Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@@H:4]2[C@H:7]([CH:8]=1)[C:6](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2.N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:34]([CH3:37])([O-:36])=[O:35]>>[CH3:1][C:2]1[CH2:3][C@@H:4]2[C@H:7]([CH:8]=1)[C@@:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH2:37][N+:34]([O-:36])=[O:35])[CH2:5]2
Reactant: CC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 6 h

Procedure:
Tert-butyl(±)-(1S,5R)-3-methylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.21 g, 5.50 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6.0 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 6 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.14 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]([OH:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]=2[OH:40])[N:21]=[C:20]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:43][C:42]=2[OH:57])[N:19]=1.[OH-].[K+].S(OC)(O[CH3:64])(=O)=O>COCCOCCOC>[OH:57][C:42]1[CH:43]=[C:44]([O:47][CH2:48][CH:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:45]=[CH:46][C:41]=1[C:20]1[N:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]([OH:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]=2[OH:40])[N:23]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:2]=2[O:1][CH3:64])[N:19]=1
Reactant: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3ccc(OCC(O)COCCCC)cc3O)n2)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3ccc(OCC(O)COCCCC)cc3OC)n2)c(O)c1
Temperature: 80 °C
Yield: 57.6 %

Procedure:
A mixture of 11.9 g (15.0 mmol) of 2,4,6-tris[2-hydroxy-4-(3-n-butoxy-2-hydroxypropoxy)phenyl]-1,3,5-triazine in 80 ml of diglyme (Fluka 99.5%) is heated under nitrogen to 80° C. To the solution there are added in succession 1.0 g (15.1 mmol) of pulverized KOH (Fluka, 85%) and 2.5 g (19.8 mmol) of dimethyl sulfate (Fluka, 99%), with stirring. After stirring at 80° C. for 20 h the mixture is cooled, the precipitate is filtered off and the solvent is stripped off from the filtrate. The crude product is purified by column chromatography (silica gel 60, 230-60 mesh, Ø=5 cm, h=30 cm; CH2Cl2/methanol 95:5). Stripping the solvent from the main fraction and drying at 100° C./0.9 mmHg for 3 h give 7.0 g (57.8%) of the title compound (Compound 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C[Mg+].[Br-].[CH3:13]COCC>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:13])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (2.52 g, 13.74 mmol) in THF/NMP (86 mL/6 mL) was added Fe(acac)3 (485 mg, 1.37) and the mixture was cooled to 0° C. 3.0 M MeMgBr in Et2O (6.87 mL, 20.61 mmol) was added dropwise. After 30 min at 0° C., the reaction was complete and quenched with saturated aqueous NH4Cl solution. Et2O was added and the layers were separated and the aqueous layer was further extracted with several portions of Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 10% EtOAc/Hex) gave the desired product as a white solid (1.45 g, 65%). 1H NMR (500 MHz, CDCl3): 8.47 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:17][C@@H:18]1[C@:22]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH:23]([F:25])[F:24])[O:21][C@@H:20]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[C@H:19]1O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C@@H:18]1[C@:22]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH:23]([F:25])[F:24])[O:21][C@@H:20]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[C@@H:19]1[F:7])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)[nH]1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2F)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
Diethylaminosulfur trifluoride (7.6 g, 47.4 mmol) was added to a suspension of compound 34 (1.5 g, 3.16 mmol) in dry THF (150 mL). The mixture was stirred at 60° C. for 16 h and then cooled to room temperature. The mixture was quenched by the addition of saturated aqueous NaHCO3 solution and then extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (4:1)] afforded 39 as a brown solid (700 mg, 46%). LC-MS (M+H)+=477.4
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCC/C=C\CCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCC/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a stirring solution of 1.71 g (14.7 mmol) of thiotetronic acid in 20 mL of dimethylformamide is added 2.22 mL (15.9 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-dimethylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.0 g (17.7 mmol) of petroselinic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.2 g (21%) of 4-hydroxy-3-[(Z)-1-oxo-6-octadecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][N:3]1[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].Cl>CCOC(C)=O>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][N:3]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)CN1CCN(c2ccccn2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CN1CCN(c2ccccn2)C1=O

Procedure:
A solution of tert-butyl 2-oxo-3-pyridin-2-ylimidazolidin-1-yl)acetate from Step B (150 mg, 0.54 mmol) in EtOAc (10 mL) at 0° C. was saturated with HCl (g). The mixture was stood at 0° C. for a total of 30 min, then concentrated in vacuo to give the title compound as a white solid. MS: m/z=222 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=O)=[C:6]([NH2:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[C:6]([NH2:10])[N:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CCNc2nc(N)c(N=O)c(N)n2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCNc2nc(N)c(N)c(N)n2)cc1
Yield: 64.8 %

