Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9]([NH2:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid (0.703 g, 2.50 mmol) in 15 mL of tetrahydrofuran under nitrogen was added carbonyldiimidazole (0.438 g, 2.70 mmol), and a few crystals of4-N,N-dimethylaminopyridine [DMAP]. The reaction mixture was stirred for 1.5 hours and then 0.25 mL of 15N ammonium hydroxide was added. After 20 minutes, the reaction mixture was concentrated in vacuo and the residue slurried in water. The resulting solid was isolated by filtration and dried in vacuo to afford 0.58 g (80%) of crude product as an off-white powder. The crude product was recrystallized from ethanol to afford 0.403 g (57%) of 3-phenyl-3-(1-oxoisoindolin-2-yl)-propionamide as white prisms: 1H NMR (DMSO-6, 250 MHz) 7.8-7.2 (m, 10H), 6.92 (br s, 1H), 5.81 (overlapping dd, 1H) 4.59 (d, J=17.5 Hz, 1H), 4.16 (d, J=17.5 Hz, 1H), 3.1-2.8 (m, 2H); 13C NMR (DMSO-d6) 171.3, 167.0, 140.7, 132.2, 131.4, 128.6, 127.9, 127.5, 126.9, 123.5, 122.8, 51.5, 46.3, 37.9; Anal. Calcd for C17H16N2O2 : Theory C, 72.84; H, 5.75; N, 9.99. Found: C, 72.46; H, 5.68; N, 9.91.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([C:20]([F:23])([F:22])[F:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:24][CH2:25][CH2:26]O)[C:6]=2[C:5]([C:28]([O:30][CH3:31])=[O:29])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([O:30][CH3:31])=[O:29])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:13]([C:20]([F:22])([F:21])[F:23])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25][CH2:24][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C(F)(F)F)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of methyl 4-chloro-1-(3-hydroxypropyl)-2-{[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]amino}-1H-benzimidazole-7-carboxylate (1.50 g, 3.27 mmol) and triethylamine (0.91 mL, 6.53 mmol) in tetrahydrofuran (30 mL) was added methanesulfonyl chloride (0.38 mL, 4.90 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. A mixture of the residue and potassium carbonate (1.81 g, 13.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 13 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give the title compound (1.33 g, 2.95 mmol, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:14])C)[CH:8]=2)[O:3]1.[O:16]1CCOCC1.Cl[O-].[Na+].[OH-].[Na+]>O>[CH3:15][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:16])[CH:8]=2)[O:3]1
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: CC1(C)CCc2cc(C(=O)O)ccc2O1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A mixture of 5.8 g (28.4 mmol) of 2,2-dimethyl-6-acetylchroman (Compound 57), 75 ml of dioxane, 300 ml of 10% sodium hypochlorite solution and 50 ml of a 20% solution of NaOH in water was heated at 65° C. for 0.5 hour. The mixture was then treated with another 200 ml of 10% sodium hypochlorite solution and then heated at 65° C. for a further 65 hours. The mixture was cooled to room temperature and washed with ether. The aqueous layer was then treated with sodium metabisulphite solution until it was negative to the potassium iodide-starch test. The aqueous solution was then acidified to pH=4 with dilute H2SO4 and stored in the refrigerator for 48 hours. The solution was then diluted with water and extracted with ether. The ether layers were combined and washed with saturated NaCl solution and then dried (MgSO4). The solution was filtered and the solvent was removed in-vacuo to give the title compound as a white solid. PMR (CDCl3): & 1.36 (6H, s), 1.84 (2H, t, J~6.8 Hz), 6.81 (1H, d, J~8.4 Hz), 7.82-7.89 (2H, m). MS exact mass, m/e 206.0942 (calcd. for C12H14o3 206.0943).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S1C=CC=C1[Cl:19]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: Clc1cccs1
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1F

Procedure:
A solution of 42 g of 2-fluoro-5-nitro-benzoic acid [prepared by Chim. et Ind. 1970, p. 892] melting at 139°-140° C. and 120 ml of thienyl chloride was refluxed for two hours and was then distilled at 40° C. under a pressure of 30 to 40 mm Hg. The residue was taken up in benzene and the solution was evaporated to dryness to obtain 44 g of 2-fluoro-5-nitro-benzoyl chloride melting at 59°-60° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([Cl:41])[CH:32]=5)[O:28][N:27]=4)=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH:38]([CH3:39])[CH3:40])=[C:33]([Cl:41])[CH:32]=4)[O:28][N:27]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC(N)(CO)CO)no2)cc1Cl
Yield: 40 %

