Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH:43][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1F
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
Combine a mixture (1 mmol total) of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole with 2-fluorobenzylamine (0.63 g, 5.0 mmol), potassium carbonate (0.41 g, 3.0 mmol) and a mixture of acetonitrile:water (80:20) and heat (80° C.) for 30 hours. Cool the reaction mixture and concentrate to give a residue. Purify the residue by column (silica) chromatography (ethyl acetate). Combine the appropriate fractions and concentrate to give the title compound (0.36 g, 94% Yield) as an oil. Purity by LC/MS (APCI)=100% area, [M+H]+=383 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)nc(-c3ccccc3)nc2c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
7-Chloro-2-phenylquinazolin-4(3H)-one (3.11 g, 12.1 mmol) in POCl3 (40 mL) was heated with stirring at 90° C. under N2 for 2 d. The reaction was cooled to rt and evaporated to dryness under high vacuum. The residue was stirred for 30 min at 0° C. under Ar as a suspension in NH3/ i-PrOH (2 M, 45 mL). Later DCM (˜100 mL) was added and stirring was continued for 1 h at rt. Aq NH4OH (conc, 50 mL) was added and layers were separated. The aqueous layer was extracted with DCM (2×). The organic phase was washed (satd NaHCO3, H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a light yellow solid; 1H NMR (400 MHz, CD2Cl2) δ 8.56-8.46 (m, 2H), 8.14 (d, J=9.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.56 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.52-7.45 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCCCCCOCCCCCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCCCCCc2ccccn2)cc1
Reaction time: 1 h

Procedure:
2-[6-[(6-Bromohexyl)oxy]hexyl]pyridine (4.99 g) was added dropwise to benzylamine (22 ml) at 140° C. under nitrogen. The solution was stirred at 140° for 1 h and distilled under vacuum to remove benzylamine. The residue was partitioned between ethyl acetate (300 ml) and 8% aqueous sodium bicarbonate (200 ml). The dried organic layer was concentrated and the residual oil was purified by FCC eluting with ethyl acetate-triethylamine (100:1) to give the title compound as a pale yellow oil (4.65 g), t.l.c. (ethyl acetate+few drops triethylamine) Rf 0.23.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[N:36][OH:37])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, 3-(4′-methanesulfonyl-biphenyl-3-yl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.8:1) as a white foam, MS (ESI+): m/z=485.19 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(Nc2nc(Cl)ncc2F)n1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2-amino-6-methylpyridine gave 2-chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (d, 1H, J=3 Hz), 7.55 (bs, 1H), 7.69 (t, 1H, J=7.4 Hz), 9.35 (d, 1H, J=7.5 Hz); 19F NMR (CDCl3): −44073; LCMS: purity: 96%; MS (m/e): 239 (M+).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([O:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:22][O:21][C:15]1[CH:20]=[CH:19][C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C
Yield: 44.6 %

Procedure:
Phenylacetyl chloride (30.9 g, 0.2 mol) in CH2Cl2 (100 ml) was added dropwise to a solution of AlCl3 (32 g, 0.24 mol) and anisole (21.6 g, 0.2 mol) in CH2Cl2 (400 ml) at room temperature. The reaction was complete (by TLC) after 4 hours and was poured over an ice; 10% HCl slurry. The organic layer was washed with H2O and brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was chromatographed SiO2 (1500 g), eluting with toluene to afford 11 (20.2 g, 63.7%, para isomer), m.p. 74°-75.5° C.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:16].[CH:17]1[CH:22]=CC=C[CH:18]=1.C(=O)CC>[Zn].CS(C)=O>[Cl:14][C:6]1[C:5]([Cl:15])=[C:4]2[C:9]([CH2:10][CH2:11][C:2](=[CH:18][CH2:17][CH3:22])[C:3]2=[O:16])=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: c1ccccc1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(Br)CC2
Agent: [Zn]
Solvent: CS(C)=O
Solvent: CCC=O
Product: CCC=C1CCc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2-Bromo-7,8-dichloro-6-methoxy-1-tetralone (0.01 mole), benzene (50 ml), dimethyl sulfoxide (5 ml), propionaldehyde (3 ml, 0.04 mole) and zinc dust (6.5 g, 0.1 mole) were stirred under nitrogen. After 48 hours, the reaction mixture was poured into ice water, washed with brine, dried over MgSO4 and filtered, treated with 300 mg of para-toluene sulfonic acid, then refluxed for 15 minutes. The reaction mixture was cooled, filtered, evaporated and chromatographed on 140 g SiO2 (ethyl acetatehexane 3:7) to yield 1.25 g of 7,8-dichloro-6-methoxy-2-propylidene-1-tetralone which was directly used in Step C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:12]([NH:20][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: NCCc1ccccc1
Solvent: CCO
Product: O=C(NCCc1ccccc1)c1ccccn1

Procedure:
A mixture of 20 ml of ethyl pyridine-2-carboxylate and 27 ml of phenethylamine was stirred at 180° C. for 5 h., with the ethanol formed being distilled off over a 30 cm Vigreux column. Distillation of the residue yielded 30.9 g of pyridine-2-carboxylic acid phenethyl-amide as a yellowish oil, b.p. 150°-155° C./0.8 mbar.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 8.9 %

Procedure:
