Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10]1([N:16]=[C:17]=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: S=C=NC1CCCCC1
Product: S=C(Nc1ccc(Cl)c(Cl)c1)NC1CCCCC1

Procedure:
A mixture of 16.2 gm. (0.1 mole) of 3,4-dichloroaniline and 14.1 gm. (0.1 mole) of cyclohexyl isothiocyanate is heated together on the steam bath for four hours. The solid is crystallized from ethanol-water; 18 gm. (59%), m.p. 159°-162°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])(=[O:3])[CH3:2].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>N1C=CC=CC=1>[CH:12]1([C:18]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)c1cccc(C)c1O
Reactant: O=C(Cl)C1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1cccc(C)c1OC(=O)C1CCCCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Acetyl-6-methylphenol (3.0 g) was dissolved in pyridine (15 ml) and to the solution was added dropwise cyclohexanecarbonyl chloride (3.08 g) with stirring at room temperature. After stirring for 4 hours, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with water, diluted hydrochloric acid and then water and dried (MgSO4). The solvent was distilled off under reduced pressure to obtain the title compound (5.2 g) as oil in a quantitative yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20]Br)[CH:11]=1.Cl>CN(C=O)C>[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20][O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1COCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (0.5 g of 60% dispersion in oil) in DMF (10 ml) was added trifluoroethanol (0.92 ml) and the mixture stirred for 30 minutes. After this time the mixture was cooled to 0° C. and a solution of methyl 4bromo-2-bromomethylbenzoate (3.52 g) in DMF was added, and the resultant mixture stirred at room temperature for 1 hour. 0.5M HCl was added and the mixture extracted with ether. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to yield methyl 4-bromo-2-trifluoroethoxymethylbenzoate (3.89 g) as a yellow oil, NMR (CDCl3) 3.9(s,3H), 4.0(q,2H), 5.1(s,2H), 7.5(dd,1H), 7.85(d,1H), 7.9(s,1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:13]([CH3:12])[CH:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)[CH:3]=[CH:2]1
Reactant: CNC1CCCc2cccnc21
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1cccc2cc[nH]c12)C1CCCc2cccnc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of indole-7-carboxaldehyde (0.48 g, 3.36 mmol) in 1,2-dichloroethane (10 mL) was treated with N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.60 g, 3.70 mmol), sodium triacetoxyborohydride (1.07 g, 5.05 mmol) and a catalytic amount of acetic acid (2 drops). The resulting mixture was warmed to 65° C. and stirred for 2 h. The reaction mixture was cooled to room temperature and a saturated aqueous solution of sodium bicarbonate was added. The product was extracted with dichloromethane. The combined organic layers were dried over potassium carbonate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.75 g (76% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 12.69 (bs, 1H), 8.61 (d, J=4.4 Hz, 1H), 7.85-7.81 (m, 1H), 7.68-7.65 (m, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.44-7.38 (m, 2H), 7.12 (dd, J=4.4, 7.2 Hz, 1H), 7.03-6.96 (m, 2H), 6.55 (t, J=2.0 Hz, 1H), 4.22-4.17 (m, 1H), 4.00 (d, J=13.4 Hz, 1H), 3.84 (t, J=6.8 Hz, 1H), 3.73 (d, J=13.4 Hz, 1H), 3.42 (t, J=6.8 Hz, 1H), 2.92-2.72 (m, 2H), 2.28 (s, 3H), 2.14-2.04 (m, 1H), 2.00-1.88 (m, 1H), 1.85-1.70 (m, 1H); ESI+ MS: m/z (rel intensity) 292.1 (90, [M+H]+).
Reaction SMILES: CNC1N=C[C:10]2[CH2:9][CH:8]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:7][CH2:6][C:5]=2N=1.C(N(C1CCCCC1=[O:33])CCC)CC.CN(C)C.CN(C(N(C)C)N(C)C)C.Cl.CNC(N)=N>>[CH2:14]([N:13]([CH2:17][CH2:18][CH3:19])[CH:8]1[CH2:7][CH2:6][C:5](=[O:33])[CH2:10][CH2:9]1)[CH2:15][CH3:16]
Reactant: CCCN(CCC)C1CCCCC1=O
Reactant: CCCN(CCC)C1CCc2nc(NC)ncc2C1
Agent: CN(C)C
Agent: CN(C)C(N(C)C)N(C)C
Agent: CNC(=N)N
Product: CCCN(CCC)C1CCC(=O)CC1