Procedure:
When the product of Step D was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 40% yield, as a fluffy white solid. 1H-NMR (DMSO-d6) 1.32 (d, 6H, J=5.54 Hz); 2.99 (s, 2H), 3.29 (m, 6H); 3.53 (m, 2H); 4.58 (m, 2H); 6.77 (d, 1H, J=7.46 Hz), 7.13 (tr, 1H), 7.24 (d, 1H, J=7.47 Hz), 7.39 (d, 1H, J=8.7 Hz), 7.82-7.84 (m, 1H); 8.05 (d, 1H, J=7.75 Hz); 8.12 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1>C1COCC1.[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: COCCC=Cc1cccc(Br)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COCCCCc1cccc(Br)c1

Procedure:
A suspension of the title B compound, 1-bromo-3-(4-methoxy-but-1-enyl)-benzene (1.8 g, 7.46 mmol) and Pd/c 5% (0.36 g) in THF (20 mL) is shaked under an hydrogen atmosphere. After completion of the reaction, the mixture is filtered through a pad of celite, the solvent is evaporated under reduced pressure and the residue purified by flash chromatography on silica gel (hexane/EtOAc 98/2) to give the title compound as a yellow oil: MS 260.1, 261.9 [M+18]. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.45 min.
Reaction SMILES: O[N:2]=[C:3]1[CH2:11][CH:10]2C[C:6]3(NC(=O)OC(C)(C)C)[CH2:7][CH:8]([CH2:13][CH:4]1[CH2:5]3)[CH2:9]2.[ClH:22]>O1CCOCC1>[CH3:13][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:3][NH2:2].[ClH:22]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(=NO)C(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCN
Temperature: 25 °C

Procedure:
A solution of oxime 12A (0.17 mmol) in 1,4-dioxane (2.0 mL) was diluted with a solution of 4 N HCl in dioxane (1.0 mL) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was concentrated and dried to provide amine 10 in 88% yield as a hydrochloric acid salt.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[CH:6]=[CH:5][C:3]=1N.[OH:13]S(O)(=O)=O.N([O-])=O.[Na+]>O>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[CH:6]=[CH:5][C:3]=1[OH:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2,4-dimethyl-3-nitroaniline (105.6 g) is added to a reaction mixture containing 300 ml of H2SO4 and 300 ml of H2O. The reaction mixture is stirred at a temperature of 105°-108° C. for one half hour and then cooled to 0° C. A solution of sodium nitrite (52.6 g) in H2O (124 ml) is added dropwise. After addition is complete the reaction mixture is poured into a 50% aqueous H2SO4 solution (2,000 ml) and refluxed for one and one half hours. The reaction mixture is cooled over the weekend to ambient temperature, and filtered leaving a yellow and black solid which is washed with H2O, dried and boiled with hexanes (8 1). The hexane extract is concentrated and filtered to obtain 65.4 grams of a yellow solid, M.P. 99°-101° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3]>[Ni].C(O)C>[CH2:20]([OH:21])[CH2:19][CH:17]([CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:18]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reaction time: 48 h
Yield: 96.7 %

Procedure:
To a solution containing 50 g (169 mmol) of phytol (3,7,11,15-tetramethyl-hexadec-2-en-1-ol, 97% mixture of isomers) and 200 ml ethanol, reaction catalysis Raney nickel (5 g, 50% slurry in water) was added. After stirring the mixture under hydrogen atmosphere (15 psi) for 2 days, the catalyst was removed by vacuum filtration several times through the combination layers of silica and Celite bed on the top. The filtrate was concentrated under reduced pressure to give phytanol (48.8 g, 97.0%) as a colourless oil. 1H NMR in CDCl3: δ0.83, 0.85, 0.86, 0.88, 0.91 (5s, each 3H, CH3), 0.94-1.71 (m, 25H, 10CH2+4CH+OH), 3.58-3.78 (m, 2H, CH2OH).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=O)C.O.[NH2:20][NH2:21]>>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[O:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([NH:20][NH2:21])=[O:3])[CH2:7][CH2:8]1
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2cnccn2)CC1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cnccn2)CC1
Temperature: 120 °C