A mixture of 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.41 g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether. To the mixture was added sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and to the residue was 1N hydrochloric acid (2 ml). The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 2) (0.1 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[NH2:15])([O-])=O>[Ni].CCO>[F:12][C:11]([F:13])([F:14])[O:10][C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:15])=[CH:6][CH:7]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(OC(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-nitro-4-trifluoromethoxy-phenylamine Compound 16a (0.5 g, 2.25 mmol) was dissolved into EtOH (30 mL) and Raney Ni (˜0.5 g, prewashed with EtOH) was added. The mixture was shaken in a Parr shaker under H2 (50 psi) at room temperature overnight, filtered through Celite and the solvent was evaporated to dryness to provide 4-trifluoromethoxy-benzene-1,2-diamine Compound 16b (0.373 g, yield 86%) as a red-brown semi-solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([Cl:10])=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Fc1cnc(Nc2ccc(Cl)c(C(F)(F)F)c2)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylaniline were reacted to yield N2,N4-bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.05 (bs, 1H), 7.89 (bd, 1H), 7.77 (dd, 1H, J=2.4 and 9 Hz), 7.65 (dd, 1H, J=2.4 and 8.7 Hz), 7.49 (d, J=8.1 Hz), 7.40 (d, 1H, J=6.2 Hz), 7.03 (s, 1H), 6.91 (s, 1H); 19F NMR (CDCl3): δ −17864 (s, 3F), −17894 (s, 3F), −46550 (s, 1F); LCMS: ret. time: 38.81 min.; purity: 75%; MS (m/e): 485 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])=[O:5])C.O.Cl>[OH-].[K+]>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Temperature: 80 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
A suspension of 2-ethoxycarbonyl-1-methyl-7-trifluoromethylimidazo [1,2-a]quinoxalin-4(5H)-one (960 mg, 2.8 mmol) in 2M potassium hydroxide (30 ml) was stirred at 80° C. for 4 h. The reaction mixture was added water (25 ml) and pH adjusted to pH 7 with 1N hydrochloride acid. The precipitate was filtered off and washed with water. Recrystallization from glacial acetic acid afforded 650 mg (74%) of the title compound as the acetate. M.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH2:19][C:20](OCC)=[O:21])([CH2:15][N+:16]([O-])=O)[CH2:10]2)[C:5]([F:25])=[CH:4][N:3]=1>CO.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:15][NH:16][C:20](=[O:21])[CH2:19]3)[CH2:10]2)[C:5]([F:25])=[CH:4][N:3]=1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: [Ni]
Solvent: CO
Product: O=C1CC2(CCC[C@H](Nc3nc(Cl)ncc3F)C2)CN1
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-((3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(nitromethyl)cyclohexyl)ethanoate, 62b, (1.60 g, 4.27 mmol) in MeOH (20 mL) was added Raney Nickel (0.03 g, 0.43 mmol). The reaction was shaken on a Parr apparatus at 40 psi of H2 overnight. The reaction was filtered, concentrated in vacuo and purified by silica gel chromatography (CH2Cl2:20% MeOH in CH2Cl2) to give 155 mg of 62c. LCMS+: 299.13 at 2.87 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>CN(C=O)C>[CH2:13]([NH:16][C:10]1[C:5]2[S:4][CH:3]=[C:2]([Br:1])[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1)[CH:14]=[CH2:15]
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(Br)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To 5 ml of a solution of 426 mg (1.5 mmol) of 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine in DMF was added 188 mg (3.3 mmol) of allylamine under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 1 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 359 mg (yield: 78.6%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]([NH2:17])[CH2:6][C:7]([F:16])([F:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl.O>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]([NH:17][C:32]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:33])[CH2:6][C:7]([F:16])([F:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a mixture of (S)-2-amino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester hydrochloride (2.50 g, 8.94 mmol) and diisopropyl amine (22.3 mmol, 2.89 g) in dry dichloromethane (40 mL) under N2 is added drop wise morpholine carbonyl chloride (13.4 mmol, 2.0 g). The mixture is stirred at room temperature for 15 hours, and then diluted with water (50 mL). The aqueous layer is extracted with dichloromethane (30 mL). The organic layers are dried over magnesium sulfate and then concentrated in vacuum. Purification over 110 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid methyl ester (2.82 g, 88.5%).