Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N+:26]([O-])=O)=[C:21]([CH3:29])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Zn]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:20]=[C:21]([CH3:29])[C:22]([NH2:26])=[C:23]([CH3:25])[CH:24]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc(C)c1N
Reaction time: 3 h

Procedure:
To (3,5-Dimethyl-4-nitro-phenyl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (9.5 g) in ethanol (150 mL) was added zinc dust (22 g) and acetic acid (13 mL). The reaction mixture was stirred 3 hours and then filtered. The solution was concentrated in vacuo, redissolved in ethyl acetate (100 mL) and extracted with water (2×50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an off white compound. Yield. 6.5 g (78%). LC-MS (m/z) 395 (MH+); tR=3.06, (UV, ELSD) 89%, 96%. 1H NMR (500 MHz, CDCl3): 1.40 (s, 9H), 2.10 (s, 6H), 3.50 (broad, 2H), 4.75 (s, 2H), 6.70 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]2[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Br[C:27]1[CH:39]=[CH:38][C:30]2[C:31]([C:34]([O:36][CH3:37])=[O:35])=[N:32][S:33][C:29]=2[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].C1(C)C(C)=CC=CC=1>[CH:15]1([C:14]2[O:13][N:12]=[C:11]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])[C:10]=2[CH2:9][O:8][CH:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:27]3[CH:39]=[CH:38][C:30]4[C:31]([C:34]([O:36][CH3:37])=[O:35])=[N:32][S:33][C:29]=4[CH:28]=3)[CH2:2][CH2:3]2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1nsc2cc(Br)ccc12
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1nsc2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Temperature: 130 °C
Yield: 47.6 %

Procedure:
To an oven dried flask purged with argon, add 4-((azepan-4-yloxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol (0.51 g, 1.34 mmol), methyl 6-bromobenzo[d]isothiazole-3-carboxylate (0.30 g, 1.10 mmol), cesium carbonate (0.51 g, 1.56 mmol), X-Phos (0.04 g, 0.084 mmol), xylene (10 ml) and Pd2(dba)3 (0.025 g, 0.028 mmol). Purge the mixture with argon and heat to 130° C. until the starting materials are consumed as confirmed by TLC. Cool the reaction mixture to room temperature, filter through celite and concentrate in vacuo. The crude product is purified by flash chromatography on silica gel eluting with 6:4 hexane/ethyl acetate to give 0.30 g (47.0%) of the title compound as an off white solid. ES/MS m/z 571.11 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][CH3:12])=[N:5][NH:6]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC(OC)=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][CH3:12])=[N:5][NH:6]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: COc1n[nH]c2cccc(Br)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]nc(OC)c12

Procedure:
3-(3-Methoxy-1H-indazol-4-yl)-3-phenyl-acrylic acid ethyl ester CLXXXVII was prepared from 4-bromo-3-methoxy-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](Cl)=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O[NH:16][C:17](=[NH:37])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[C:23]2[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][N:16]=[C:17]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:37]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: CC(C)Oc1ncc(C(=O)Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarbonyl chloride (D33; 94 mg, 0.4 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 114 mg, 0.360 mmol) and triethylamine (0.084 ml, 0.600 mmol) in dry DMF (1.5 ml) at 0° and the mixture was allowed to warm to room temperature and stirred for 45 min.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C:5]([NH2:7])=[O:6].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18].[Cl-].[NH4+]>CN(C=O)C.CCOCC>[F:3][C:4]([F:9])([F:8])[C:5]([NH:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11])=[O:6]
Reactant: NC(=O)C(F)(F)F
Reactant: C#CCCCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCCCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of sodium hydride (60% oil, 9.82 g, 245 mmol) in DMF (200 ml), trifluoroacetamide (34.7 g, 307 mmol) divided into 10 portion was added portionwise with ice cooling. Then, the reaction mixture was added with a solution of 8-iodo-1-octyne (14.5 g, 61.4 mmol) in DMF (60 ml), and stirred at room temperature for two hours. The reaction mixture was added with saturated aqueous ammonium chloride (400 ml) and ether (400 ml) for extraction. The ether layer was dried over magnesium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate mixed solvent), and crystallized from hexane to afford 10.8 g of 8-trifluoroacetamido-1-octyne (yield; 79.3%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:32]=1.C(=O)(O)[O-].[Na+].[CH3:38][N:39]=[C:40]=[O:41]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:40]([NH:39][CH3:38])=[O:41])=[CH:29][CH:30]=3)[S:7][C:6]=2[CH:32]=1
Reactant: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: CN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Temperature: 25 °C

