Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([Cl:32])[CH:26]=1>>[Cl:32][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]4[CH3:21])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:29][C:28]=1[OH:31]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CC1CCCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CCCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1

Procedure:
Intermediate 108 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H), 8.24 (s, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.44 (t, 1H), 7.15 (s, 1H), 7.08 (d, 1H), 6.93 (d, 1H), 6.84 (d, 1H), 5.37 (t, 1H), 4.36 (d, 1H), 3.75 (d, 1H), 3.66 (m, 2H), 2.93 (m, 2H), 2.80 (t, 2H), 2.42 (s, 1H), 1.75 (m, 5H), 1.38 (m, 4H).
Reaction SMILES: [CH3:1][Li].[C:3]1([C:17]([OH:19])=O)[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N#N.Cl>O1CCCC1.O>[C:3]1([C:17](=[O:19])[CH3:1])[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [Li]C
Reactant: O=C(O)c1cccc2c1Sc1ccccc1S2
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc2c1Sc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
Methyl lithium (1.6M in ether, 57 ml, 90 mmol) was added drop wise to a stirred solution of thianthrene-1-carboxylic acid (11.71 g, 45 mmol) in dry tetrahydrofuran (200 ml) at −78° C. over 30 minutes under an inert atmosphere (N2). The reaction mixture was allowed to warm to room temperature and (very thick white suspension present) was left stirring for 4 hours. Water (10 ml) was then added carefully to the solution and the pH was adjusted to 1 (pH paper) with 2N HCl. The solvent was removed in vacuo and the yellow solid formed was filtered and dried overnight in a vacuum desiccators. The solid was then purified by column chromatography (ethyl acetate/hexane; 1:9) and was recrystalised from ethanol to give the desired product (6.58 g, 57%). 1HNMR (300 MHz, CDCl3): δH=2.65 (3H, s); 7.26 (3H, m); 7.47 (2H, m); 7.62 (2H, d). m/z (LC-MS, ESP) RT=4.95 min; (M++1)=259
Reaction SMILES: C([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=2)=[CH:6][CH:5]=1)(O)=O.ClC(Cl)(Cl)C(O)=O>C1C=CC=CC=1>[CH:14]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:13](=[CH:4][CH:5]=[CH:6]2)[CH:12]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc2ccc(C(=O)O)c-2c1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)c1cccc2cccc-2c1
Temperature: 25 °C

Procedure:
The well-dried compound (18) (2.1 g) was dissolved in benzene (150 ml), and then trichloroacetic acid (0.4 g) was added. The mixture was heated under reflux for 2 hours on an oil bath. The reaction mixture was cooled to room temperature, and then passed through a column of alumina. From the eluted solution the solvent was distilled off to obtain the crude product (19), at a yield of 1.02 g. The crude product was purified on an alumina (20 g) column, eluting with hexane, to obtain the product (19) at a yield of 725 mg (91.2%) as a blue oily substance.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[OH-].[K+:12]>>[CH2:1]([NH:5][CH2:6][P:7]([O-:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[K+:12]
Reactant: O=C(O)CNCP(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CNCP(=O)([O-])O
Reaction time: 1 h

