Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:20])=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)C1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)C1CCCCC1)C(=O)COc1ccc(F)cc1Br
Yield: 74.6 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (249 mg, 1.0 mmol) and cyclohexane carboxylic acid N′-isopropyl-hydrazide (221 mg, 1.2 mmol) in DMF (10 ml) was treated with diisopropylethyl amine (0.44 mL, 2.5 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 700 mg, 1.5 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (310 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([OH:22])=O)=[CH:14]3)[CH2:6][CH2:5]1.[N:25]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:34][O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:23])([F:1])[F:24])[CH2:9][CH2:8]2)=[CH:19][CH:18]=3)=[O:22])[CH2:27][CH2:26]1)=[O:32]
Reactant: COC(=O)N1CCNCC1
Reactant: O=C(O)c1cc2cc(OC3CCN(CC(F)(F)F)CC3)ccc2[nH]1
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(CC(F)(F)F)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was prepared in analogy to example 40b), from 5-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yloxy]-1H-indole-2-carboxylic acid and methyl piperazine-1-carboxylate. Light yellow solid. MS (m/z): 469.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14]CC1C=CC=CC=1)[CH2:9]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([OH:14])[CH2:9]2
Reactant: [H][H]
Reactant: O=C1c2c(cccc2[N+](=O)[O-])CN1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1C(=O)N(O)C2
Yield: 609.2 %

Procedure:
To a solution of 7-nitro-2-benzyloxy-2,3-dihydro-1H-isoindol-1-one (Compound 186B, 2.3 g, 1.2 mmol) in methanol (30 mL) in a Parr hydrogenation flask was added 200 mg of 5% Pd/C. The mixture was hydrogenated under 40 psi hydrogen pressure at room temperature overnight. The reaction mixture was filtered through a glass filter paper and the filtrate was concentrated to afford 1.2 g of the pure product (90%). 1H NMR (CDCl3, 600 MHz): δ=4.57 (s, 2H), 5.04 (br, 2H), 6.57 (d, J=7.8 Hz, 1H) 6.65 (d, J=7.5 Hz, 1H), 7.25 (dd, J=7.5, 7.8 Hz, 1H), 10.2 (s, br, 1H).
Reaction SMILES: C([O:4][CH:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:6]([NH:8][C@H:9]([C@@H:12]([C@@H:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[OH:15])[OH:13])[CH2:10][OH:11])=[O:7])(=O)C.[OH-].[Na+]>C(O)C>[OH:4][CH:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:6]([NH:8][C@H:9]([C@@H:12]([C@@H:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[OH:15])[OH:13])[CH2:10][OH:11])=[O:7]
Reactant: CCCCCCCCCCCCCCCCC(OC(C)=O)C(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)C(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Reaction time: 1.5 h

Procedure:
A mixture of 35.62 grams (55.4 mmoles) of N-(2-acetoxy-octadecanoyl) phytosphingosine, 250 ml of 96% ethanol and 20 ml of 6.18M sodium hydroxide is stirred for 1.5 hours. An additional 5 ml of 6.18M sodium hydroxide is added and the stirring continued for 1 hour.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][CH2:21][S:22][CH3:23]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:20][CH2:21][S:22][CH3:23])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCSC)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 34.3 %

Procedure:
Step A To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (13 mL) were added K2CO3 (0.8 g, 5.9 mmol) and 1-Chloro-2-methylsulfanyl-ethane (Aldrich)(0.65 g, 5.9 mmol) sequentially. The reaction mixture was heated at 70° C. for 2 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-40% EtOAc in hexanes) to give 2-methoxy-4-(2-methylsulfanyl-ethoxy)-1-nitro-benzene as a white solid (0.25 g, 35%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13]C)=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C[C@@H](C(=O)c1cc(F)c(F)cc1F)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a solution of 3 g (S)-methyl 3-(dibenzylamino)-4-oxo-4-(2,4,5-trifluorophenyl)butanoate in 100 ml ethanol, was added 0.5 g of 10% Pd/C under an atmosphere of nitrogen. The atmosphere of nitrogen was replace with an atmosphere of hydrogen, and the reaction was carried out at 25° C. for 5 h. After completion of the reaction, the reaction mixture was filtered through diatomite. The filtrate was concentrated, and the pH was adjusted to 5˜6 by addition of 10% hydrochloric acid. The aqueous layer was washed with ethyl acetate, and then concentrated to obtain 1.47 g (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid as white solid, with a yield of 93.2%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([CH:19]=O)[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>CO.ClCCl>[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[C:7]([CH2:19][NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: COc1cccc(CN)c1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=O)cc3c21
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(CNCc2ccc3nc(N)c4ncn(CC(C)C)c4c3c2)c1
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
4-Amino-1-isobutyl-1H-imidazo[4,5-c]quinoline-8-carbaldehyde (237 mg, 0.66 mmol) and 3-methoxybenzylamine (100 mg, 1.3 mmol) were combined in methanol (25 mL) and dichloromethane (1 mL). The solution was purged with nitrogen gas and a 1M solution of sodium cyanoborohydride in THF (2 mL) was added. The reaction was stirred for 30 minutes. Additional sodium cyanoborohydride in THF (1M, 1 mL) was added and the reaction was stirred for an additional 15 minutes. Aqueous sodium carbonate (1%, 0.25 mL) was added and the reaction was stirred for 7 days. The solvent was removed under reduced pressure and approximately equal portions of chloroform and water were added. The fractions were separated and the organic fraction was sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-20% CMA). Recrystallization from acetonitrile provided 25 mg of 1-isobutyl-8-{[(3-methoxybenzyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 125-126° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=[O:14].S(Cl)(Cl)=O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:14][C:13]([C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1])=[O:15])[CH3:21]
Reactant: CCO
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (10.0 g, 0.05 mol) and thionyl chloride (18.0 ml, 0.25 mol) in ethanol (100 ml) was refluxed for 5 h before it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution, and brine, before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (10.24 g): 1H NMR (CDCl3, 200 MHz): δ=7.61 (m, 2H), 7.43 (m, 3H), 4.25 (q, J=7.0 Hz, 2H), 2.73 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]2[N:7]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester in the form of a yellow liquid (73.4 g, 185.8 mmol) and a solution of potassium hydroxide (20.9 g, 371.6 mmol) in distilled water (400.0 mL) were added to methanol (400.0 mL). The reaction mixture was stirred at 70° C. for 4 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 70.0 g of the titled compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Na]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: [Na]c1ncc[nH]1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)cc1

