Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[CH2:12]1[CH:17]([NH2:18])[CH2:16][CH2:15][CH:14]([OH:19])[CH2:13]1.O>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:16]1[CH:17]([N:18]2[C:3](=[O:10])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:11])[CH2:12][CH2:13][CH:14]([OH:19])[CH2:15]1
Reactant: NC1CCC(O)CC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirring solution of isobenzofuran-1,3-dione (90 g, 0.6 mol) and (1r,4r)-4-aminocyclohexanol (70 g, 0.6 mol) in toluene (250 mL) and DMF (250 mL) was stirred at 130° C. overnight. The reaction was cooled to room temperature, water was added and the product was filtered, washed with water and dried under vacuum to give the desired product as a white solid, which was used for the next step without further purification (119 g, 0.48 mol, yield: 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.84-7.79 (m, 2H), 7.72-7.68 (m, 2H), 4.18-4.10 (m, 1H), 3.80-3.73 (m, 1H), 2.40-2.29 (qd, J1=3.4 Hz, J2=130 Hz, 2H), 2.12-2.09 (dd, J=6.2 Hz, 2H), 1.78-1.74 (dd, J=6.6 Hz, 2H), 1.49-1.39 (qd, J1=3.3 Hz, J2=125 Hz, 2H).
Reaction SMILES: C(O)(=O)C.[NH3:5].[C:6]([OH:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]/[CH:15]=[CH:14]\[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:25])=[O:24].[NH3:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Separately, a 200-ml capacity beaker was charged with 1.44 g of granular acetic acid, 2.08 ml of aqueous ammonia having a concentration of 0.736 mole/l and 50 ml of water, and the mixture was heated at 90° C. under agitation on by a glass rod to completely emulsify stearic acid and form an ammonia soap suspension.
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].CS(O)(=O)=O.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Yield: 77.6 %

Procedure:
Cycle 1: A pressure reactor was charged with N-acetyliminodiacetic acid monohydrate (19.3 g), water (16.6 g), phosphorous acid (9.8 g) and methanesulfonic acid (15 g). The mixture was heated to 120° C. and 42% formaldehyde (6.9 mL) was added drop wise over a 3/4 hour period. After another 3/4 hour at 120° C. the mixture was cooled. The mixture was filtered and the solid was washed with water to give 17.6 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7](C)[CH:6](NC=O)[N:5]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15](CC)[CH2:16]C)C.O=P(Cl)(Cl)Cl>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:16][N+:15]#[C-:13])[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCN(CC)CC
Reactant: CN1OC(C2CC2)=NC1NC=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCl3 (60 mmol) at 0° C. The mixture was then left for 30 minutes with stirring at 0° C., whereafter a solution of 60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorbtion band at 2160 cm-1.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:14][CH:13]=1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of known tert-butyl D-(-)-lactate (160 mg), 4-chlorophenol (108 μl) and triphenylphosphine (287 mg) in dry tetrahydrofuran (6 ml) on an ice bath, diethylazodicarboxylate (173 μl) was added dropwise over about 5 minutes. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was then evaporated with a rotary evaporator (water bath temperature 25° C.). The residue thus obtained was purified by silica gel chromatography [silica gel 30 g, eluant:ethyl acetate-hexane (1:10)] to give tert-butyl (2S)-(-)-2-(4'-chlorophenoxy)-propionate (173 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.CCOCC>C(O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][CH:30]=1)[NH:31][C:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)=[C:16]2[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CCCC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Triethylamine (5 mL, 3.6 g, 36 mmol) was added dropwise to a stirred suspension of 4-chloro-δ-oxobenzenepentanoic acid (7.91 g, 35 mmol) and (4-chlorophenyl)hydrazine hydrochloride (6.29 g, 35 mmol) in ethanol (54 mL) and the mixture was stirred at room temperature for 3 h. Ether (500 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (120 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (250 mL) was added and the mixture was extracted with ethyl acetate (300 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from EtOAc/isohexane to give the title compound (7.6 g, 65%). 1H NMR (250 MHz, DMSO-d6) δ 12.01 (1H, br s), 11.36 (1H, s), 7.56-7.47 (5H, m), 7.26 (1H, d, J 8.5 Hz), 7.01 (1H, dd, J 8.5, 2.0 Hz), 2.96 (2H, t, 8.0 Hz), and 2.43 (2H, t, 8.