Procedure:
To a glass container of approximately 4 liter capacity was added 1264.1 grams of glyphosate acid with an assay of 95.7%. The container was placed in an ice/water bath to provide cooling. The container was equipped with an overhead stirrer with a propeller blade approximately one half the diameter of the container. A commercial 45% potassium hydroxide solution (VWR Scientific Products) was added. The addition rate was controlled to avoid obvious boiling of the resulting solution. The stirrer height was adjusted as the volume of the liquid changed to insure good mixing. A total of 966.2 grams of potassium hydroxide solution were added. The concentration was adjusted by the addition of 195.3 grams of deionized water. Stirring was continued for approximately 1 hour. The final yield was 2418.4 grams which represents a weight loss of 7.2 grams. The calculated assay was 50.0% glyphosate acid or 61% of potassium glyphosate and the calculated neutralization was 108%. The pH of a 10% dilution in deionized water was 4.76. The density of the resulting solution at 20° C. was approximately 1.4661 grams/milliliter and the volume of 1000 grams at 20° C. was therefor approximately 682 ml. This corresponds to a weight/volume concentration of about 730 grams/liter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][Cl:26])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][Cl:26])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
The ester (Step 1) (0.500 g, 1.23 mmol) was dissolved in THF-ethanol-water (7:2:1; 10 mL). It was treated with sodium hydroxide (0.49 mL, 1.23 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 mL). Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCl. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The combined extracts were dried over MgSO4, filtered, and evaporated to yield a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a yellow solid (0.371 g, 80%): mp 154.4–156.4° C. 1H NMR (acetone-d6/300 MHz) 7.88 (s, 1H), 7.53 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.94 (q, 1H, J=7.1 Hz), 3.83 (t, 2H, J=6.5 Hz), 2.68 (t, 2H, J=6.8 Hz), 2.12–2.04 (m, 2H). ESLRMS m/z 377 (M−H). ESHRMS m/z 376.9930 (M−H, Calc'd. 376.9959). Anal. Calc'd. for C16H11Cl2F3O3+1.18% H2O: C, 5.0.08; H, 3.02; Cl, 18.48. Found: C, 50.11; H, 2.73; Cl, 18.28.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.O[NH3+:23].O[NH3+]>>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:23])=[CH:11][CH:10]=1
Reactant: [NH3+]O
Reactant: Cc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 8000 parts by weight of anhydrous sodium sulfate, 1602 parts by weight of 4-methylbenzaldehyde and 1149 parts by weight of hydroxylammonium sulfate. Following evacuation to 35 mbar, the mixture is heated to 80° C. and stirred at this temperature for 21/2 hours. It is subsequently heated at 125° C. at a pressure of 80 mbar and held for 10 minutes; the pressure is then reduced to 60 mbar and held for a further 20 minutes, during which a total of about 480 parts by weight of water are removed by distillation. The distillation of the nitrile is initiated and controlled by successive reduction of the pressure to 10 mbar and subsequent raising of the jacket temperature to 170° C. 1265 parts by weight of 4-methylbenzonitrile are obtained with a purity of over 98% (HPLC), and also 37 parts by weight of a mixed fraction essentially consisting of 4-methylbenzonitrile and 4-methylbenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:36])[NH:28][C:29]([CH3:35])=[CH:30][C:31]=1[CH:32]([CH3:34])[CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[C:27](=[O:36])[NH:28][C:29]([CH3:35])=[CH:30][C:31]=1[CH:32]([CH3:33])[CH3:34])=[O:9]
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 7 h
Yield: 50.1 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, ˜0.7 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (200 mg, 0.91 mmol) in DMSO (5.3 mL) was added PyBOP (550 mg, 1.05 mmol) and hunig base (366 ul, 2.10 mmol). The reaction mixture was stirred at 23° C. for 7 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 Ethylacetate/MeOH=10/1+10% triethylamine). The crude compound was triturated from ethylacetate/hexane, and dried to give the titled compound as a white solid (166 mg, 50% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.06 (d, J=2.4 Hz, 1H), 7.01-7.05 (m, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.04 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.49-3.57 (m, 1H), 3.02 (q, J=6.8 Hz, 2H), 2.80-2.84 (m, 2H), 2.61-2.69 (m, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 2.23 (s, 3H), 1.86-1.90 (m, 2H), 1.66-1.70 (m, 4H), 1.21 (d, J=6.8 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+Na] 495.2; HPLC 95.7% purity.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=O.[C:14]([CH2:16]C(O)=O)#[N:15].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>CN(C)C=O>[CH3:1][C:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][CH2:16][C:14]#[N:15]
Reactant: N#CCC(=O)O
Reactant: CC(C=O)CCC(C)CC(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=CCC#N)CCC(C)CC(C)(C)C
Temperature: 180 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
438 g (2.38 moles) of 2,5,7,7-tetramethyloctanal, 202 g (2.38 moles) of cyanoacetic acid, 350 ml of toluene, 350 ml of dimethylformamide and 28.5 g of ammonium acetate were heated under a water separator for 4 h, while stirring. Thereafter, the toluene was distilled off and the remaining residue was heated for 2 h at 180° C. The cooled residue was poured onto ice water and 10 extracted with diethyl ether. The organic phase was washed in succession with NaHCO: solution and water and then distilled. 450 g (yield: 91% of theory) of 4,7,9,9-tetramethyldec-3-enenitrile of boiling point 83°-88° C./-.3 mbar were obtained. The fragrance note was waxy, floral and fresh.
Reaction SMILES: ClC1C=CC(CNC([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2O)=[CH:17][C:16](C(O)=O)=[CH:15][C:14]=3F)=O)=CC=1.C1(P([N:41]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[NH2:41][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:19]2
Reactant: O=C(O)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1ccc2ncccc2c1

Procedure:
Compounds of the present invention may also be prepared by following the procedures described in Chart T. In CHART T, 3-{[(4-Chlorobenzyl)amino]-carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid of example t-1 is converted to the 6-tert-butyl carbamate t-2 by treatment with diphenylphosphoryl azide in tert-butanol with heating. The carbamate is removed with trifluoroacetic acid to afford the 6-aminoquinoline t-3. The amine is sulfonylated with 4-methoxyphenylsulfonyl chloride in pyridine to yield the 6-sulfonamide t-4.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:49]1([S:52](Cl)(=[O:54])=[O:53])[CH2:51][CH2:50]1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:52]([CH:49]1[CH2:51][CH2:50]1)(=[O:54])=[O:53])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C3CC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 75 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added cyclopropanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 75% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[C:19]3[O:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=C(S(O[Na])(=O)=O)C=CC=2OC)CCCCC1.N#N>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][C:16]1([CH3:21])[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:6]3[CH:5]=[C:4]([C:32]4[CH:31]=[N:30][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:34][CH:33]=4)[N:3]=[CH:2][N:7]=3)[C:19]=2[O:18][CH2:17]1
Reactant: CC1(C)COc2c(CCNc3ccnc(Cl)n3)cccc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)O[Na])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(-c3cc(NCCc4cccc5c4OCC5(C)C)ncn3)cn2)CC1
Temperature: 90 °C
Yield: 37 %