Procedure:
Following the above procedure (±)-2-methylamino-6-di-n-propylamino-5,6,7,8-tetrahydroquinazoline was prepared from di-n-propyaminocyclohexanone by reaction with tris-(dimethylamino methane and N-methylguanidine hydrochloride tris-(dimethylamino)methane. Five hundred mg of starting 4-di-n-propylaminocyclohexanone gave 306 mg of a brown oil comprising the free base which was converted to the dihydrochloride salt and purified by dissolution in DMF and the DMF solution added to ether. Crystalline (±)-2-methylamino-6-di-n-propylamino-5,6,7,8-tetrahydroquinazoline dihydrochloride thus prepared was obtained as a methanol solvate after recrystallization from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[CH:3]=1.[CH2:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C@@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:29]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([N:35]3[CH2:34][CH2:33][C:32]4([CH2:28][N:29]([C:43]([O:45][CH2:46][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)=[O:44])[C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31]4)[CH2:37][CH2:36]3)[CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(C)n2)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(C)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of (R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine (21 g) in dioxane (200 ml) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (15 g) and Na2CO3 (14 g). The reaction was heated to 90° C. for 48 h, then cooled to RT, filtered, and concentrated in vacuo. Purification of the residue on normal phase column chromatography on silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.COCCOC>[C:16]1([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:23]4[O:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)=[CH:32][CH:33]=3)=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(-c2nc3ccccc3o2)cc1
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-c4nc5ccccc5o4)cc3)c3ccccc23)cc1
Yield: 81.9 %

Procedure:
In a 50 mL three-neck flask, 1.0 g (3.0 mmol) of 9-bromo-10-phenylanthracene, 0.72 g (3.0 mmol) of 4-(benzoxazol-2-yl)phenylboronic acid, 0.10 g (0.32 mmol) of tri(ortho-tolyl)phosphine, 20 mL of ethylene glycol dimethyl ether (DME), and 3.0 mL (6.0 mmol) of a 2.0 M potassium carbonate solution were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 14 mg (0.062 mmol) of palladium(II) acetate was added, and the mixture was stirred under nitrogen stream at 80° C. for 6 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give an oily substance. The oily substance was purified by silica gel column chromatography (toluene:hexane=2:1) and recrystallized with toluene/methanol, giving 1.1 g of the target pale yellow powder in a yield of 81%.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:25])=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:8]=1)=[CH2:2].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:22][C:6]1[CH:5]=[C:4]([F:25])[C:3]([CH2:1][CH3:2])=[CH:8][C:7]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:14][CH2:15]1
Reactant: C=Cc1cc(NC2CCN(C3CCOCC3)CC2)c([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCc1cc(NC2CCN(C3CCOCC3)CC2)c(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of N-(5-ethenyl-4-fluoro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D79, 300 mg, 0.86 mmol) and ammonium formate (536 mg, 8.6 mmol) in methanol (50 ml), under argon, was treated with 10% Pd—C, then stirred overnight at room temperature. The mixture was filtered through a celite pad and the solvent evaporated under vacuum. The residue was dissolved in dichloromethane Na2SO4 and concentrated under vacuum to leave 230 mg of title compound as a brown oil (83% yield).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.S(OC)(O[CH3:16])(=O)=O>CO>[CH3:16][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc2ccccn2n1
Agent: [Na]
Solvent: CO
Product: COc1cc2ccccn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
Sodium (92 mg) was dissolved in 5 ml of absolute methyl alcohol with moderate cooling. To this solution 2-hydroxypyrazolo[1,5-a]pyridine (500 mg) was added and then dimethyl sulfate (500 mg) was added. The mixture was stirred for 30 min. at room temperature and refluxed for 8 hr. The reaction mixture was concentrated to remove methyl alcohol, and water was added to the residue. The solution was extracted with n-hexane, and the n-hexane solution was dried over sodium sulfate. The dried n-hexane solution was concentrated and the residue was distilled to give 280 mg of oily product under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C(S([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:32])=[O:31])=[CH:26][N:25]=1)(=O)=O)CCCCC.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:31])=[O:32])=[CH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: CCCCCCS(=O)(=O)c1ccc(S(=O)(=O)CCCCCC)nc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To 4.33 g of 4-bromophenol dissolved in a 22 ml THF/22 ml DMSO mixture was added 3.1 g of t-BuOK and then 9.39 g of 2,5-bis(n-hexylsulfonyl)pyridine, and the resulting mixture heated at 59° C. for 1 hr. The reaction mixture was cooled to room temperature and then added to approximately 4 to 5 volumes of water. The yellow precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the product, 2-(4-bromophenoxy)-5-(n-hexylsulfonyl)pyridine, (52% yield), as white shiny prisms, m.p. 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:23])=[C:17]([CH:22]=1)[C:18]([O:20]C)=[O:19])=[N:9][NH:8][C:7]2=[O:24].Cl>[OH-].[K+]>[F:23][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:7](=[O:24])[NH:8][N:9]=2)=[CH:22][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1cc(Oc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(Oc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)-2-fluorobenzoate (5e) (1 g, 2.87 mmol) was dissolved in 1M potassium hydroxide solution, stirred for two hours at room temperature, and then concentrated hydrochloric acid was added dropwise to adjust the reaction mixture pH=3, stirred for two hours at room temperature, and filtrated to give 2-fluoro-5-(8-chloro-4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (5f), 900 mg white solid (yield 90%). ESI-MS m/z: calculated for 334.02. found 357.10 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[C:12]=3[CH:31]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([OH:53])C.O>C(OCC)(=O)C.C(O[Pd]OC(=O)C)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH2:28])=[O:53])=[CH:29][CH:30]=4)[C:12]=3[CH:31]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C#N)cc1)CC2C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C(N)=O)cc1)CC2C
Temperature: 60 °C
Yield: 50.8 %

