Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[OH:8][CH2:9][C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:25][P:26](Cl)(Cl)=[O:27]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:25][P:26]1(=[O:27])[O:24][CH2:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:9][O:8]1
Reactant: CP(=O)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COP(C)(=O)OC2
Temperature: 0 °C

Procedure:
Et3N (943 μL, 6.76 mmol) and tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (790 mg, 3.22 mmol) were combined in CH2Cl2 (25 mL) and cooled to 0° C. A solution of methylphosphonic dichloride (428 mg, 3.22 mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h. The reaction was then allowed to warm to room temperature over 1 h. It was subsequently diluted with saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to give the desired product as a colorless solid that was used without purification. MS: cal'd 306 (MH+), exp 306 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O.C(O)(=O)C>O>[C:1]1([N:7]2[C:11](=[O:12])[C:10]3[C:22]([CH3:24])=[CH:21][C:20](=[O:25])[N:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(Nc2ccccc2)=NN1c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)n(-c2ccccc2)c2[nH]n(-c3ccccc3)c(=O)c12
Yield: 34.5 %

Procedure:
25 g of 1-phenyl-3-anilino-2-pyrazoline-5-one, 180 g of ethyl acetoacetate, and 150 ml of acetic acid were heated while refluxing for 6 hours. The reaction solution was diluted with water, and the solid formed was crystallized from acetonitrile to obtain 10.9 g of 2,7-diphenyl-4-methylpyrazolo[3,4-b]pyridine-3,6-dione. Melting point: 145° to 147° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[CH2:13]([O:15][C:16](=[O:28])[C:17](=[C:23](OCC)[CH3:24])[C:18](OCC)=[O:19])[CH3:14]>COCCOCCOC>[CH3:24][C:23]1[N:1]=[C:2]2[S:3][C:4]([N:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)=[N:5][N:6]2[C:18](=[O:19])[C:17]=1[C:16]([O:15][CH2:13][CH3:14])=[O:28]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)OCC
Reactant: Nc1nnc(N2CCOCC2)s1
Solvent: COCCOCCOC
Product: CCOC(=O)c1c(C)nc2sc(N3CCOCC3)nn2c1=O
Temperature: 0 °C

Procedure:
2-amino-5-morpholino-1,3,4-thiadiazole (5 g) was reacted with diethyl(1-ethoxy-ethylidene)-malonate (6.2 g) in diglyme (40 ml) at 150° C. for 20 hours. After cooling the reaction mixture was diluted with ice water and extracted with ethyl acetate; after evaporation in vacuo to dryness, the residue was purified over a SiO2 column using chloroform-methanol 98:2 as eluent. Crystallization from isopropyl ether gave 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 196°-198° C. (2.6 g), which was reacted with 2-amino-pyridine (2.25 g) in polyphosphoric acid (130 g) under stirring at 120° C. for 4 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water to give 1.9 g of 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p. 285°-287° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(2-Thienyl)-L-alanine (2.24 g., 13.1 mmol.) was suspended in water/p-dioxane (20 ml./10 ml.) at room temperature under argon. Sodium carbonate (1.39 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (2.87 g.) was added, and the resulting mixture was stirred for 4.5 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 2.70 g. of the title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-153.6° (c= 0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.5.
Reaction SMILES: BrCC1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].Cl.[C:18]([O:22][C:23](=[O:32])[C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:25][CH2:26][CH3:27])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:6]([C:5]1[CH:4]=[C:27]([CH:10]=[C:9]([F:11])[CH:8]=1)[CH2:26][NH:25][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:32])#[N:7]
Reactant: N#Cc1cc(F)cc(CBr)c1
Reactant: CCN[C@H](CC(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(bromomethyl)-5-fluorobenzonitrile (4.0 g, 0.02 mol) in dry DMF (40 mL) were added sodium bicarbonate (3.9 g, 0.046 mol) and ethyl D-leucine tert-butyl ester hydrochloride (4.2 g, 0.019 mol). The reaction mixture was stirred at RT for 16 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (d, J=9.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=9.8 Hz, 1H), 3.78 (d, 1H), 3.64 (d, 1H), 2.97 (d, 1H), 2.60 (brs, 1H), 1.97-1.71 (m, 1H), 1.36 (m, 11H), 0.86 (d, 3H), 0.80 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[H][H]>C(O)C.[Pd]>[NH2:12][C:4]1[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=[CH:2][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]c(=O)oc12
Temperature: 45 °C
Yield: 94 %

