Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[F:29])[CH:11]=[C:12]([C:14]2[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:7]>O.C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[C:10]1[CH:11]=[C:12]([C:14]2[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][CH:18]=2)[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2F)cc(-c2ccnn2C(C)C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3C(C)C)c2)c(F)c1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (524 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (468 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[NH2:63][C@@H:64]([CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:65]([C@@:67]1([CH3:70])[CH2:69][O:68]1)=[O:66].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:63][C@@H:64]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:65]([C@@:67]2([CH3:70])[CH2:69][O:68]2)=[O:66])=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: C[C@]1(C(=O)[C@@H](N)Cc2ccccc2)CO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (10.0 g, 33.9 mmol) in DMF (10 mL) at 0° C. was added HOBt (4.81 g, 37.3 mmol) and HBTU (14.1 g, 37.3 mmol). The mixture was stirred for 5 min to the dissolve solids at which time (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one TFA salt (10.2 g, 33.9 mmol) and DIEA (17.4 mL, 0.101 mol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-60% ethyl acetate/heptane) provided tert-butyl ((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (13.4 g, 82%) as an colorless amorphous solid. MS (EI) for C27H34N2O6, found 483.3 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5](=O)[CH2:6][CH:7]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH3:3].B.CSC.Cl>C1COCC1>[CH2:19]([O:18][P:16]([CH:7]([P:8]([O:10][CH2:11][CH3:12])(=[O:9])[O:13][CH2:14][CH3:15])[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])(=[O:17])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCCN(CCC)C(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCCN(CCC)CCC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
A solution of N,N-dipropyl-3,3-bis(diethoxyphosphinyl)propionamide (1.25 g, 2.9 mmol) in THF (7.1 ml) was cooled to 0° C., and borane-methylsulfide (0.71 ml, 7.1 mmol) was added via syringe. The reaction was stirred at 0° C. for 20 minutes, then warmed at 65 C. for 3 hours. The reaction mixture was cooled to 0° C. and 6N HCl (6 ml) was added carefully. The solvent was removed m vacuo, and the residue was treated with methanol (5 ml) and concentrated. The residue was dissolved in water (10 ml) and extracted with Et2O (3×10 ml). The aqueous layer was made basic to phenolphthalein with solid KOH and saturated with NaCl. The product was extracted into dichloromethane (5×20 ml), dried (Na2SO4) and concentrated to give the title compound (0.71 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][NH:36][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH2:32][CH2:33]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-(4-benzylpiperazin-1-yl)ethanamine (25.0 mg, 0.12 mmol). The title compound was obtained as a solid (12.0 mg, 22% yield). MS m/z: 552.08, 554.08 [M+H]+.
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.C(C1(O)CC1)C>>[CH2:6]([C:1]1([O:7][S:8](=[O:10])(=[O:11])[NH2:9])[CH2:2][CH2:3]1)[CH3:5]
Reactant: NS(=O)(=O)Oc1ccccc1
Agent: CCC1(O)CC1
Product: CCC1(OS(N)(=O)=O)CC1

Procedure:
Sulfamic acid 1-ethyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-ethylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234) to obtain sulfamic acid 1-ethyl-cyclopropyl ester.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>C(N(CC)CC)C.C(OC(=O)C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, Example 9 (100 mg, 0.186 mmol), Pd(PPh3)4 (10 mg, 0.0093 mmol), CuI (1.8 mg, 0.0093 mmol) and Ethynyltrimethylsilane (32 ul, 0.223 mmol) in triethylamine (0.4 ml) was heated to 80° C. for 4 hours. The mixture was cooled to room temperature, diluted with ethylacetate, filtered and the solvent was removed in vacuo. The crude brown oil was purified on SiO2 (Heptane/AcOEt 0%-40%,15 minutes) to provide the title compound (50 mg, 53%, yellow foam); M+H=590.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][C:13](=[O:16])[CH2:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.C([O-])([O-])=O.[K+].[K+].Cl[C:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>CC(=O)CC.CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Cl-].[Zn+2]>[CH3:31][C:28]1([CH3:32])[O:1][C:2]2[C:3]3[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=3[CH:9]=[C:10]([O:12][C:13](=[O:16])[CH2:14][CH3:15])[C:11]=2[CH:30]=[CH:29]1
Reactant: C#CC(C)(C)Cl
Reactant: CCCc1cc(=O)oc2cc(OC(=O)CC)cc(O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(=O)oc2cc(OC(=O)CC)c3c(c12)OC(C)(C)C=C3
Temperature: 70 °C
Yield: 27.3 %