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:29]=[CH:28][C:26]([NH:27][C:14]([C@@H:9]3[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Reference 5, but substituting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid and 4-(4-fluorophenoxy)aniline, gave (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>C(#N)C>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 0.164 g of 4-((S)-5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl-morpholin-3-one hydrochloride (MW=327.77; 1 eq.) in 7 mL of acetonitrile were added 0.101 g of triethylamine (MW=101.12; 2.0 eq.). After stirring for 10 min at room temperature, the suspension was cooled to 0° C. and then 0.091 g of 5-chloro-thiophene-2-carbonyl chloride (MW=181.04; 1.0 eq.) were added. After stirring for 80 min at 0° C., the resulting slurry was filtered and the cake washed with 5 mL of acetonitrile and 5 mL of water. After drying in vacuo at 30° C., 0.180 g of the title compound in the form of a white crystalline powder was isolated. Yield=82.7%.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (R)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of THF was cooled to −20° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and then 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added thereto, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 68% ((2S,3R):(2R,3R)=92:8).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][OH:13].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:11](=[O:14])[CH2:12][O:13][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[CH3:17]
Reactant: CCOC(=O)CO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
32 ml (256 mmol) of phenyl chloroformate are added slowly at room temperature to a solution of 25 g (240 mmol) of ethyl glycolate and 55 ml (315 mmol) of diisopropylethylamine in 500 ml of toluene. Stirring is continued at room temperature for 2 hours. The salt formed is separated out and the filtrate is concentrated under reduced pressure. 53.7 g of oily product are obtained, and are used without further purification in the following step.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][N+:23]([O-:25])=[O:24]>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:22]2[N+:23]([O-:25])=[O:24])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CBr
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a mixture of N-benzylmaleimide (7.40 g) and K2CO3 (5.50 g) in 500 mL of CH3CN was added bromonitromethane (5.60 g) dropwise. The reaction mixture was stirred for 24 h at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 4:1 (v/v) PE/EA) to give the title compound as a pale yellow solid (3.90 g, 40.00%), HPLC: 93.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 247.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 3.34 (d, J=1.8 Hz, 2H), 4.51 (t, J=1.6 Hz, 1H), 4.53 (s, 2H), 7.22-7.42 (m, 5H) ppm.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>C(Cl)Cl>[S:26]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCO
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
A cold (0°) solution of 23.3 g of tetraethylene glycol and 19 g of pyridine in 100 ml of methylene chloride, is treated portionwise while stirring vigorously with a total of 19 g of p-toluenesulphonyl chloride. After completion of the addition the mixture is stirred at room temperature for a further 5 hours. 200 ml of methylene chloride and 100 ml of water are then added thereto and the organic phase is separated. The organic phase is washed successively with 100 ml of 2N hydrochloric acid, 100 ml of 5% sodium hydrogen carbonate solution and 100 ml of water and dried over sodium sulphate. The solvent is removed in a vacuum and the residue is chromatographed over 400 g of silica gel with methylene chloride-ethyl acetate-methanol (5:4:1) as the eluent. In addition to small amounts of tetraethylene glycol ditosylate there are isolated 17 g of tetraethylene glycol monotosylate as a colourless liquid. RF (silica gel/methylene chloride-ethyl acetate-methanol 5:4:1): 0.6.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)=O)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.B.C1COCC1.O.[OH-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCCC(c2ccc3c(c2)OCO3)C1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OC[C@H](CN1CCCC(c3ccc4c(c3)OCO4)C1)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 83.8 %

Procedure:
(3-Benzo[1,3]dioxol-5-ylpiperidin-1-yl-(R)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethanone (285 mg, 0.77 mmol) was dissolved in dry DMF (2.5 ml) and 1 M BH3THF (3.10 ml, 3.10 mmol) was slowly added under a nitrogen atmosphere. The reaction mixture was stirred for 4.5 h at RT and then cooled to 0° C. Water was slowly added and the mixture basified with 2.5 M NaOH and extracted three times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The crude product was dissolved in methanol (25 ml) and 5 M HCl (1.5 ml) was slowly added. The mixture was stirred for 1 h at RT and then at 60° C. for 2 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc and washed twice with 1 M Na2CO3 and water. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness to give 228 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]([CH2:2][C:3]([CH3:5])=[CH2:4])[C:17](=[O:19])[CH3:18]
