Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one (4.96 g, 0.020 mol) in dichloroethane (50 ml) is added N-methylpiperazine (2.7 ml, 0.024 mol) at 0° C. and the mixture is stirred at room temperature. After 4 h, sodium triacetoxy-borohydride (5.04 g, 0.024 mol) is added and the mixture is further stirred at room temperature for 24 h. After addition of 1N sodium hydroxide at 0° C., the mixture is poured into water and extracted three times with dichloromethane. The organic layer is combined and extracted three times with 1N hydrochloride. The water layer is basified with 2N sodium hydroxide and extracted three times with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound as yellow solids (6.04 g) in 91% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:32]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:3][CH2:4]4)=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCCC1=O
Reactant: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.33 mmol) of 4-({3 chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile and 306 mg (1.98 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 122 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-ethoxy-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 203-207° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:24])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Cl:23].Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:11][O:12][C:13](=[O:24])[CH2:14][C:15]1[C:16]([Cl:23])=[CH:17][C:18]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][C:20]=1[Cl:21]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)Cc1c(Cl)cc(N)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Cc1c(Cl)cc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 46.5 h

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (5.0 g, 31.4 mmol), (4-amino-2,6-dichloro-phenyl)-acetic acid methyl ester (7.8 g 33.3 mmol), and a 4 N solution of HCl in dioxane (12 mL, 48.0 mmol, 2.9 equiv) in MeOH/dioxane (60 mL; 1:1, v/v) is stirred for 46.5 h at 100° C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (Hexane/EtOAc, 4:1), followed by trituration in diethyl ether, provides the title compound: ES-MS: 355.9/357.9 [M+H]+; tR=5.33 min (System 1); Rf=0.25 (Hexane/EtOAc, 4:1).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH2:1])=[CH:5]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: N[C@@H](Cc1cn(C(=O)OCc2ccccc2)cn1)C(=O)O

Procedure:
reacting L-histidine with benzyl chloroformate, resulting in an N′-carbobenzoxy-L-histidine;
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:22])[O:20][CH3:21]>C(Cl)Cl.[NH4+].[Cl-]>[CH3:21][O:20][C:19]([N:9]([C:4]1[CH:3]=[C:2]([I:1])[C:7]([CH3:8])=[CH:6][N:5]=1)[C:19]([O:20][CH3:21])=[O:22])=[O:22]
Reactant: COC(=O)Cl
Reactant: Cc1cnc(N)cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(C(=O)OC)c1cc(I)c(C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 4-iodo-5-methylpyridin-2-amine (90 g, 380 mmol) in DCM (3800 mL) were added DIEA (192 mL, 930 mmol) and methyl carbonochloridate (58.8 mL, 760 mmol) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 h and was then diluted with aqueous saturated NH4Cl. The organic solvent was separated and the aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine and concentrated to give dimethyl(4-iodo-5-methylpyridin-2-yl)imidodicarbonate (110 g, 80%) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:17][C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[NH2:21][C:19](=[O:20])[C@@H:18]([NH:17][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=1)[CH3:22]
Reactant: C[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1)C(N)=O
Temperature: 50 °C
Yield: 83.3 %

Procedure:
To a solution of the tert-butyl 2,6-dichloropyrimidine-4-carboxylate (0.626 g, 2.51 mmol) in acetonitrile (10 mL) was added (S)-2-aminopropanamide hydrochloride (0.319 g, 2.56 mmol) and iPr2NEt (0.96 mL, 5.5 mmol). The mixture was heated at 50° C. for 6 h then concentrated in vacuo. The residue was chromatographed over silica gel using 50-100% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-tert-butyl 6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxylate as an off-white foam (0.628 g, 2.09 mmol, 83% yield). LC/MS: m/z=301.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[K].Cl[C:11](=[CH:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:8]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cl)=CO
Reactant: Nc1ccc(Br)cn1
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 78 °C

