(benzylamino-methyl)-2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester (200 mg, 0.37 mmol, 1.0 eq) in tetrahydrofuran (6 mL). After 16 hours stirring at 60° C., tetrahydrofuran is removed and the residue is extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1 to 3:1, v/v) to afford [trans-4-(1-benzyl-6-methoxy-1,2-dihydro-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a light yellow solid (110 mg, 59% yield).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@@H:32]([C:39]([NH2:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:49].SC(O)C>O1CCOCC1>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@@H:32]([C:39]([NH2:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:49]
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: CC(O)S
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 99 %

Procedure:
2.20 g (3.32 mmoles) of BOC-Trp-Nle-Asp-D-Phg-NH2 are treated with 25 ml of 4 n hydrochloric acid in dioxane in the presence of 1.20 ml (17 mmoles) of mercaptoethanol. After 15 minutes the solution is evaporated in vacuo, the residue is triturated with ether, and the solid is filtered off. 1.99 g (99.0%) of H-Trp-Nle-Asp-D-Phg-NH2.HCl are obtained; m.p.: 217°-221° C. (decomposition), Rf7 :0.35, [α]D :-54.2° (c: 1.0, in dimethyl formamide).
Reaction SMILES: Cl.C(O)(=[O:4])C.[C:6]([C:12]#[N:13])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)(O)[O-].[Na+]>>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6](=[O:11])[C:12]([NH2:13])=[O:4]
Reactant: CC(C)(C)C(=O)C#N
Reactant: CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)C(=O)C(N)=O
Yield: 75.1 %

Procedure:
Hydrogen chloride was passed into a mixture of 60 g (1 mole) of glacial acetic acid and 111.0 g (1 mole) of pivaloyl cyanide at 20° to 25° C. and under 8 bars for 5 hours. The reaction mixture was then let down and poured onto an excess of a saturated sodium bicarbonate solution. The mixture was extracted three times with 200 ml of methylene chloride each time. The combined organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue which remained crystallized after a short time. Recrystallization from petroleum ether gave 97 g (75.2% of theory) of trimethylpyruvic acid amide of melting point 68° to 69° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[C:25]([C:30](Cl)=[O:31])=[N:26][CH:27]=[CH:28][N:29]=1.O>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:30]([C:25]2[C:24]([C:23]([F:33])([F:22])[F:34])=[N:29][CH:28]=[CH:27][N:26]=2)=[O:31])=[CH:13][CH:14]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: O=C(Cl)c1nccnc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1-c1ccc(Cl)cc1)c1nccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Triethylamine (0.32 g: 1.5 mmole) was added to a solution of 4′-chlorobiphenyl-2-ylamine (0.3 g: 1.5 mmole) and 3-trifluoromethylpyrazine-2-carboxylic acid chloride (0.32 g: 1.5 mmole) in THF (10 mL), followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture to suspend the reaction, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the subject compound (0.47 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:28])=[CH:25][CH:24]=1.O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:28])=[CH:39][CH:40]=2)=[CH:17][CH:18]=1
Reactant: O=C(OCCOc1ccccc1)c1ccc(CCl)cc1
Reactant: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NOCc1ccc(C(=O)OCCOc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
2.0 Grams (0.008 mole) of 5-(4-fluorophenoxy)-1,3-dimethylpyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.65 g (0.0116 mole) of powdery potassium hydroxide, the resulting solution was stirred at 30° C. for 30 minutes. To this solution was added 2.5 g (0.00865 mole) of 2-phenoxyethyl 4-chloromethylbenzoate, and reaction was carried out at from 50° to 60° C. for 1 hour. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 3.0 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[N:6][CH:7]=1.[ClH:17].CCOCC>CO>[ClH:17].[ClH:17].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101 %