Procedure:
107.5 g (1 mole) of 5-chloro-7-nitro-2(3H)-benzoxazolone prepared according to Example 1d was suspended in 1000 ml of ethanol. 9.25 g of Pd/C 5% and 50 ml of ethanol were added and the mixture was hydrogenated at 4 bar hydrogen pressure for four to six hours at 60-65° C. while vigorously stirring. When the hydrogenation was complete, the mixture was cooled to 45° C. and filtered over Hyflo®. The Hyflo® was washed twice with 175 ml of methanol. 500 ml of solvent was distilled off under reduced pressure at 50° C., followed by addition of 250 ml of water and removal of 300 ml of solvent was by distillation under reduced pressure at 50° C. The last procedure was repeated twice and finally 250 ml of water was added and 400 ml of solvent was distilled of. The resulting mixture was cooled to 0-5° C. in about one hour. The solid was filtered off and, washed three times with 125 ml of cold water, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 94%.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37](=[N:39]O)[NH2:38])[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[N:39]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:38]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: NC(=NO)c1ccc(F)c(Cl)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(F)c(Cl)c3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 41 mg (0.22 mmol, 1.1 eq.) of 3-chloro-4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 51 mg (46% of theory)
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>ClCCl>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[I:1])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1I
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccccc1I)C(=O)OCC
Temperature: 110 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
2-Iodoaniline (50 g, 228.3 mmol) and 2-ethoxymethylene-malonic acid diethyl ester (50 mL, 251.1 mmol) were mixed and the solution was stirred at 110° C. for 3 h. The crude was dissolved in dichloromethane and it was purified by silica plug. The product was eluted with ethyl acetate/hexanes (10-50%) and the solvent removed under reduced pressure to afford 2-[(2-iodo-phenylamino)-methylene]-malonic acid diethyl ester as an off-white powder (81.4 g, 91.6%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (t, 3H), 1.54 (t, 3H), 4.40 (q, 2H), 4.52 (q, 2H), 7.01-7.05 (m, 1H), 7.36-7.39 (m, 1H), 7.52-7.56 (m, 1H), 8.59 (d, 1H). Exact mass calculated for C14H16INO4 389.01, found 390.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[P:10]([Cl:14])(Cl)(Cl)=[O:11]>>[P:10]([Cl:14])(=[O:11])([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(Cl)cc1Cl
Product: O=P(Cl)(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the general method of Example 1 with the following modifications. (1) The molar ratio of 2,4-dichlorophenol to phosphorus oxychloride was increased from 1.33 to 1.85 by using 189.99 g (1.165 mole) of 2,4-dichlorophenol and 96.60 g (0.63 mole) of phosphorus oxychloride. (2) The reaction time at 120° was increased to about 24 hours. (3) The product was crystallized using a larger quantity of hexane (570 ml, or 3 ml per gram of starting 2,4-dichlorophenol) at -15°. Analysis by GLPC indicated 82% purity (by weight) of bis(2,4-dichlorophenyl) phosphorochloridate, with contamination by a trace of 2,4-dichlorophenyl phosphorodichloridate and 18% (by weight) of tris(2,4-dichlorophenyl) phosphate. The yield of the bis(2,4-dichlorophenyl) phosphorochloridate when corrected for purity was 125 g (53%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:30]1[CH2:31][CH2:32][N:1]([C:2]2[CH:3]=[C:4]([C:8]3([N:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20]4)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:29]1
Reactant: BrCCOCCBr
Reactant: CC1CCC(c2cccc(N)c2)(N2CCN(c3ccccc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCC(c2cccc(N3CCOCC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
1-(3-Aminophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl cyclohexane (cis isomer) (150 mg) was dissolved in 1 mL dry DMF under a nitrogen atmosphere. 2-Bromoethyl ether (150 mg) and potassium carbonate (150 mg) were added and the mixture was heated to 90° C. for 6 hours. The mixture was cooled to room temperature, diluted with 20 mL ethyl acetate, and transferred to a separatory funnel. The mixture was washed 5×10 mL water and 1×10 mL brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography, eluting with 9/1 hexanes/ethyl acetate to give 68 mg 1-(3-morpholinophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl cyclohexane (cis isomer) as a clear oil. m.p. (HCl salt)=178-180° C.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[H-].[Na+].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:1][CH:2]([CH2:8][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:3]([OH:5])=[O:4]
Reactant: BrCc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A solution of diethyl methylmalonate (23 g) in anhydrous tetrahydrofuran (100 cc) is added under nitrogen to sodium hydride (4 g, 80% strength in oil) and anhydrous tetrahydrofuran (60 cc). After 1 hour's stirring, a solution of 4-bromomethyl-2-phenylquinazoline (9.9 g) in anhydrous tetrahydrofuran (100 cc) is added, and the mixture is stirred for a further 2 hours at room temperature (approximately 20° C.). Water (100 cc) is added and the mixture is extracted with ethyl acetate (3×100 cc). The organic phase is dried over magnesium sulphate and then evaporated to dryness under reduced pressure. The residue is taken up in concentrated hydrochloric acid (100 cc) and acetic acid (100 cc) and the mixture is brought to 110° C. for 24 hours. After the mixture has cooled, the precipitate is filtered off and washed with water and then ispropyl ether. After being dried, α-methyl-2-phenyl-4-quinazolinepropanoic acid (4 g), m.p. 180° C., is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]>>[CH3:31][C:15]1([CH3:14])[O:20][C:19]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([N:2]([CH3:1])[CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][C:5]=3[CH3:13])=[O:29])[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Reactant: CNCc1c(C)oc2ccccc12
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Yield: 81.3 %