Procedure:
To a stirring suspension of 5-bromopyridin-2-amine (1.2 g, 7.05 mmol) and ethyl 2-chloro-3-hydroxyacrylate potassium salt (6.6 g, 28.19 mmol) (prepared in a similar manner as 22) in EtOH (100 mL) at room temperature was added sulfuric acid (751 μL, 14.10 mmol) dropwise. The reaction mixture was heated at 78° C. overnight. The reaction was cooled to room temperature and the solvent was concentrated. The residue was taken in water and the pH was adjusted between 6-8 with saturated sodium bicarbonate. The crude product was extracted with ethyl acetate. The organic was washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s). MS m/z 270.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([F:19])([F:18])[F:17])[CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([F:19])([F:18])[F:17])[CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:20]
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-N-methyl-2-nitro-5-(3-(trifluoromethyl)piperidin-1-yl)aniline (250 mg, 0.7 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) was stirred for 4 h at 35° C. under a hydrogen atmosphere (3.2 bar). The catalyst was removed by filtration and the mixture was concentrated to give the sub-title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14](B(O)O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:10]1[C:14]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[N:11]1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Reactant: Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(O)cc1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
To a solution of 4-iodophenol (75 mg, 0.34 mmol) in a mixture of water (1 mL) and 1,4-dioxane (2 mL) was added [1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]boronic acid (Preparation 7, 90 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium(II) (18.3 mg, 0.03 mmol) and cesium carbonate (240 mg, 0.74 mmol). The resulting mixture was heated at 90° C. in a Reactivial™ for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and brine (2×10 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude material was purified by flash column chromatography using the ISCO™ system (12 g column), eluting with 70:30 heptane/ethyl acetate. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a white solid (61 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[C:14]([O:24]CC)(=[O:23])[CH2:15][C:16]([C:18](OCC)=O)=O.[Na].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH3:13])[C:18]3=[CH:16][C:15]([C:14]([OH:24])=[O:23])=[N:10][N:9]3[C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: CNc1ccc(N)cc1C(=O)NN
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: Cn1c2ccc(N)cc2c(=O)n2nc(C(=O)O)cc12
Temperature: 25 °C
Yield: 59 %

Procedure:
The procedure of Sircar, et al., (J. Med. Chem., 24:735-742 (1981)) was followed. A mixture of 5-amino-2-methylaminobenzoic acid hydrazide (35.05 g, 0.194 mol) and 95% diethyl oxalacetate, sodium salt (47.33 g, 0.214 mol, Aldrich Chemical Co.) in 1 L of water was refluxed for 2 hours. The dark solution was cooled to room temperature and sodium carbonate (22.68 g, 0.214 mol) was added. The solution was refluxed for 1 hour, then allowed to cool to room temperature overnight. A small amount of solid formed. The mixture was filtered through a pad of Celite, the filtrate was cooled and acidified by dropwise addition of 10% hydrochloric acid. At a pH of about 4, a solid formed, the mixture was filtered, and the yellow-green solid was washed with water and vacuum-dried to give 29.65 g (59%) of the title compound, mp 249°-252° C., dec.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H].[OH-].[Na+]>C(O)C.Cl>[C:13]1([CH3:16])[CH:12]=[CH:11][C:10]([C@H:5]2[C@@H:4]([NH2:1])[CH2:9][CH2:8][CH2:7][NH:6]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc([C@@H]2NCCC[C@@H]2N)cc1

Procedure:
A stirred solution of 3-nitro-2-p-tolylpyridine (5.0 g) in ethanol (200 ml) and concentrated hydrochloric acid (15 ml) was hydrogenated over pre-reduced platinum oxide (1.5 g) at 23°1 atm until hydrogen uptake was complete (~3 lh). The mixture was filtered through hyflo washing the pad of hyflo with water then the filtrate was evaporated in vacuo. Recrystallisation from isopropanol water gave a cream solid. The solid was treated with 2N sodium hydroxide solution and extracted with dichloromethane (5×200 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound as an orange-brown oil which partially crystallised on standing (2.20 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(OC)ccc2C)cc1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2cc(OC)ccc2C)cc1C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 3-[4-(5-methoxy-2-methyl-phenoxy)-2-methyl-phenyl]-acrylic acid ethyl ester (1.18 g, 3.63 mmol) and palladium under carbon (10%) (0.39 g, 0.36 mmol) in ethanol (20 mL) and acetic acid (2 mL) is stirred under 1 atm of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure and purified by flash chromatography by eluting with hexane:ethyl acetate 5:1 to afford the title compound (1.02 g, 85%). Rf=0.42 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.26 (t, 3H, J=6.9 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.56 (t, 2H, J=7.3 Hz), 2.90 (t, 2H, J=7.3 Hz), 3.72 (s, 3H), 4.17 (q, 2H, J=6.9 Hz), 6.45 (d, 1H, J=2.4 Hz), 6.62 (dd, 1H, J=2.8, 8.5 Hz), 6.67 (dd, 1H, J=2.4, 8.1 Hz), 6.74 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=8.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:16]=3)[N:11]=[C:10]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:4][CH:3]=1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([O:23][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])([CH3:21])[CH3:22])[CH:16]=3)[N:11]=[C:10]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccc(C(C)(C)O[Si](C)(C)C(C)(C)C)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.00 g of 3-[(4-bromophenyl) methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone in 2.0 ml of DMF is added 0.438 g of t-butyldimethylsilyl chloride followed by 0.4 g of imidazole. The reaction mixture is stirred at room temperature for 18 hours and then diluted with water and extracted with ether. The combined ether extracts are dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (1:5) to provide the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 4.7 %