Procedure:
6-Hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-aminophenyl]benzo[b]thiophene (80 mg) was dissolved in THF (5.0 mL), treated with sodium bicarbonate (45 mg) while stirring at ambient temperature, cooled to 0° C. in an ice bath before treated with methyl isocyanate (42 μL) under argon. The reaction mixture. was stirred at ambient temperature for 24 h and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the title compound (50 mg).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].O>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:32]([F:33])([F:34])[F:35])[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:8]=1
Reactant: COC(=O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.1 %

Procedure:
Methyl 6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoro-methyl)nicotinate (1.21 g), sodium hydroxide (0.26 g) and water (5 ml) were added to ethanol (40 ml) and stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, diluted hydrochloric acid and t-butyl methyl ether were added and then extracted. The target compound (1.11 g) was obtained by concentration under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C@@H]3O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]3O)=[CH:12][C:7]=2[O:6][C:4](=[O:5])[CH:3]=1>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 1 h

Procedure:
To evaluate the activity of various promoters, GUS fluorescence was assayed by the method of Jefferson (1987). Maturing seeds at 17 DAF were homogenized in GUS extraction buffer (50 mM NaPO4 (pH 7.01, 10 mM 2-mercaptoethanol, 10 mM Na2-EDTA, 0.1% SDS, 0.1% Triton X-100). After centrifugation, 10 μl of the supernatant was mixed with 90 μl assay buffer containing 1 mM 4-methylumbelliferyl-β-D-glucuronide (MUG). After incubating for one hour at 37° C., 900 μl of 0.2 M Na2CO3 was added to the mixture to terminate the reaction. Values obtained using a fluorometer were compared with those obtained from serial dilutions of 4-methylumbelliferone (4MU). The protein amount was determined using a BIORAD Protein Assay kit, with serum albumin as the standard. Three seeds were assayed for each transgenic plant.
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C>[OH:1][C:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH3:26])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
To a solution of 0.6 g of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 31/2 hours and concentrated to a solid after which a minimum amount of methanol to to dissolve the residue is added. 10% aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanol-butanone to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, M.P. 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:37][N:38]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:38][CH3:37])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)NC
Yield: 82 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (100 mg, 0.21 mmol), methylamine hydrochloride (35 mg, 0.52 mmol), WSC hydrochloride (120 mg, 0.63 mmol) and HOBT (28 mg, 0.21 mmol), to obtain 84.2 mg of the title compound as a white solid (82%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:23])([F:22])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][C:10]=1[NH2:11]>C1(C)C=CC=CC=1>[F:5][C:6]([F:22])([F:23])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:12][C:10]=1[N:11]=[C:1]=[O:2]
Reactant: Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 0.5 h

Procedure:
To a cooled (15°-20° C.) solution of 67.6 g. (0.684 mole) of phosgene in 250 ml. of toluene is added dropwise over one hour a solution of 49.5 g. (0.171 mole) of 2,5-bis-(2,2,2-trifluoroethoxy)aniline in 350 ml. of toluene. After addition is complete, stirring is continued for 30 minutes, then the mixture is heated to its reflux temperature and maintained at reflux for 30 minutes. The solution is evaporated to provide a liquid residue which gradually crystallizes. The solid is recrystallized from heptane to provide 2,5-bis(2,2,2-trifluoroethoxy)phenyl isocyanate as a white solid, m.p. 50°-52° C.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 41.9 %

Procedure:
To a mixture of 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (2.51 g, mmol) in dioxane (3.3 mL) and water (3.3 mL), were added 2-chloro-4-methoxyphenylboronic acid (2.3 g, 12.5 mmol) and Na2CO3 (6.3 g). The mixture was purged with nitrogen gas for 10 min, then Pd(PPh3)4 (1.2 g, 1.0 mmol) was added. The mixture was stirred in a sealed vessel at 85° C. for 6 hrs, then extracted by ethyl acetate. The organic layer was washed with water, dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (10/1) yielded 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (1.31 g). tR=2.96 min (method 1).
Reaction SMILES: [N:1]#[N:2].C(O[C:8]([N:10](C)[C@@H:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:14])[CH3:12])=O)(C)(C)C>C(OCC)(=O)C.Cl>[N:1]#[N:2].[CH3:8][NH:10][C@@H:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:14])[CH3:12]
Reactant: C[C@H](C(=O)NCCCc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CN[C@H](C)C(=O)NCCCc1ccc(F)cc1

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N2 -methyl-N-[3-(4-fluorophenyl)propyl]-D-alaninamide (2.77 g.) in hydrogen chloride-ethyl acetate (3.4N, 15 ml.) was stirred for thirty minutes at room temperature, then concentrated, affording N2 -methyl-N-[3-(4-fluorophenyl)propyl]-D-alaninamide as a crystalline solid (2.06 g., m.r. 148°-150° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12]C1C=CC=CC=1>>[Cl:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Clc1ccccc1
Reactant: Cc1ccc(CC(=O)O)cc1
Product: O=C(O)Cc1ccc(CCl)cc1

