Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([O:20]C)=O)[CH:12]=2.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[NH:22][C:18]([C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:1][C:2]=3[CH3:7])[NH:10]2)=[CH:15][CH:14]=1)=[O:20]
Reactant: Nc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc2cc(-c3c(C)cccc3C)[nH]c2c1
Product: Cc1cccc(C)c1-c1cc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1

Procedure:
The title compound was prepared from methyl 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylate and 2-aminoquinoline analogous to Example 3-6. 1H NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1H), 11.01 (s, 1H), 8.40 (s, 2H), 7.95 (d, J=7.83 Hz, 1H), 7.89 (d, J=8.46 Hz, 1H), 7.80 (d, J=9.60 Hz, 1H), 7.74 (t, 1H), 7.65 (d, J=8.34 Hz, 1H), 7.52 (t, 1H), 7.28 (m, 1H), 7.19 (d, J=7.45 Hz, 1H), 6.44 (s, 1H), 2.15 (s, 6H). MS (m/z) 392.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C@@H:14]2[CH2:20][C:19]([F:22])([F:21])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[Li+].[OH-].O.Cl>CO.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:11][CH:10]=2)[C@@H:14]2[CH2:20][C:19]([F:22])([F:21])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
3-(4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester (65 mg, 0.13 mmol) was dissolved in methanol (0.5 ml) and treated with 2 N LiOH in water (0.25 ml, 0.5 mmol) overnight at 40° C. The reaction mixture was distributed between 4 N HCl and ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product (50 mg) was purified using column chromatography (dichloromethane/methanol 90:10) to yield 45 mg (71%);
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+].[C:24]([O:27][CH2:28]Br)(=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH2:28][O:27][C:24](=[O:26])[CH3:25])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CC(=O)OCBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cncn34)C[C@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(c2csc3cncn23)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution-of 60.2 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1.4 ml of DMF was added 67.7 mg of acetoxymethyl bromide under the atmosphere of argon at a temperature of −30° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted twice with 20 ml of ethy acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 22.1 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[N:17]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH3:29].C(O)C>Cl.O>[CH:14]([N:7]1[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=3[O:28][CH3:29])=[N:17][C:6]1=2)([CH3:16])[CH3:15]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Yield: 67.5 %

Procedure:
A mixture of 0.076 g (0.0003 mole) of 2-chloro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-43), 0.060 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.078 g of 4-(9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-43a) as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:16])[CH2:14]Cl)=[O:4].[NH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[O:16]=[C:13]1[CH2:14][NH:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][OH:23])[CH2:2][C:3](=[O:4])[NH:5][CH:6]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[NH:12]1
Reactant: NCCNCCO
Reactant: O=C(CCl)N[C@@H]1CCCC[C@H]1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CNCCN(CCO)CC(=O)NC2CCCCC2N1
Temperature: 82 °C

Procedure:
Into a 5 l. erlenmeyer flask containing 5 l. of anhydrous acetonitrile was placed 17.4 g. (65 mmol.) of N,N'-bis(chloroacetyl)-trans-1,2-diaminocyclohexane (see Example 2), 6.8 g. (65 mmol.) of 2-(2-aminoethylamino)ethanol and 130 g. (1.23 mmol.) of sodium carbonate. The reaction mixture was heated at 82° C. under nitrogen for 50 hours. After eliminating sodium carbonate by filtration, acetonitrile was eliminated under vacuum until the volume was reduced to 500 ml. A precipitate formed immediately and the reaction mixture was stirred for several hours at room temperature. The precipitate was filtered off and was washed with a few ml. of acetonitrile and dried under vacuum. 8.2 g. of compound (A) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:24]/[C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:25])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2cc(C=O)ccc21
Reactant: COc1ccc(C(C)=O)cc1
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC)cc3)ccc21
Yield: 91 %