Procedure:
A mixture of cis/trans-4-(pyrazin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1.11 g, 4.41 mmol) and hydrazine hydrate (0442 g, 8.83 mmol) was heated at 120° C. for 72 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude cis/trans-hydrazide was triturated in ethyl acetate (5 ml). The precipitate was collected by filtration and dried in vacuo to give the crude title compound (0.236 g, 23%) as white solid, which was used in the next step without further purification. MS m/e: 237 (M+H+)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][F:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:15][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: FCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCF
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
N-hydroxyphthalimide (80 g) and bromofluoromethane (63.2 g) were added to dry dimethyl sulfoxide (350 ml) which had been cooled to 0° C. Potassium carbonate (135 g) was added further, followed by stirring at room temperature for 4 hours. Thereafter, nitrogen gas was introduced for 1 hour. The reaction mixture was added to ice water (800 ml), followed by extraction three times with ethyl acetate (500 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The solvent was distilled off under reduced pressure. Deposited crystals were washed with isopropyl ether and petroleum ether to obtain the target product (55 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29]1(Br)[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(N2CCC(N(C)C(=O)COc3nc(C)c(NC(=O)OC(C)(C)C)c(C)n3)CC2)cc1

Procedure:
The title compound was synthesized from Compound 31 and phenetyl bromide in the same manner as in Example 32.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1C=CC=CC=1.Cl.[N:19](=[CH:27][CH2:28]Cl)[CH2:20][CH2:21][CH2:22][CH2:23]CCCl.C([O-])=O.[NH4+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.CO.[Pd].O>[N:19]1([CH2:4][CH2:3][O:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:28][CH2:27]1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: ClCC=NCCCCCCCl
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(OCCN2CCCCCC2)cc1
Temperature: 60 °C
Yield: 59879.3 %

Procedure:
Add sodium hydride (18 g, 0.45 mol) into a solution of 4-benzyloxylphenol (41 g, 0.20 mol) and 2-(hexamethyleneimino)ethyl chloride hydrochloride (44 g, 0.22 mmol) in THF (600 mL) and DMF (100 mL) at room temperature. Heat to 60° C. for 30 minutes. Pour the solution into ice and water. Dilute with ethyl acetate (500 mL) and separate layers. Dry the organic layer with magnesium sulfate, filter and concentrate under reduced pressure to give brown oil. Dissolve the oil in ethyl acetate (500 mL) and methanol (500 mL). Add ammonium formate (100 g, 1.59 mol) and palladium on carbon (10 g, 9.4 mmol). Heat the mixture to reflux for 30 minutes. Add ammonium formate (100 g, 1.59 mol) and palladium on carbon (10 g, 9.4 mmol). Heat the reaction mixture for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 ml). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 31 g (64%) of 4-(2-azepan-1-yl-ethoxy)-phenol.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5]([CH3:7])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5](=[N:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH3:7]
Reactant: CC(=O)C(=NO)C(=O)N(C)C
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C(C)C(=NO)C(=O)N(C)C)cc1