Procedure:
According to the procedure of Example 43d, methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (124 mg, 0.71 mmol) and 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (160 mg, 0.64 mmol) were coupled to yield the title compound (211 mg, 81%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1s, 1H), 8.20 (1s, 1H), 7.92 (1s, 1H), 7.54-7.58 (m, 2H), 7.46-7.48 (m, 1H), 7.17-7.25 (m, 3H), 4.72-4.93 (m, 2H), 3.32 (s, 3H), 3.04 (s, 2H), 2.47 (s, 3H), 1.43 (1s, 6H); MS (ESI) m/e 406 (C23H23N3O4+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[N:5]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)ncc1CO
Product: COCc1nc(-c2ccc(OC(F)(F)F)cc2)ncc1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].C(N(C(C)C)CC)(C)C.Cl[CH2:22][O:23][CH3:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:22][O:23][CH3:24]
Reactant: OC/C=C/c1ccccc1Cl
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC/C=C/c1ccccc1Cl
Temperature: 0 °C
Yield: 92.2 %

Procedure:
To a 250 ml round-bottomed flask, (E)-3-(2-chlorophenyl)prop-2-en-1-ol (2.96 g, 17.5 mmol, Preparation example 1) and Dichloromethane (17.5 ml) were added and the reaction mixture was cooled to 0° C. Diisopropylethylamine (6.1 ml, 35.1 mmol) was added and stirred at 0° C. Methyl chloromethyl ether (2.77 ml, 35.1 mmol) was added dropwise and stirred for overnight. The reaction mixture was quenched with 1N NaOH solution, extracted by dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (3.43 g, 85˜95%).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([OH:26])(=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>CCOC(C)=O>[CH:7]([O:26][C:16](=[O:25])[C@@H:17]([OH:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of diphenyldiazomethane (0.528 g, 2.719 mmol) in EtOAc (5 mL) was added portionwise with cooling (ice bath) and stirring to a solution of (S)-mandelic acid (0.500 g, 3.286 mmol) in EtOAc (5 mL). The purple reaction mixture was stirred at room temperature for 1 h and was then washed successively with saturated NaHCO3 (3×5 mL) and brine (2×5 mL), dried over anhydrous MgSO4 and evaporated to 0.9864 g of a yellow solid, which was recrystallized from hexanes to give 0.67 g (80%) of 2g. 1H NMR (400 MHz) in CDCl3 (J, Hz): δ 3.4515 (d, 1H, OH), 5.2782 (d, 1H, CHOH), 6.75 (s, 1H, CHPh2), 7.20-7.45 (m, 15H, ArH).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=1)=[O:37]>O1CCCC1>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:44]=2)=[O:37])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a suspension of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg) in tetrahydrofuran were added triethylamine (18.8 mg) and 4-methoxycarbonylphenyl chloroformate (39.8 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed, and ethyl acetate and water were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:n-hexane=2:1, V/V) to give 8-[2,6-dichloro-3-[N-[(4-methoxycarbonylphenoxycarbonyl)glycyl]-N-methylamino]benzyloxy]-2-methylquinoline (30 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate (28 mg, 0.091 mmol) and 1-(3-methoxy phenyl)piperazine (27 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:2) mixture and concentration gave 26 mg of the titled compound (yield, 64%). 1H NMR (300 MHz, CDCl3) δ 3.27-3.29 (m, 4H), 3.78-3.81 (m, 7H), 3.94 (s, 3H), 3.97-3.98 (m, 1H), 4.00 (s, 3H), 4.15 (s, 3H), 6.47-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.11 (s, 1H), 7.14-7.27 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13](C=O)C>C(Cl)Cl.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.[C-]#N.[Zn+2].[C-]#N>[F:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[CH2:9][OH:10])[C:12]#[N:13]
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(F)c(CO)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of (4-bromo-2,6-difluorophenyl)methanol (1.12 g, 5.0 mmol), Pd(PPh3)4 (323 mg, 0.28 mmol) and zinc cyanide (587 mg, 5.0 mmol) was prepared in DMF (7 mL) under nitrogen atmosphere and heated at 90° C. for 18 hours. The mixture was diluted with DCM and water. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.28-7.21 (2H, m), 4.83 (2H, d, J=6.7 Hz), 1.95 (1H, t, J=6.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH2:11])=[N:7][CH:6]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH:11][C:23](=[O:24])[CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:26][CH3:27])=[N:7][CH:6]=1
Reactant: Cn1c(Cc2ccccc2Cl)cnc1N
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)n1C)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-1-methyl-1H-imidazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (13 mg, 0.035 mmol, 18%). ESI-MS m/z calc. 367.2. found 368.1 (M+1)+ Retention time 2.42 minutes.