Procedure:
A mixture 4-fluorobenzonitrile (3 g, 25 mmol) and imidazolyl sodium (2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80° C. under Ar for 12 h. Progress of reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 mL water and stirred. The aqueous mixture was extracted with EtOAc (2×50 mL). Combined EtOAc extracts was dried over anhydrous MgSO4, concentrated, and the 4-(1-imidazolyl)-benzonitrile was isolated by column chromatography (3.6 g, 78%). LCMS: MH+=170; 1H NMR (CDCl3) δ 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and phenethylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.FC(F)(F)C([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][C:30]1([CH3:33])[CH2:32][O:31]1)=O.[OH-].[NH4+]>CCO>[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][C:30]([OH:31])([CH3:33])[CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC1(COc2ccccc2NC(=O)C(F)(F)F)CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(COc1ccccc1N)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 5 h
Yield: 76.9 %

Procedure:
A solution of 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (1.10 g, 5.05 mmol), 2,2,2-trifluoro-N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}acetamide (1.39 g, 5.05 mmol) in EtOH (95%, 20 ml,) was stirred for 2 h at 78° C. Ammonium hydroxide (25%, 7.5 ml) was added to the reaction mixture and heating was continued for additional 5 h. After standing over night at room temperature the reaction mixture was concentrated and the residue was purified on silica (dichloromethane-methanol, 12:1, containing 1% of NH4OH (25%)) to give the subtitle compound (1.54 g).
Reaction SMILES: CO[C:3](=O)[CH:4]=[CH:5]C1C=CC=C(OC)C=1.[CH2:15]([O:17][C:18](=[O:29])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:16].[I-:30].[CH:31]([P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:33])[CH3:32].C([Li])CCC.OS(O)(=O)=O>C1COCC1>[I-:30].[CH:31]([P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:33])[CH3:32].[CH2:15]([O:17][C:18]([C@H:19]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[C:4]1([CH3:5])[CH3:3])=[O:29])[CH3:16]
Reactant: CCOC(=O)C=Cc1cccc(OC)c1
Reactant: COC(=O)C=Cc1cccc(OC)c1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@H](c2cccc(OC)c2)C1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cyclopropanation of 3-methoxy-cinnamic acid methyl ester was carried out following the procedure of Ahmand et al., J Med. Chem 2001, 44, 3302-3310. Isopropyl-triphenylphosphonium iodide was prepared as described by Grieco et al., Tet. Lett. 1972, 36, 3781-3783. Briefly, a solution of 3-methoxy-cinnamic acid ethyl ester (14.6 g, 70.9 mmol) in 300 mL THF was cooled in a dry ice/acetone bath to approximately −78° C., and added dropwise to a −78° C. stirring solution of isopropyl-triphenylphosphonium iodide (51 g. 118 mmol) and n-butyl-lithium (54 mL, 135 mmol) in THF. The reaction mixture was allowed to warm to 0° C. with stirring for two hours, then was stirred at room temperature for 15 hours. The reaction mixture was poured onto ice and the resulting aqueous mixture was adjusted to neutral pH by addition of 1M aqueous H2SO4. The aqueous solution was extracted three times with a 1/1 mixture of hexanes/EtOAc and once with EtOAc. The combined organic layers were filtered through silica, and the filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure to give 15.22 g of crude trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:18]([NH:20][C@H:21](C)[CH2:22][OH:23])=[O:19])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13].N[C@H](C)CO>>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)N[C@H](C)CO)ccc2C)c1=O
Agent: C[C@@H](N)CO
Product: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)NCCO)ccc2C)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 5 of the synthesis of 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-1(6H)-yl]-N-[(1R)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting ethanolamine for (R)-(−)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.19 (s, 1H), 7.90 (m, 1H), 7.73 (s, 1H), 7.57 (q, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.00 (m, 2H), 5.51 (q, 2H, J=12.4 Hz), 3.69 (t, 2H, J=6.0 Hz), 3.48 (t, 2H, J=5.6 Hz), 2.51 (q, 2H, J=7.6 Hz), 2.17 (s, 3H), 1.05 (t, 3H, J=7.6 Hz). ESHRMS m/z 444.1704 (M+H calculated for C23H24F2N3O4 requires 444.1729).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.CN(C)C(=O)C>O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 77 %