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide (500 mg, 1.64 mmol) in 5 mL of MeOH was added HCl (4.10 mL, 16.4 mmol, 4M in dioxane). The reaction mixture was stirred at room temperature for 2.5 h, during which time a white precipitate was formed. 20 mL of Et2O was added. After stirring for an additional 20 min, the reaction mixture was filtered, washing with 10 mL of Et2O. 454 mg (99%) of the title compound was isolated as a white solid after drying under high vacuum.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>>[NH2:2][C:1]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[N:26]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NNc1ccc(Br)cc1
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2nn(-c3ccc(Br)cc3)c(N)c2C(N)=O)cc1
Yield: 31.7 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (928 mg, 4.0 mmol), 4-bromophenylhydrazine hydrochloride (894 mg, 4.0 mmol) and sodium hydroxide (176 mg, 4.4 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 10% methanol in CH2Cl2) and recrystallisation from ethyl acetate to give the title compound as white crystals (470 mg) m.p. 222-223°. δH (CDCl3) 7.63 (2H, dt, J 8.8, 2.2 Hz), 7.52 (2H, dt, J 8.5, 2.6 Hz), 7.48 (2H, d, J 7.4 Hz), 7.28 (2H, d, J 8.3 Hz), 5.74 (2H, br s), 5.29 (2H, br s), 2.41 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[CH:14]=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:4][CH:3]=1.FC1C=CC(CN2C=[CH:33][N:32]3[C:35](=O)[CH:36]=[C:37](O)[C:38](O)=[C:31]3C2=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][N:10]3[C:13](=[O:19])[C:14]([CH2:33][N:32]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:31]4)=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=c1c2c(O)c(O)cc(=O)n2ccn1Cc1ccc(F)cc1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Product: O=c1c2c(O)c(O)c(CN3CCCCC3)c(=O)n2ccn1Cc1ccc(F)cc1

Procedure:
The title compound was prepared using a procedure similar to that described in Example 11, except that 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione was substituted with 2-(4-fluorobenzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione (Example 14).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH3:28])[C:18](=[O:29])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:19]([CH3:28])[C:18](=[O:29])[CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cn1c(-c2ccccc2)nc(CCl)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(-c2ccccc2)nc(CN2CCN(c3ccc(O)cc3)CC2)cc1=O
Yield: 65.6 %

Procedure:
According to the same procedure as described in Example 20, starting from 3.39 g (19 mmol) of 1-(4-hydroxyphenyl)piperazine and 4.20 g (17.9 mmol) of 6-chloromethyl-3,4dihydro-3-methyl-2-phenylpyrimidin-4-one, using 1.24 g (9 mmol) of K2CO3, 4.42 g (=65.6% yield) of 4-(4-hydroxyphenyl)-1-(3,4-dihydro-3-methyl-2-phenylpyrimidin-4-on-6-ylmethyl)piperazine were obtained; melting point 206°-207° C., analysis: C22H24N4O2 (MW 376.46) calc. C 70.19 H6.43 , N 14.88; found C 69.2, H 6.4, N 14.5%. For workup of the reaction mixture, the DMF had been evaporated off in vacuo, the residue had been taken up in water/CH2Cl2 and neutralized, and the CH2Cl2 extract residue had been crystallized from CH3OH.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=1>C(#N)C>[CH:1]1([C:4]([N:40]2[CH2:41][CH2:42][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:23]4[N:22]([CH3:21])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)[CH:32]=3)[CH2:38][CH2:39]2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cn1c(-c2cccc(N3CCN(C(=O)C4CC4)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a solution of cyclopropanecarboxylic acid (0.06 g, 0.68 mmol) in acetonitrile (8 mL) was added CDI (0.11 g, 0.68 mmol) and the resulting suspension was stirred at room temperature for 5 h. 1-Methyl-2-(3-piperazin-1-yl-phenyl)-1H-benzoimidazole dihydrochloride (0.20 g, 0.55 mmol) was added and the resulting solution heated at 65° C. overnight. The reaction was then cooled to room temperature, the solvent removed under reduced pressure. The crude product was redissolved in dichloromethane (15 mL) and washed with saturated NaHCO3 solution (2×3 mL) The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: cyclohexane:EtOAc, gradient from 100% cyclohexane to 100% ethyl acetate) to afford 0.17 g (85%) of the title compound.