Procedure:
To a solution of 7-propionate 7a (0.83 g, 3.0 mmol) in 2-butanone (40 mL) and DMF (4 mL) were added tetrabutylammonium iodide (1.11 g, 3 rnmol), K2CO3 (1.04 g, 7.5 mmol), and 3-chloro-3-methyl-1-butyne (1.11 g, 3 mmol). The reaction mixture was heated at 60° C. for 1 h before ZnCl2 (3.9 mL of 1.0 M solution in ether, 3.9 mmol) was added. The temperature was then raised to 70° C. and maintained at that temperature for 21 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl (100 mL). The mixture was extracted with EtOAc (100 mL×2) and the combined organic layers were washed with brine (100 mL) and dried over Na2SO4. Evaporation of the solvent gave the crude product (1.9 g). After column chromtographic purification, 280 mg (27.1% yield) of the desired product 5a was obtained as a waxy solid. 1H NMR (DMSO-d6) 1.00 (3H, t, J=7.2 Hz), 1.16 (3H, t, J=7.5 Hz); 1.47 (6H, s), 1.61 (2H, m), 2.71 (2H, q, J=7.5 Hz), 2.89 (2H, t, J=7.8), 5.84 (1H, d, J=9.9 Hz), 6.17 (1H, s), 6.41 (1H, d, J=10.2 Hz); 13C NMR (DMSO-d6) 8.6, 13.7, 22.8, 26.6, 27.2, 37.4, 78.3, 103.6, 107.2, 110.8, 113.4, 115.5, 130.1, 148.5, 151.4, 154.4, 156.9, 159.3, 172.2; IR 1767 (s and sharp), 1723 (s and sharp), 1616 (s and sharp) cm−1; MS m/e 343 (M+1); Anal. Calcd. for C20H22O5: C, 70.16; H, 6.47. Found: C, 70.37; H, 6.51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([N:56]1[CH2:60][CH2:59][C@@H:58]([NH2:61])[CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[NH4+].[Cl-]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:49]([N:56]1[CH2:60][CH2:59][C@@H:58]([NH:61][C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Yield: 74 %

Procedure:
To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate (1.0 g) in dioxane (70 mL) was added palladium(II) acetate (88 mg), 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (231 mg), cesium carbonate (1.79 g), and (3R)-1-benzyl-3-pyrrolidinamine (760 mg). The mixture was heated at 90 for 24 hours. The resulting mixture was poured into sat NH4Cl aq solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by silica gel column chromatography eluted with chloroform:methanol=9:1 to give ethyl (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g) as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH:33]([F:35])[F:34])=[C:27]([F:36])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:35][CH:33]([F:34])[O:32][C:28]1[C:29]([F:31])=[CH:30][C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)=[CH:26][C:27]=1[F:36]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OC(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OC(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (45 mg, 0.251 mmol) with 2-bromo-N-{4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (125 mg, 0.313 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 20 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 5.32 (s, 2H), 6.23 (s, 1H), 7.28 (t, J=72.3 Hz, 1H), 7.35 (s, 1H), 7.79 (d, J=9.6 Hz, 2H), 7.90 (s, 1H), 12.73 (br s, 1H); ESI-MS (m/z) 498.08 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>CC#N.O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@@H:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H](Cc1ccc(Br)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a solution of (R)-2-amino-3-(4-bromophenyl)propionic acid (50 g, 0.2 mol) in MeCN (700 mL) was added a solution of NaOH (16.4 g, 0.4 mol) in water (700 mL) at −5° C. After stirring for 10 minutes, a solution of (BOC)2O (44.7 g, 0.2 mol) in MeCN (100 mL) was added. The mixture was warmed to room temperature and stirred overnight. After evaporation of the MeCN, the residue was diluted with DCM (800 mL) and acidified with 1 M HCl to pH 2 at −5° C. The aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were washed with saturated aqueous NaCl (500 mL), dried over anhydrous Na2SO4 and concentrated to yield the title compound as a white solid (64.2 g). LC-MS: [M+Na]:366, [2M+Na]:709.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1>C1COCC1.O>[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 110 °C