Procedure:
The title compound (7.75 g, 91%) was prepared from the product of Example 1 Step 2 and 1-(4-methoxy-phenyl)ethanone using the method of Example 2 Step 1; MS(ES+) m/e 322 [M+H]+.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.S(=O)(=O)(O)O>[OH:2][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]([OH:16])=[O:15]
Reactant: O=N[O-]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 14 g (217 mmol) of sodium nitrite in 20 ml of water was added dropwise to a solution of 14 g (85 mmol) of L-phenylalanine in 100 ml of 1 N sulfuric acid at 0° C. over 3 hours, and the mixture was stirred overnight at room temperature. After extraction with three 100-ml portions of ethyl acetate, the organic phase was dried over sodium sulfate. The optical purity of (2S)-2-hydroxy-3-phenylpropionic acid in this extract was 93.0% ee. The solvent was distilled off under reduced pressure to give 12 g of crude (2S)-2-hydroxy-3-phenylpropionic acid. Further, this crude product was purified by recrystallization using 35 ml of ethyl acetate to give 7.5 g (yield 53%) of the desired (2S)-2-hydroxy-3-phenylpropionic acid. The proton concentration (normality) in the reaction of this comparative example was 1.0 mol/kg, the amount of the protonic acid was 1.2 equivalents (relative to L-phenylalanine), and the reaction temperature was 0° C. to room temperature.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10])(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NCCc1ccccc1Cl
Reactant: CCCCCCC(=O)Cl
Product: CCCCCCC(=O)NCCc1ccccc1Cl

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and n-heptanoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-n-heptanoylamino-2-(2-chlorophenyl)ethane as an oil. The product was successively reacted in the same way as in steps (b), (c), (d), (e), (f), (g) and (h) of Example 13 to afford 1-n-hexylisoquinoline-5-acetonitrile.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].[CH2:26]([SH:28])[CH3:27].C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:28][CH2:26][CH3:27])=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:23])(=[O:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CCS
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCSC1=C(C(=O)c2ccc3c(c2Cl)S(=O)(=O)CCC3(C)C)C(=O)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.7 g (1.75 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one is dissolved in 20 ml of tetrahydrofuran, and 0.11 g (1.75 mmol) of ethanethiol and 0.19 g (1.92 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for 2 hours, stirred into water, extracted with ethyl acetate and the organic phases were extracted with 1N hydrochloric acid and dried and the solvent was removed. This gave 0.4 g of beige crystals.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=1)=[O:5].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH2:47]([O:49][CH:50]([O:53][CH2:54][CH3:55])[CH2:51][NH2:52])[CH3:48]>C(Cl)Cl.CN(C=O)C>[CH2:47]([O:49][CH:50]([O:53][CH2:54][CH3:55])[CH2:51][NH:52][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[N:13]([C:10]3[CH:9]=[N:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:2]=4[F:1])=[CH:12][N:11]=3)[C:14]([C:25]([F:28])([F:27])[F:26])=[N:15][C:16]=2[CH:21]=1)=[O:23])[CH3:48]
Reactant: O=C(O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Reactant: CCOC(CN)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (xiii) (50 mg, 0.11 mmol, 1.00 equiv) in DCM (15 ml) and DMF (1 drop). To the above stirred solution was added oxalyl dichloride (70 mg, 0.55 mmol, 5.00 equiv) dropwise at 0° C. The resulting solution was allowed to stir at 0° C. for 4 hours then was concentrated by evaporation under vacuum using a rotary evaporator. The residue was then taken up by DCM (10 ml) and then add dropwise to a stirred solution Of Et3N (40 mg, 3.00 equiv) and 2,2-diethoxyethanamine (15 mg, 0.11 mmol, 1.00 equiv) in DCM (10 mL) at 0° C. The resulting solution was allowed to stir overnight at room temperature, then was washed with H2O (2×100 mL) and dried over Na2SO4. Removal of the solvent and volatile components afforded the crude product 1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 64% yield) as a yellow solid that was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Cl)cc4)CC3)C2)c2ccccc21
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCOCC5)cc4)CC3)C2)c2ccccc21