Procedure:
4-chloromethylphenylacetic acid was prepared in the same manner as in Example 1 except for using 30 g of 4-methyl phenylacetic acid instead of 2-methyl phenylacetic acid and using 90 g of monochlorobenzene.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[CH2:28]([CH2:30][NH2:31])[OH:29]>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([NH:31][CH2:30][CH2:28][OH:29])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: NCCO
Solvent: CS(C)=O
Product: CCOCn1c(NCCO)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (4.45 g, 10.0 mmol) potassium carbonate (2.76 g, 20.0 mmol) and ethanolamine (1.22 g, 20.0 mmol) in dimethylsulfoxide (30 ml) was stirred at 80° C. for two hours. After cooling to room temperature, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution, with water, and dried over magnesium sulfate. Concentration under reduced pressure provided (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-(2-hydroxyethylamino)-3-methylxanthine (3.95 g, 93% yield) as a beige powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:8][C:5]1[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:3][C:2]([C:34]2[CH:35]=[CH:36][C:30]3[O:29][CH2:28][CH2:27][N:26]([C:20]4[C:19]5[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=5)[N:23]=[CH:22][N:21]=4)[CH2:32][C:31]=3[CH:33]=2)=[CH:7][N:6]=1
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(Cl)c(NS(C)(=O)=O)c5)cc4C3)ncnc2c1

Procedure:
Synthesized according to the method of example 5 using N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (reagent preparation 25) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.92 (br s, 1H), 8.75 (s, 1H), 8.62 (d, 1H), 8.19 (d, 1H), 8.10 (d, 1H), 7.89 (s, 1H), 7.62 (dd, 1H), 7.33 (dd, 1H), 7.25 (d, 1H), 7.04 (d, 1H), 5.41 (s, 2H), 4.65 (s, 2H), 4.47 (s, 2H), 3.96 (s, 3H), 3.19 (s, 3H); MS (EI) for C24H22ClN5O4S: 514 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]3=[O:31])=[CH:14][CH:13]=2)[C:6](=[O:10])[N:7]([CH3:9])[CH:8]=1>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3=[O:31])=[CH:14][CH:13]=2)[C:6](=[O:10])[N:7]([CH3:9])[CH:8]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3=O)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3=O)cn2)c1=O
Temperature: 65 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with HCl in 1,4-dioxane (20 mL) and 332d (706 mg, 1.47 mmol). The mixture was stirred for at 65° C. for 6 h. It was then concentrated under reduced pressure to afford 332e as a yellow solid (500 mg, 90%). MS: [M+H]+ 379.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]([CH3:27])=[C:20]([CH:28]=[O:29])[C:19]=2[CH3:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]([CH3:27])=[C:20]([CH:28]([OH:29])[CH2:7][CH2:2][CH2:3][CH3:4])[C:19]=2[CH3:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC(O)c1c(C)c(C)c(OC)c(C(CCCCCC(=O)OC)c2ccc(F)cc2)c1C
Reaction time: 1 h
Yield: 132.7 %

Procedure:
To a solution methyl 7-(4-fluorophenyl)-7-(3-formyl-6-methoxy-2,4,5-trimethylphenyl)heptanoate (3.7 g) in anhydrous tetrahydrofuran (75 ml) was added 1.6 M solution of n-butyl lithium-hexane (6.2 ml) at -78° C. over 25 minutes. The mixture was stirred at the same temperature for 1 hour and aqueous potassium hydrogen sulfate was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 7-(4-fluorophenyl)-7-[3-(1-hydroxypentyl)-6-methoxy-2,4,5-trimethylphenyl)heptanoate (2.8 g) (Compound 65). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([C:11]2[CH:12]=[CH:13][C:14](/[C:19](/[C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)=[CH:20]/[CH2:21][CH2:22][NH2:23])=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1.Cl>N1C=CC=CC=1>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14](/[C:19](/[C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)=[CH:20]/[CH2:21][CH2:22][NH:23][C:1](=[O:3])[CH3:2])=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1
Reactant: COc1nc(/C(=C/CCN)c2ccc(SC)cc2)ccc1C1CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1nc(/C(=C/CCNC(C)=O)c2ccc(SC)cc2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (85 mg) was added to a solution of (3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-amine (95 mg) in pyridine (1 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to give N-{(3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-yl}acetamide as a colorless amorphous (87 mg, 81%).