Procedure:
A mixture of 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (150 mg, 0.37 mmol), triphenylphosphine (194 mg, 0.74 mmol) and diacetoxypalladium (8.3 mg, 0.037 mmol) in mixed solution of ethanol (6 mL) and water (2 mL) was heated at 60° C. for 30 minutes under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL*3). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to afford 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzamide as a white solid (80 mg, 50.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[OH-].[K+].Cl>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(-c2c(F)cccc2F)oc1-c1cccs1
Temperature: 55 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylate (0.096 g, 0.29 mmol) in MeOH (6 mL) was added 1M potassium hydroxide solution (8 mL, 8.0 mmol) and the resulting mixture stirred at 55° C. overnight. The reaction was cooled to room temperature, acidified with 4N HCl and extracted with DCM. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylic acid (0.078 g, 0.25 mmol, 89%) as an off white solid which was used without further purification. LCMS (1) Rt: 1.41 min; m/z (ES+) 308.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: OC(c1cccc(F)c1)c1cccc(Cl)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1cccc(F)c1)c1cccc(Cl)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-chloro-phenyl)-(3-fluoro-phenyl)-methanol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[CH3:13]O>C(O)=O.[Fe]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=2[N:9]=[CH:13]1
Reactant: CNc1cc(O)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Fe]
Solvent: O=CO
Product: Cn1cnc2ccc(O)cc21
Temperature: 100 °C