Procedure:
A mixture of 4,6-diamino-2-[2-(4-methoxyphenyl)-ethyl]amino-5-nitrosopyrimidine (13.3 g), absolute ethanol (150 ml) and water (150 ml) was heated almost to reflux. Sodium dithionite was added slowly, portionwise until the red colour disappeared. The mixture was filtered hot. After cooling the solid was removed by filtration, triturated with isopropyl alcohol, and dried to give 2-[2-(4-methoxyphenyl)ethyl]amino-4,5,6-triaminopyrimidine as a solid (8.2 g) m.p. 134°-138° C.; NMR: DMSO-d6 ; 2.65-2.85(t, 2H, CH2 --CH2), 3.25-3.5(t, 2H, CH2 -NH),3.7(s, 3H, OCH3), 6.45-6.65 (b, 2H, NH2), 6.7-6.85(b, 1H, NH), 6.8-6.9 (d,2H, aromatic-H), 7.1-7.25(d,2H, aromatic-H). Also 2.8-4.0 (v.br, 4H, 2×NH2).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH:37]([N:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1)([CH3:39])[CH3:38]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:49]1[CH2:48][CH2:47][CH:46]([N:43]2[CH2:42][CH2:41][N:40]([CH:37]([CH3:39])[CH3:38])[CH2:45][CH2:44]2)[CH2:51][CH2:50]1)=[O:14])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CC(C)N1CCN(C2CCNCC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(C)C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 210 mg (0.99 mmol) 1-isopropyl-4-piperidin-4-yl-piperazine.
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[CH3:19][C:20]([O:23][C:24]([N:26]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:37]([SH:44])=[CH:36][C:35]=1[CH3:45])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])[CH3:21].C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:33][C:30]([O:29][C:27]([N:26]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:37]([S:44][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:36][C:35]=1[CH3:45])[C:24]([O:23][C:20]([CH3:19])([CH3:21])[CH3:22])=[O:25])=[O:28])([CH3:31])[CH3:32]
Reactant: Cc1cc(S)c(C(C)(C)C)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of tosyl bromide (17.1 g, 72.73 mmol) and NEt3 (7.36 g, 72.73 mmol) in CCl4 (250 mL) was cooled to 0° C. To this solution was added [5-(1,1-dimethylethyl)-4-mercapto-2-methylphenyl]-imidodicarbonic acid bis(1,1- dimethylethyl) ester obtained from Example FFFF in CCl4 (250 mL) dropwise over an 8 hour period. The mixture was then allowed to warm to room temperature overnight. Chloroform was added, and the solution was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The resulting material was flash chromatographed on silica gel, eluting with 4:1 CHCl3 :hexanes to afford the title compound. 1H NMR (CDCl3) δ 1.16 (s, 9 H), 1.40 (s, 18 H), 2.10 (s, 3 H), 2.40 (s, 3 H), 7.07 (s, 1 H), 7.19 (d, 2 H), 7.40 (s, 1 H), 7.44 (d, 2 H).
Reaction SMILES: CC(OC(N[C@@H:9](CC1C=CC(C2N=C(C(N(C)OC)=O)N(C)C=2)=CC=1)[CH2:10][CH2:11][C:12]([O:14][C:15](C)(C)C)=[O:13])=O)(C)C.[I:38][CH:39]([CH3:41])[CH3:40].CCN(C(C)C)C(C)C.CN(C=[O:55])C>>[OH:55][C:40]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:41][C:39]=1[I:38]
Reactant: CN(C)C=O
Reactant: CON(C)C(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cn1C
Reactant: CC(C)I
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of compound 1 (200 mg, 1.077 mmol) and 2-iodopropane, (322 uL, 3.23 mmol) in DMF (10 mL) was added DIEA (750 uL, 4.31 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction was monitored by LC/MS. After the reaction was done it was cooled to room temperature. The reaction mixture was quenched with HCl (0.5N, 30 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated and dried under high vacuum. The resulting residue was purified by reverse phase chromatography (using a mixture of acetonitrile and water) to give compound 2 (50 mg, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(N(C(C)C)CC)(C)C.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>CN(C)C=O>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 75 °C
Yield: 57.7 %

Procedure:
A stirred solution of 2-bromo-4-fluoro-5-nitrobenzotrifluoride (1.15 g, 4.0 mmol) in dimethylformamide (15 ml) at room temperature under argon was treated with diisopropylethylamine (1.8 ml, 10 mmol) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.90 g, 4.5 mmol), then heated at 75° C. for 3 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (30 ml) and extracted with ethyl acetate (2×40 ml). The combined extract was washed with brine (40 ml), then dried (Na2SO4) and concentrated under vacuum to leave an orange solid which was purified by chromatography on silica gel (20 g) eluting with dichloromethane to afford the title compound as a yellow solid (1.08 g, 58%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[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][NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:9]=1)([CH3:3])[CH3:2].[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>C1COCC1.C1(C)C=CC=CC=1>[CH3:24][O:23][C:22](=[O:25])[N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:26][CH3:27])[CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([C:29]([F:28])([F:38])[F:39])[CH:31]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)NCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cccc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reaction time: 2 h