Procedure:
0.518 g of potassium hydroxide was added to a solution of 0.428 g of ethyl 4-(2,4-difluorophenoxy)benzoate in 2 ml of THF/water (1:1). The solution was heated at 110° C. for 6 hours. The THF was then removed in vacuo, and the aqueous phase was freeze dried and purified by preparative HPLC. This resulted in the product with the molecular weight of 250.04 (C13H8F2O3); MS (ESI): 251 (M+H+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:43](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH2:43])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(N)=O)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-162), 0.05 g (0.13 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.03 mL (0.16 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.010 g (0.16 mmole) of ammonium chloride was added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 0.029 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-163).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[C:23]([O:25]CC)=O)=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:23](=[O:25])[C:19]3[CH2:20][CH2:21][CH2:22][C:18]=3[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=S)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)CCC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=S)[nH]c3c(c2=O)CCC3)ccc1Cl

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-4-oxo-2-thioxo-3H-cyclopenta[d]pyrimidin-3-yl)benzoate.
Reaction SMILES: [ClH:1].C([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[S:30][C:25]3=[N:26][CH2:27][CH2:28][CH2:29][N:24]3[C:23]=2[CH2:31][CH2:32][CH3:33])=[O:21])=[CH:15][CH:14]=1)=[O:6])C.[OH-].[Na+]>C(O)C>[ClH:1].[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[S:30][C:25]3=[N:26][CH2:27][CH2:28][CH2:29][N:24]3[C:23]=2[CH2:31][CH2:32][CH3:33])=[O:21])=[CH:15][CH:14]=1)([OH:6])=[O:4]
Reactant: CCCC1=C(C(=O)Nc2ccc(SCCCCCC(=O)OCC)cc2)SC2=NCCCN21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1=C(C(=O)Nc2ccc(SCCCCCC(=O)O)cc2)SC2=NCCCN21
Yield: 69.7 %

Procedure:
In 30 ml of ethanol was dissolved 750 mg of N-[4-(5-ethoxycarbonyl-pentylthio)phenyl]-3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide hydrochloride obtained in Example 89. To the solution was added 3.22 ml of 1N sodium hydroxide aqueous solution, followed by reflux under heating for 2 hours. After cooling the mixture, ethanol was removed under reduced pressure. The aqueous solution was made acidic with consentrated hydrochloric acid, following by removing a little amount of water. To the residue was added isopropylalcohol-diethylether and the precipitated crystals were collected by filtration. This crystals were recrystallized from methanol-diethylether to obtain 494 mg of the titled compound.
Reaction SMILES: [CH2:1]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)[C:6](=[O:9])[CH:7]=[CH2:8])[CH2:2]C=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([N:5]2[CH2:1][CH2:2][CH:8]=[CH:7][C:6]2=[O:9])=[CH:15][CH:14]=1
Reactant: C=CCCN(C(=O)C=C)c1ccc(OCC(F)(F)F)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=C1C=CCCN1c1ccc(OCC(F)(F)F)cc1
Temperature: 45 °C
Yield: 66.4 %

Procedure:
A mixture of N-But-3-enyl-N-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-acrylamide (1.6 g, 5 mmol) and Grubbs catalyst (0.24 g) in 30 mL of DCM was heated to 45° C. overnight. The mixture was evaporated to dryness. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=5:1) to obtain the title compound as grey solid (0.9 g, 66%). LC-MS: 272.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
4-Trifluoromethylaniline (0.258 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.123 g, 0.238 mmol, 44%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[C:17](/[C:16]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=1)\[C:18]#[N:19]
Reactant: O=Cc1cc2ccccc2o1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc3ccccc3o2)cc1OC
Yield: 76.5 %

Procedure:
2-Benzofurancarboxaldehyde (166 mg) was condensed with 3,4-dimethoxybenzyl cyanide (201 mg) through Method A (production step 2), to thereby yield the target product (yield: 265 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:33])([F:32])[C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[F:15][C:16]([F:32])([F:33])[C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C(F)(F)F)cc(C(F)(F)F)c3)nc2n(CC)c1=O
Yield: 60.7 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.73 g (16.7 mmol) of 3,5-bis(trifluoromethyl) cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 4.09 g (yield 61%) of Compound 153 as pale yellow needles.