Procedure:
Fe Powder (4.33 g, 77.4 mmol) was added to a solution of 3-(methylamino)-4-nitrophenol (1.3 g, 7.74 mmol) in HCOOH (30 mL) and the mixture heated to 100° C. for 16 h. After cooling to room temperature, MeOH (250 mL) was added to mixture and filtered over a pad of Celite. The filtrate was collected, concentrated and the residue purified by column chromatography to give the crude desired product (1.2 g) and was used directly in the next step. LCMS (m/z): 149.06 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([S:8]([C:11]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[S:17]1[C:13]2[CH:12]=[C:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:20])=[O:3])(=[O:10])=[O:9])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2ncsc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To a solution of 778 mg (2.48 mmol) of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid ethyl ester in THF/water (1/1, 24 mL) are added 208 mg (4.97 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 5 h. The organic solvent is removed under reduced pressure. The basic aqueous layer is washed with diethyl ether (10 mL), then cooled in an ice bath and acidified with 6M aqueous HCl solution to pH 2. The acidic aqueous layer is extracted with ethyl acetate (3×15 mL). The combined organic extracts are dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 686 mg of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid as a pale yellow solid. Yield: 66%; ES-MS: m/z 569 [2M−H]; 1H NMR (250 MHz, DMSO-d6) δ ppm 1.51 (6H, s), 7.91 (1H, dd, J=8.68, 1.98 Hz), 8.30 (1H, d, J=8.68 Hz), 8.79 (1H, d, J=1.83 Hz), 9.70 (1H, s);
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:29])[CH:9]([N:14](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:6])[O:4][CH3:5]>CO.[C].[Pd]>[CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:29])[CH:9]([NH2:14])[CH2:10][CH:11]([CH3:12])[CH3:13])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(O)C(CC(C)C)N(Cc1ccccc1)Cc1ccccc1)OC
Agent: [Pd]
Solvent: CO
Product: COP(=O)(CC(O)C(N)CC(C)C)OC
Temperature: 39.5 °C
Reaction time: 12 h

Procedure:
Reaction 4: A diastereomeric mixture of the crude (3-dibenzylamino-2-hydroxy-5-methyl-hexyl)-phosphonic acid dimethyl ester, compound 4, obtained in reaction 3, was treated with palladium-carbon (2.0% wt) as the catalyst in methanol (40 mL). The mixture reaction was stirred for 12 h under a hydrogen gas atmosphere at 37-42° C., and after this period of time, the mixture was filtered through a pad of Celite, and the solvents were removed under reduced pressure to leave (3-amino-2-hydroxy-5-methyl-hexyl)-phosphonic acid dimethyl ester, compound 5, as a crude oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([C:12]([O:15][C:16]([C:19](OC)=[O:20])([F:18])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].[NH:23]([CH2:25][C:26]([OH:28])=[O:27])[CH3:24].[OH-].[K+:30]>C(O)(C)C>[C:1]([O:5][C:6]([C:9]([C:12]([O:15][C:16]([C:19]([N:23]([CH2:25][C:26]([O-:28])=[O:27])[CH3:24])=[O:20])([F:18])[F:17])([F:14])[F:13])([F:10])[F:11])([F:7])[F:8])([F:3])([F:4])[F:2].[K+:30]
Reactant: COC(=O)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: CNCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CN(CC(=O)[O-])C(=O)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 60 °C

Procedure:
In a three-necked 100-mL flask fitted with a stirrer, thermometer, and condenser were placed 18 grams (0.05 mole) of CF3OCF2CF2CF2OCF2C(O)OCH3, prepared in Example 1, Part A, and dry sarcosine (4.5 grams, 0.05 mole). The reaction mixture was heated under nitrogen at 60° C. using a heating mantle for 48 hours and then cooled to about 30° C. Isopropanol (23 grams) and potassium hydroxide (2.8 grams, 0.05 mole) were added to provide a solution of CF3OCF2CF2CF2OCF2C(O)N(CH3)CH2C(O)O—K+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:22]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 82.3 %

Procedure:
0.5 g (0.00216 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene, treated with 0.313 ml (0.0027 mol) of benzoyl chloride and boiled at reflux for 6 hrs. The suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3) as the eluent. 0.525 g (82%) of 1-benzyl-piperidin-4-yl benzoate was obtained as yellowish oil.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:13]([O:11][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([F:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
A mixture of 4-fluoro-2-methyl-5-nitrophenol (4.69 g, 27 mmol), (prepared as described for the starting material in Example 8), benzyl bromide (3.59 ml, 30 mmol) and potassium carbonate (7.58 g, 55 mmol) in DMF (100 ml) was heated at 80° C. for 4 hours. The reaction mixture was allowed to cool and diluted with water and stirred for 15 minutes. The precipitated product was collected by filtration, washed with water and dried to give 5-benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (6.4 g, 89%).