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
At 25° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added dropwise to a solution of N-(2-bromo-5-nitropheny)acetamide (3.6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 mL). The reaction mixture was stirred at 25° C. overnight. The reaction mixture was then filtered and the filtrate was treated with sat. Na2CO3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to provide N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide as a golden solid (3.1 g, 85%). ESI-MS 313 m/z (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:15]#[CH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.7 %

Procedure:
To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargyl bromide, 1.5 mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4×40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH:34](=O)[CH:35]([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:34][CH:35]([CH3:37])[CH2:36][NH:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CNc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichlorothane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)3 (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N2O2: 483.1883 [M+H]+, found: 483.1932. 1H NMR (CDCl3) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6H).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 28 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A solution of 2-[(6-methoxy-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester (260.0 g, 1.365 mol, 1.0 eq) in diphenyl ether (500 mL) is heated to reflux. While the ethanol formed is removed by azeotropic distillation the reflux temperature reached 245° C. The reaction mixture is kept at 245° C. for 3 hours, then it is cooled to 28° C., a brown solid precipitated and is collected by filtration and washed with hexane (500 mL). The solid is dried under vacuum to afford 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a brown powder (74.2 g, 32% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([F:13])[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C2CC2)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
4-Cyclopropyl-2-fluoro-1-nitrobenzene (prepared as described in General Procedure 1.2C) (2.2 g, 12.14 mmol) was dissolved in 7 mL of an ethanol:THF:water 3:3:1 (v/v) mixture. To this was added ammonium chloride (1.02 g, 19.07 mmol) followed by iron powder (3.50 g, 62.7 mmol). The resulting mixture was heated in a 90° C. oil bath under a nitrogen atmosphere with rapid stirring for one hour. The reaction mixture was vacuum filtered through a sand and diatomaceous earth plug. The filtrate was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to provide an orange oil (1.90 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.SCC[C:11]([OH:13])=[O:12].[CH3:14]C1C=CC2C(=CC=C(C)C=2)C=1.CC(C1C=CC(O)=CC=1)=O>C(#N)C>[CH3:14][O:13][C:11]([CH:5]1[CH2:4][CH2:3][O:7][CH2:1][CH2:6]1)=[O:12]
Reactant: Oc1ccccc1
Reactant: Cc1ccc2cc(C)ccc2c1
Reactant: O=C(O)CCS
Agent: CC(=O)c1ccc(O)cc1
Solvent: CC#N
Product: COC(=O)C1CCOCC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 94 g (1.0 mol) of phenol, 5.31 g (0.0500 mol) of 3 mercaptopropionic acid, 10 g of Lewatit BG ion exchange resin and 1.0 g of 2.6-dimethylnaphthalene (internal standard for liquid chromatography analysis) was heated under a static nitrogen atmosphere to 65° C. in a round bottom flask equipped with a condenser, an internal thermometer and a mechanical stirrer. To this mixture was added 11.35 g (0.08336 mol) of 4-hydroxyacetophenone. The mixture was stirred with heating while samples were obtained periodically. Three to four drops of the reaction solution was added to 10 mL of acetonitrile for liquid chromatography analyses. After about 8 hrs., the reaction mixture was separated from the ion exchange resin by filtration and the THPE was isolated by the addition of methylene chloride (about 400 mL). The results monitoring reaction completion versus Comparative Example 1 are found in Table I. The THPE was washed with additional methylene chloride and dried. To determine the level of color bodies, 0.2 grams of THPE was dissolved in 10 mL of methanol and the UV absorption was measured at 422, 500, and 600 nm. The results measured at different wavelengths can be found in Table II.