Procedure:
As shown in step 3-vii of Scheme 3, a solution of -chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine (60 mg, 0.197 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (71.86 mg, 0.237 mmol), Na2CO3 (296.2 μL of 2M, 0.592 mmol), and [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium (VPhos, 8.1 mg, 0.0158 mmol) in i-PrOH (1.6 mL) was degassed using a stream of N2 for 30 minutes. Pd(OAc)2 (0.88 mg, 0.0039 mmol) was added and the solution was heated to 90° C. for 2 hours. The solution was concentrated under reduced pressure and purified by medium pressure chromatography on silica gel (0 to 100% (10% MeOH/EtOAc) in hexanes) to give N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 68, 32.4 mg, 36%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.49 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 6.94-6.90 (m, 2H), 6.77 (t, J=7.3 Hz, 1H), 6.62 (d, J=8.9 Hz, 1H), 6.55 (s, 1H), 5.30 (s, 1H), 4.20 (s, 2H), 3.60 (s, 6H), 2.86 (t, J=6.4 Hz, 2H), 2.45 (s, 4H), 2.28 (s, 3H) and 1.27 (s, 6H) ppm; ESMS (M+H)=445.09.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:28])=[CH:4][CH:3]=1.[C:31](=[NH:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31](=[N:44][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:28])=[CH:4][CH:3]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(-c2cnc3[nH]c(=O)n(Cc4ccc(Cl)cc4)c3n2)cc(OC)c1OC
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnc3[nH]c(=O)n(Cc4ccc(N=C(c5ccccc5)c5ccccc5)cc4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a mixture of 1-(4-chlorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one (19 mg, 0.04 mmol; Example 28), benzhydrylideneamine (16 mg, 0.08 mmol), Pd2(dba)3(7 mg, 0.007 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl0bis[diphenylphosphine] also known as XantPhos (13 mg, 0.027 mmol) in toluene (0.5 mL) was added sodium tert-butoxide (10 mg; 0.1 mmol) and the resultant mixture was heated to 95° C. overnight. After cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. Concentration of the organic phase under reduced pressure afforded a crude residue, which was purified by silica gel chromatography [EtOAc/hexane (3:2)] to afford 1-[4-(benzhydrylidene-amino)benzyl]-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (14 mg) as a yellow oil.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCC1.NC1SC=NC=1.C([O:49][C:50](=[O:54])C(S)C)C>>[CH:24]1([N:16]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:50]([OH:54])=[O:49])=[CH:9][N:10]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CCOC(=O)C(C)S
Agent: C[C@H]1CC[C@H](NC2CCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCC2)CC1

Procedure:
{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclobutyl-(trans-4-methylcyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH:36]([CH2:42][CH3:43])C(OCC)=O)[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.Cl>O1CCCC1>[CH2:42]([CH:36]([O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:18]2[C:17](=[O:44])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:30][CH2:31]1)[C:32]([OH:35])([CH3:33])[CH3:31])[CH3:43]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2nc(C)nn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate (0.20 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. Methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.11 g, 60%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[NH:11][CH2:12][CH2:13][Cl:14])([CH2:7][CH3:8])[CH3:6]>C(O)=O>[CH:5]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][Cl:14])[N:1]=[O:3])([CH2:7][CH3:8])[CH3:6]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)NCCCl)C(C)CC)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)N(CCCl)N=O)C(C)CC)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Sodium nitrite fine powder (0.6 g ) was slowly added to a solution of 3-sec-butyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (2.24 g, 5.64 mmol) in formic acid (10 ml) with thorough stirring at 0° to 5° C. spending 1 hour, and stirring was continued for further 2 hours at the same temperature. After confirmation by TLC that the reaction was finished, 20 g of an ion exchange resin (H+ form, registered trade mark: Amberlite IR-120) was added to the reaction mixture at 0° to 5° C., and the mixture was thoroughly stirred for 30 minutes. The ion exchange resin was filtered off, and the filtrate was vacuum-concentrated at 25° C. and crystallized from methanol and water, giving 1.41 g of 3-sec-butyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 58.7%, m.p. 68°-70° C., [α]D20 +67.5° (C 1.0, methanol).