Procedure:
a mixture of 142 parts of N,N-dimethyl-2-hydroxyiminoacetoacetamide (a compound of Formula III), 1200 parts of toluene, 123 parts of p-anisidine and 1 part of p-toluenesulfonic acid was refluxed overnight in a flask fitted with a Dean-Stark distilling trap and water condenser. Eighteen parts of water were removed in this manner. On cooling, a heavy slurry of solid product precipitated. This was filtered and washed with butyl chloride thereby providing a product which melted at 201.5°-203° C. Recrystallization from acetonitrile gave 151 parts of N,N-dimethyl-2-hydroxyimino-3-(4-methoxyphenylimino)butyramide (a compound of Formula II) as a yellow solid, m.p. 204°-205.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
1.78 g (9.70 mmoles) of 2,4,6-Trichloro-pyrimidine was dissolved in 10 mls of anhydrous THF and chilled to −78° C. 4.9 mls (9.8 mmoles) of benzyl magnesium chloride (2M in THF) was added dropwise and the solution allowed to warm to ambient temperature. The reaction was stirred for 3 hours, then quenched with 20 mls of water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over NaSO4 and evaporated under reducd pressure. The crude residue was purified by flash chromatography, using EtOAc/Heptane as the eluent to yield 1.08 g (47%) of 4-benzyl-2,6-dichloro-pyrimidine as a light yellow oil. 1H NMR (CDCl3 03-499-77b)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:17])[NH:9]2)[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (10 g, 38 mmol) and metal Sn (23 g, 190 mmol) in CH3CH2OH/con. HCl (60 mL/40 mL) was stirred under reflux for 3 hours. The mixture was cooled to room temperature and adjusted to pH=7 by saturated NaOH and filtered though a Celit pad. The filtrate was extracted with EtOAc, washed by brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using silica gel chromatography (petroleum ether:EtOAc=10:1) to get 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8 g, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 9.86 (s, 1H), 7.10˜7.20 (m, 3H), 6.33˜6.91 (m, 2H), 5.15˜5.21 (m, 1H), 4.61 (s, 1H), 3.65˜3.71 (m, 1H), 3.04˜3.11 (m, 1H). MS (M+H)+: 265.
Reaction SMILES: [Br:1][CH:2]([CH2:15][Br:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[O:11]COC.Cl>C(O)C>[Br:1][CH:2]([CH2:15][Br:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[OH:11]
Reactant: COCOc1cnccc1OCC(Br)CBr
Agent: Cl
Solvent: CCO
Product: Oc1cnccc1OCC(Br)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of intermediate (8) (0.0248 mol), HCl (35.42 ml)and ethanol (40 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The concentrate was cooled on an ice-water bath. The mixture was neutralized with a saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated till dryness. The residue was purified by open column chromatography (eluent: CH2Cl2; CH2Cl2/MeOH (98/2, 96/4 and 90/10)). The pure fractions were collected and the solvent was evaporated, yielding 4.27 g of (±)-4-(2,3-dibromopropoxy)-3-pyridinol (intermediate 9).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:13]([NH:15][C@H:16]([C:31](O)=[O:32])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[CH:19]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:57]([O:59][C:60](=[O:67])[C@H:61]([CH2:63][CH2:64][S:65][CH3:66])[NH2:62])[CH3:58]>CN(C)C=O>[CH2:57]([O:59][C:60](=[O:67])[C@H:61]([CH2:63][CH2:64][S:65][CH3:66])[NH:62][C:31](=[O:32])[C@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[CH:19]=1)[NH:15][C:13](=[O:14])[C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH:3][CH:1]=[O:2])[CH3:58]
Reactant: CCOC(=O)[C@@H](N)CCSC
Reactant: O=CN[C@@H](Cc1ccc(F)cc1)C(=O)N[C@@H](Cc1cccc(N(CCCl)CCCl)c1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1cccc(N(CCCl)CCCl)c1)NC(=O)[C@H](Cc1ccc(F)cc1)NC=O
Temperature: 15 °C

Procedure:
554 g of N-formyl-p-fluoro-L-phenylalanyl-m-di-(2-chloroethyl)amino-L-phenylalanine are dissolved in 4.5 liters of dimethyl formamide (DMF). The solution is heated slowly for the dissolution step and then cooled to 15° C. While stirring add: 172 g of N-hydroxysuccinimide+225 g of dicyclohexylcarbodiimide+1,235 g-moles of L-methionine ethyl-ester dissolved in DMF. After 16 hours of stirring at room temperature, the precipitated dicylcohexylurea is removed and to the stirred filtrate 18 liters of a mixture of water and ice are added. The white precipitate is filtered, washed with water and completely dried under vacuum. Yield: 710 g (97.2%); m.p.=180°-182° C.; [α]D20 =-7.0°±1° (c=2, DMF).
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2ccncc12
Product: Brc1cccc(Nc2ncnc3ccncc23)c1
Yield: 10 %

Procedure:
A mixture of 4-methylthiopyrido[4,3-d]pyrimidine (171 mg, 0.96 mmol), (see previous experimental) and 3-bromoaniline (1 mL) is heated to i00C for 2 h. A solid precipitates on cooling and is collected by vacuum filtration and then recrystallized from EtOH to yield 4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (30 mg, 10%). 1H NMR (DMSO) δ 10.33 (1H, s), 9.86 (1H, s), 8.84 (1H, d, J=5.8 Hz), 8.79 (1H, s), 8.22 (1H, s), 7.89 (1H, d, J=7.2 Hz), 7.69 (1H, d, J=5.8 Hz), 7.40 (2H, dt, Jd=8.0 Hz, Jt=1.5 Hz).