Procedure:
A mixture of 17.6 parts of 1-(phenylmethyl)piperazine, 8.4 parts of ethyl 4-fluorobenzoate and 45 parts of N,N-dimethylacetamide was stirred and refluxed for 22 hours. The reaction mixture was cooled and poured onto 500 parts of water. The product was extracted three times with benzene. The combined extracts were washed three times with a lot of water, dried, filtered and evaporated. The residue was stirred in hexane. The product was filtered off, washed with hexane and dried in vacuo, yielding 12.5 parts (77%) of ethyl 4-[4-(phenylmethyl)-1-piperazinyl]benzoate (intermediate 2).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[F:30][C:28]([F:31])([F:29])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][S:46][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:26][CH:25]=1)([OH:33])[CH3:32]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CSc2ccccc2)cc1)C(F)(F)F
Temperature: 140 °C
Yield: 78 %

Procedure:
To a 5-mL microwave vial was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.200 g, 0.378 mmol, Intermediate B), potassium carbonate (0.105 g, 0.757 mmol), thiophenol (0.076 mL, 0.76 mmol, Aldrich, St. Louis, Mo.), and acetonitrile (3.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 40 min. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 40% acetone in hexanes) to afford 1,1,1-trifluoro-2-(4-((2R)-2-((phenylsulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.160 g) as a mixture of two isomers:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:12][NH2:13].[BH4-].[Na+].[OH-].[NH4+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:12][NH:13][CH:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CNC(C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
In THF (50 mL), was added 4-acetylbenzonitrile (5.0 g; 34 mmol), methylamine (20.5 mL; 2 M; 41 mmol) and titanium (IV) isopropoxide (5.6 mL; 18.9 mmol). The mixture was stirred overnight at RT. Sodium borohydride (5.5 g; 145 mmol) was added and the reaction was stirred at RT for 2 h. Ammonium hydroxide solution 25% (100 mL) was added and the reaction was stirred at RT for 1 h30. It was then filtered through a pad of celite which was washed 3 times with EtOAc. The filtrate was poured in a separatory funnel and the organic phase was washed with a saturated solution of NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduce pressure affording the title compound as a light yellow oil (5.4 g; 97%). It was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10].C(N(CC)CC)C>ClCCl>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(Cl)(Cl)N(CCCl)CCCl
Temperature: -78 °C
Yield: 87 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (6.3 g, 35 mmol), suspended in 80 mL dichloromethane, was cooled to −78° C. under argon and stirred. A solution of phosphoryl chloride (5.41 g, 35 mmol) in 10 mL dichloromethane, followed by a solution of triethylamine (3.53 g, 70 mmol) in 10 mL dichloromethane, was added slowly by syringe. Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with 0.01N hydrochloric acid (3×25 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N,N-bis(2-chloroethyl)phosphoramidic dichloride as a light orange oil that solidified on standing (7.9 g, 87% yield). A 2.2 g aliquot of the crude N,N-bis(2-chloroethyl)phosphoramidic dichloride was purified by flash chromatography on a 12 g silica cartridge, eluting with a gradient of 100% hexane to 67% hexane/33% ethyl acetate over 10 minutes followed by 67% hexane/33% ethyl acetate for a further 10 minutes, to give 1.5 g pure N,N-bis(2-chloroethyl)phosphoramidic dichloride as a white solid after evaporation of the solvents. MS (ES): m/z=275 [C4H8Cl4NOP+NH4+].
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>C(#N)C>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCN(C(=O)c2ccccc2)CC1

Procedure:
0.10 g (0.53 mmol) 1-benzoylpiperazine and potassium carbonate 0.22 g (1.58 mmol, 3.0 eq.) were added to 5 ml acetonitrile and 0.05 g (0.53 mmol, 1.0 eq.) chloroacetone was added dropwise slowly at room temperature. After mixing for one hour, 5 ml purified water was added, and the reaction mixture was extracted with 10 ml ethylacetate three times. After collecting organic layer, drying with anhydrous magnesium sulfate, and concentrating with decompression, residues obtained were purified with silicagel chromatography (mobile phase: dichloromethane/methnol=10:1) and 0.11 g (83%) target compound as yellow serup were yielded.