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl.CCOCC>O1CCCC1.C([Li])CCC>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:38]([NH:37][C:28]2[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])=[O:39])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred room temperature solution of 3-dodecyl-5-(phenylmethyl)isoxazole (38.3 g, 0.117 mol) in tetrahydrofuran (600 mL) was cooled to -78° C. under nitrogen. To the resulting precipitate was added dropwise a 2.01M solution (58 mL, 0.12 mol) in n-butyl lithium in hexanes over 10 minutes. The mixture was stirred for 1.25 hours before a solution of 2,4,6-trimethoxyphenyl isocyanate (24.43 g, 0.1168 mol) in tetrahydrofuran (350 mL) was added dropwise over 30 minutes. The mixture was stirred for 45 minutes then quenched with a dropwise addition of 1M HCl (235 mL, 0.235 mol) followed by ether (500 mL). The mixture was allowed to warm to room temperature. The organic layer was washed with 0.2M HCl, water, saturated sodium bicarbonate, and saturated sodium chloride, dried (MgSO4), and rotoevaporated to a solid. The material was recrystallized twice from diisopropyl ether and chromatographed on silica gel (830 g, 230-400 mesh) using petroleum ether-ethyl acetate (2:1, 20×900 mL) to give a white solid; yield 40.7 g (65%), mp 106°-107° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][F:13])[CH:7]=[C:6]([O:14][CH2:15][CH2:16][F:17])[CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[F:13][CH2:12][CH2:11][O:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([O:14][CH2:15][CH2:16][F:17])[CH:7]=1)[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1cc(OCCF)cc(OCCF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(OCCF)cc(OCCF)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
The above prepared 3,5-bis-(2-fluoro-ethoxy)-benzoic acid methyl ester (1.45 g, 5.57 mmol) was dissolved in 19 ml of THF/ethanol=1/1 and treated with 9.3 ml of aq. NaOH (3M, 5 eq.). The mixture was stirred for 1.5 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 1.36 g of the title compound as white solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].[OH-].[Na+]>C(O)(C)C>[N:15]1([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: COC(=O)CCCCCCCCCCCN1CCNCC1CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)CCCCCCCCCCCC1CNCCN1CCCCCCCCCCCC(=O)O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Piperazine bislauric acid methyl ester was then dissolved in isopropanol at room temperature. A small amount of 50% NaOH solution was added to the reaction mixture. The reaction was stirred overnight at 55° C. The reaction was then stopped by cooling down to room temperature and the pH of the solution was adjusted to 10. The crude product was extracted with n-butanol twice and the organic layer was then collected and the solvent was evaporated under reduced pressure. The remaining solid material was washed with ethanol again and dried under vacuum. Both 1H-NMR and 13C-NMR spectral analysis agreed with the expected structure of the final product. The yield of the reaction was about 95%.
Reaction SMILES: [Cl:1][C:2]1[S:20][C:5]2[N:6]=[C:7]([NH:18][NH2:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+].C(Cl)Cl>C(O)(=O)C>[Cl:1][C:2]1[S:20][C:5]2[N:6]3[C:23]([CH2:22][Cl:21])=[N:19][N:18]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NNC1=Nc2sc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 g of 7-chloro-5-(o-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine are introduced, with cooling at 15° C., into 15 ml of glacial acetic acid and a solution of 0.25 g of chloroacetyl chloride in 5 ml of glacial acetic acid is slowly added dropwise thereto. The mixture is then stirred for a further 2 hours, treated with 0.3 g of sodium acetate and stirred for 1 hour. The solution is poured on to ice-water, neutralized and shaken out with methylene chloride. After evaporation of the solvent, the residue is refluxed with 30 ml of absolute xylene for 1 hour. After evaporation of solvent, the residue is recrystallized from ethyl acetate containing active carbon to yield 2-chloro-9-chloromethyl-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 101°-103° C.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].[CH3:36][O:37][CH2:38][CH:39]([NH2:42])[CH2:40][CH3:41]>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH:39]([CH2:38][O:37][CH3:36])[CH2:40][CH3:41])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: CCC(N)COC
Solvent: O=C(O)C(F)(F)F
Product: CCC(COC)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-]
Yield: 81.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (39.6 mg, 0.093 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine (191.0 mg, 1.85 mmol) were treated substantially as described in Part C of Example 19a to produce 30 mg (81%) of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 397.19 [(M+H)+, 100].
Reaction SMILES: [C:1]1([CH:7]2[O:15][CH:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>O>[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:15]
Reactant: COCCN
Reactant: c1ccc(C2OC2c2ccccc2)cc1
Solvent: O
Product: COCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 150 °C
Yield: 80 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mole) and 2-methoxyethylamine (4.51 g, 0.060 mole) was heated at 125° C. for 2 hours with an oil bath. A mass spectra analysis showed no title compound was present. The mixture was heated for another 2 hours at 150° C. The mixture was poured into water (using methanol rinse) to obtain an off-white solid. NMR analysis showed the solid contained approximately 60% unreacted stilbene oxide. The mixture was added to another 4.51 g (0.060 mole) of 2-methoxy ethylamine and the mixture heated at 135° C. for 4 hours in a stainless-steel bomb. After cooling, the reaction mixture was shown by NMR analysis to contain 20% stilbene oxide and 80% of the title compound. The solid was recrystallized from toluene to give 2.92 g (54%) of a white solid, m.p. 137°-139° C.