Procedure:
To a solution of piperidine-4-carboxylic acid methyl ester (10 g, 70 mmol, 1 eq.) and Et3N (19.5 mL, 140 mmol, 2 eq.) in 150 mL of THF was added bromo-acetic acid tert-butyl ester (13.6 g, 70 mmol, 1 eq.) in 150 mL of THF. The resulting mixture was heated at reflux overnight. After 18 h, the resulting mixture was concentrated and purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH) to give the title compound as a yellow oil (0.84 g). Exact mass calculated for C13H24N1O4 258.2. MS (ESI) m/z 258.6 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-fluorobenzoic acid (3.0 g, 21.4 mmol) in methanol (71 mL) at 0° C. is treated dropwise with thionyl chloride (3.1 mL, 42.8 mmol). The solution is stirred for 15 min at 0° C., 2.5 h at room temperature, and 2 h at 50° C. The reaction is concentrated in vacuo and the residue dissolved in ethyl acetate (150 mL). The organic solution is washed with saturated aqueous sodium bicarbonate (2×100 mL), brine (100 mL), and dried over sodium sulfate. The solution is decanted and concentrated to yield the title compound, 2.61 g (79%), as a clear, colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH:7]=[CH2:8])[C:3]#[N:4].ClC1C=CC=C(C(OO)=[O:17])C=1.Cl>>[C:3]([CH:2]1[CH2:5][CH2:6][CH:7]([CH2:8][OH:17])[O:1]1)#[N:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCC(O)C#N
Agent: Cl
Product: N#CC1CCC(CO)O1

Procedure:
The compounds of formula I wherein n is 0 are prepared by epoxidation-cyclization of novel cyanohydrins, i.e., 2-hydroxy-5-hexenenitrile or 2,5-dialkyl-2-hydroxy-5-hexenenitrile, of the formula ##STR3## wherein R1 and R2 are as defined for formula I, e.g., by epoxidation with m-chloroperbenzoic acid followed by treatment of the resulting epoxy cyanohydrin with hydrochloric acid to yield the novel 2-cyanotetrahydrofuran-5-methanol of the formula ##STR4## wherein R1 and R2 are as defined for formula I, and subsequent etherification e.g., with RCH2Cl. The 2-hydroxy-5-hexenenitriles are prepared by treating the corresponding unsaturated ketone with, acetic anhydride and potassium cyanide by the general procedure of R. Franks, R. Berry, and O. Shotwell, J. Am. Chem. Soc., 71, 3889 (1949). The unsaturated ketones are prepared by (1) reaction of an aldehyde with an unsaturated Grignard reagent followed by selective oxidation of the hydroxy group to a ketone, or (2) reaction of an allyl chloride with an alkanedione as described, for example, in F. Barbot, D. Mesnard, and L. Miginiac, Organic Preparations and Procedures International 10, 261 (1978).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl.CN(C1C=CN=CC=1)C>[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1)=[O:38])([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3)cc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647 μmol) in dichloromethane (15 mL) was added triethylamine (190 μL, 1.43 mmol) and 3-nitrobenzoyl chloride (264 mg, 1.43 mmol). The solution was stirred at room temperature for 96 hours, and DMAP (7.0 mg, 57 μmol) and 3-nitrobenzoyl chloride (120 mg, 647 μmol) was added, and the stirring continued at room temperature for 72 hours. Triethylamine (90 μL, 639 μmol), 3-nitrobenzoyl chloride (120 mg, 647 μmol) and DMAP (7.0 mg, 57 μmol) were then added. The solution was stirred at room temperature for 72 hours, evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3), to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.52 min, MH+ 459].
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[I:21]Cl.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[I:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.40 g, 1.44 mmol) in glacial acetic acid (4 ml) at room temperature was added a solution of iodine monochloride (0.28 g, 1.76 mmol) in glacial acetic acid (4 ml). Water (6 ml) was also added, and the reaction was stirred for 16 hours, after which another portion of iodine monochloride (0.4 g, 2.47 mmol) in glacial acetic acid (4 ml) was added. The reaction mixture was stirred for an additional hour at room temperature. The acidic mixture was basified with saturated NaHCO3 solution and extracted into dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (5% CH3OH in CH2CL2 with 0.1% NH4OH) to give 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as beige colored solid (0.536 g, 92%). M+H 400.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11]COC)=[C:6]([O:15][CH3:16])[CH:5]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COCOc1c(C)cc(C(=O)OC)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 3-methoxy-4-methoxymethoxy-5-methylbenzoic acid methyl ester (650 mg) in THF (5 mL) was added 6N-hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (365 mg).