Procedure:
Methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (20 mg, 0.053 mmol) was dissolved in THF (1 mL). 3-(Trifluoromethyl) benzyl bromide (122 μL, 0.79 mmol) was added followed by potassium bis(trimethylsilyl)amide (320 μL of a 0.5 M solution in toluene, 0.160 mmol). The reaction was stirred for two hours and then poured into H2O (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 25% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(trifluoromethyl)benzyl]carbamate. Rf=0.67 (15% EtOAc/hexanes). LCMS=540.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.72 (s, 1H), 7.36 (dd, J=8.0, 1.0 Hz, 1H), 7.19-7.23 (m, 2H), 7.03-7.07 (m, 3H), 6.86 (m, 2H), 6.57 (d, J=8.5 Hz, 1H), 4.41 (s, 2H), 4.05 (s, 2H) 3.36 (s, 3H), 3.22 (s, 3H), 3.73 (m, 1H), 1.25 (d, J=6.5 Hz, 6H).
Reaction SMILES: ClCCCCC(Cl)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37]>C1(C)C=CC=CC=1.C(O)C>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37].[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:38][C:39]([NH:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][C:14]2[C:13]3[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH3:9])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[CH:25][CH:26]=1)=[S:40])=[O:37]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CCCCCl)N=C=S
Agent: O=C(Cl)CCCCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCCCCl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
5-Chloropentanoyl isothiocyanate was prepared using commercially available 5-chloropentanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 5-chloropentanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 58%).
Reaction SMILES: C([CH:3]([CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O)[CH:4]=[O:5])C>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[C:16]([C:6]1[CH:3]=[CH:4][O:5][C:7]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C(=O)c1ccc(C)cc1)C(C=O)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1ccoc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
Ethyl 3-Carboethoxy-4-(4-methylphenyl)-4-(oxo)-butanal (10.00 g), trifluoroacetic anhydride (50 mL) and trifluoroacetic acid (2 drops) were mixed and stirred at 0° over ice and allowed to warm to room temperature. After 3 hours, more trifluoroacetic anhydride (50 mL) together with trifluoroacetic acid (2 drops) were added at room temperature. The next day, the solvent was removed in vacuo and the residue partitioned between 1N NaOH (200 mL) and ethyl acetate (200 mL). The layers were separated and the organic layer washed with 1N NaOH (2×200 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield a brown oil (9.95 g) which was flash chromatographed in 99:1 hexane/ethyl acetate to yield 2.57 g of an off-white solid; m.p. 79.0°-80.5°. NMR (200 MHz, CDCl3) δ7.88 (d, 2H, J=9 Hz); 7.42 (d, 1H, J=2 Hz); 7.26 (d, 2H, J=9 Hz); 6.83 (d, 1H, J=2 Hz); 4.34 (q, 2H, J=7 Hz); 2.40 (s, 3H); 1.34 (t, 3H, J=7 Hz). Anal. Calcd. for C14H14O3 : C, 73.03; H, 6.13. Found: C, 73.52; H, 6.30.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[N:25]=[C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:31][CH2:30][CH:29]([C:26]3[S:27][CH:28]=[C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])[N:25]=3)[CH2:34][CH2:33]2)=[O:16])[O:4][N:3]=1
Reactant: Fc1ccccc1-c1csc(C2CCNCC2)n1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCC(c3nc(-c4ccccc4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (109 mg, 0.377 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperidine (90 mg, 0.343 mmol) and diisopropylethylamine (0.120 ml, 0.686 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (42.0 mg, 30.6%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:8])=[O:7].[NH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(Cl)Cl>[ClH:8].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1)=[O:7]
Reactant: COc1cc2ncnc(Nc3cccc(N)c3)c2cc1OC
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2cccc(Nc3ncnc4cc(OC)c(OC)cc34)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
3-Methoxybenzoyl chloride (0.169 ml) was added to a suspension of 4-(3-aminoanilino)-6,7-dimethoxyquinazoline (300 mg) in dry methylene chloride (10 ml). The reaction was stirred at ambient temperature for 18 hours. The precipitated solid was isolated, washed with methylene chloride and diethyl ether and then dried under vacuum to yield the title compound (398 mg, 85%); NMR: 3.84 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 7.15 (m, 1H), 7.35 (s, 1H), 7.4-7.56 (m, 5H), 7.66 (m, 1H), 8.21 (s, 1H), 8.31 (s, 1H), 8.8 (s, 1H), 10.41 (s, 1H), 11.38 (s, 1H); m/s: M+H+ 431.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H](C(O)=O)N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH:22][CH:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:21])[CH3:20].C1(C(C2C=CC=CC=2)Br)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[C:19]([NH:22][C:23]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:21])[CH3:20]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: BrC(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(c1ccccc1)c1ccccc1

Procedure:
As a production method of 3,3-diphenylalanine, U.S. Pat. No. 4,766,109 describes, as shown in the following reaction scheme, a method comprising reacting diethyl acetamidomalonate with diphenylbromomethane in ethanol in the presence of sodium ethoxide to give diethyl 2-acetamido-2-(diphenylmethyl)malonate, subjecting the compound to hydrolysis in the presence of hydrogen bromide, neutralizing the reaction mixture with aqueous sodium hydroxide solution, and purifying the compound using a column to give 3,3-diphenylalanine, but the yield thereof is not concretely described.