Procedure:
A mixture of (1R)-1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30.0 mg, 0.0000816 mol, example 83), morpholine (8.5 μL, 0.000098 mol), sodium tert-butoxide (19 mg, 0.00020 mol), palladium acetate (0.5 mg, 0.000002 mol) and 2-(di-t-butylphosphino)biphenyl (0.7 mg, 0.000002 mol) was degassed and charged with nitrogen. To the mixture was added 1,4-dioxane (1.0 mL, 0.013 mol). The resulting mixture was refluxed overnight. The crude product was purified prep-HPLC. LC-MS: 419.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]O)[C:11]=2[CH3:18])[O:4][CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:32][C:33]3[NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=4[N:34]=3)[C:11]=2[CH3:18])[O:4][CH2:3]1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: -19 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
The (4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-3-methylpyridin-2-yl)methanol (500 mg, 1.87 mmol) obtained by the step (1d) was mixed with triethylamine (1.04 ml, 7.48 mmol) and tetrahydrofuran (15 ml). This mixture was cooled to −19° C. and methanesulfonyl chloride (217 μl, 2.81 mmol) was added thereto and then stirred at −19° C. for 30 minutes. Under the same conditions, 2-mercaptobenzimidazole (309 mg, 2.06 mmol) was added to the reaction mixture. After the reaction mixture was stirred overnight at room temperature, methanol and NH silica gel were added to the mixture, and then, the solvent was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (silica gel: 80 g, elution solvent: ethyl acetate/heptane=1/1 to 4/1→methanol/ethyl acetate=1/9) to obtain the title compound (599 mg, yield: 80.2%) as a light red foam.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[C:36]2[CH:37]=[CH:38][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:40][C:35]=2[CH:34]=[CH:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:40][C:35]=2[CH:34]=[CH:33]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2occc2c1
Yield: 85.4 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.366 g; 1.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.171 g (85%) of the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2C(OC(C)(C)C)=O)=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.OP(O)(O)=O.[OH-].[Na+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[O:24][C:23]([C@@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)o1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1nnc([C@@H]2CCCN2)o1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a THF (3.8 mL) solution of the compound (3.832 g) obtained in Example 9-(2), H3PO4 (6.1 mL, 85% aqueous solution) was added and the mixture was stirred at room temperature for an hour. To the reaction mixture, THF (50 mL) was added and the resulting mixture was added to NaOH (150 mL, 1.0 N aqueous solution) and ice (50 g), followed by extraction with CHCl3 (300 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give a crude product, which was further purified by NH-form silica gel chromatography (MeOH/CHCl3) to give the titled compound (1.261 g, colorless oil.)
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[S:6])([CH3:3])[CH3:2].Cl[CH2:13][N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[C:8]([N:7]=[C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:15](=[O:16])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][S:6]1)([CH3:9])([CH3:11])[CH3:10]
Reactant: O=C(Cl)N(CCl)c1ccc(F)cc1
Reactant: CC(C)NC(=S)NC(C)(C)C
Product: CC(C)N1C(=O)N(c2ccc(F)cc2)CSC1=NC(C)(C)C

Procedure:
In a similar manner, 1.7 g (0.01 mole) of 1-isopropyl-3-t-butylthiourea was reacted with 2.2 g (0.01 mole) of N-chloromethyl-N-(p-fluorophenyl)-carbamoyl chloride to obtain 2-t-butylimino-3-isopropyl 5-(p-fluorophenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 282): ##STR140## in the form of hydrochloride melting at 160°-195° C. Yield 2.8 g (80%). The crystals were suspended in 20 ml of water and treated in a manner similar to that described above to obtain white crystals of the free base melting at 109°-110° C. (isopropanol). Yield 2.0 g (63%).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:21]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:21][N:20]([CH3:19])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: CN(N)c1ccccc1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(NN(C)c2ccccc2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and N-methyl-N-phenyl-hydrazine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO at 60° C.) δ 9.12 (br, 1H), 7.68 (d, 1H), 7.22 (t, 2H), 6.95-6.75 (5H), 6.24 (s, 1H), 3.96 (br, 2H), 3.82 (s, 3H), 3.16 (s, 3H) and 2.94 (t, 2H); MS (ESI) (M+H)+ 349.
Reaction SMILES: [CH3:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>CN(C=O)C.C1COCC1.O>[CH3:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(=O)oc2cc1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 6-methyl-5-(methyloxy)-1,3-benzoxazol-2(3H)-one (1.76 g, 9.8 mmol) in DMF (20 mL) was added NaH (470 mg, 11.8 mmol) in two portions. The reaction mixture was stirred for 30 minutes at room temperature, and ethyl bromoacetate (1.09 mL, 9.8 mmol) was added. The reaction mixture was stirred for 3 hour until all starting material was consumed, then poured into cold water (100 mL). The precipitate which formed was collected by filtration, washed with water, and dried in the air to afford a pale solid. This solid was dissolved in THF (20 mL) and NaOH (2.0 M, 4.9 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours, poured into cold water (100 mL), and extracted with EtOAc (2×100 mL). The aqueous layer was acidified with HCl (6 N) to pH˜1, extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (2.16 g, 93%) as a pale solid. MS (ES) m/e 238 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:54][CH3:55])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:54][CH3:55])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:49]=2)[O:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCCCC(=O)O)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Ethyl 4-(3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyrate (88 mg) is dissolved in a mixed solvent of ethanol (1 ml) and tetrahydrofuran (1 ml) and thereto is added a 1M-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is made acidic with 10% aqueous citric, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 4-(3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyric acid (71 mg). MS (m/z): 747 [M+H]+