Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[N:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:31]=2)=[CH:26][CH:25]=1>C(O)C>[NH2:13][C:12]1[O:35][C:33]2[N:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:31]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[C:34]=2[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]=1[C:10]#[N:14]
Reactant: N#CCC#N
Reactant: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn(-c3ccccc3)c3c2C(c2ccc(F)cc2)C(C#N)=C(N)O3)cc1
Reaction time: 0.02 h
Yield: 63.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (764 mg, 2.87 mmol, 1 equ.). The precipitate formed was filtered off and washed with ethanol and hexanes, and re-crystallized from ethanol to afford 6-amino-4-(4-fluorophenyl)-3-(4-methoxyphenyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (800 mg, 1.83 mmol, 64%) as white solid. 1H-NMR (400 MHz) DMSO: 7.93-7.91 (d, 2H), 7.55-7.53 (m, 4H), 7.41-7.37 (t, 1H), 7.26-7.23 (m, 4H), 7.07-7.05 (t, 2H), 6.84-6.82 (d, 2H), 5.11 (s, 1H), 3.72 (s, 3H) 13C-NMR (100 MHz) DMSO: 162.6, 159.6, 159.0, 146.6, 145.5, 140.7, 140.6, 137.9, 130.0, 129.9, 129.8, 128.3, 127.1, 125.0, 121.1, 120.2, 115.6, 115.4, 114.1, 97.3, 59.6, 55.5, 37.0; LC/MS-MS: 439.2→373.0 m/z; GS1 and GS2 at 30, DP=61, CE=35, CXP=24, tR=4.28 min.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][Br:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[Br-:30].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: BrCCOc1ccccc1
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Solvent: CO
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 71.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0693 g, 0.227 mmol) and 2-bromoethyl phenyl ether (0.056 g, 0.279 mmol) in 1 MeOH/1 CHCl3 (3.0 mL) were reacted to give the desired product (0.0822 g, 74.7%). EI-MS m/z 426(M+) Rt (2.00 min).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 5-aminopentanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 5 of European Patent Application 136,883 to give (±)-5-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]pentanoic acid, methyl ester.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[NH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>CC(C)=O.CN(C=O)C>[N:19]1([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: c1ccc2c(c1)CCCN2
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1nc(N2CCCc3ccccc32)sc2ncccc12
Yield: 73 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.595 mg (10.12 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 770 mg of ammonium thiocyanate, 15 ml of acetone, 1.35 g of 1,2,3,4-tetrahydroquinoline and 10 ml of acetone were used. As a result, 2.18 g of 2-(1,2,3,4-tetrahydroquinolin-1-yl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])([O-:3])=[O:2].N[CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][CH2:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: NCCCO
Reactant: NCc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CNCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of 2-nitrobenzyl amine (17 g, 78 mmol) in DMF (50 mL) was cooled to 0° C. and treated dropwise with a solution of 3-amino-1-propanol (50 mL, 0.65 mol) in DMF (150 mL) over 0.5 hours. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature for 2 hours, and evaporated to a red oil. The crude product residue was purified by flash chromatography (SiO2, 10% 0.5 M NH3-methanol/dichloromethane) to afford 3-[(2-nitrobenzyl)amino]propan-1-ol (16 g, 98%) as a yellow oil:
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][C:11]([C:13]1[O:14][C:15]([CH3:36])=[C:16]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:17]=1)=[O:12]>CN(C)C=O>[CH3:9][O:10][C:11]([C:13]1[O:14][C:15]([CH3:36])=[C:16]([CH2:18][N:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH3:3])[CH:17]=1)=[O:12]
Reactant: COC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 36 h
Yield: 63.8 %

Procedure:
Iodomethane (91 mg, 0.64 mmoles) and potassium carbonate (88 mg, 0.64 mmoles) were added to a solution of 4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (170) (62 mg, 0.16 mmoles) in N,N-dimethylformamide (10 ml) and the mixture stirred at room temperature for 36 hours under an argon atmosphere. The mixture was then heated at 35° C. for 21 hours. The mixture was partitioned between dichloromethane and water, the organic phase separated and dried (MgSO4). After evaporation of the solvent, the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 99:1 v/v as eluent, to afford compound 175 (41 mg) as a brown oil. This was used directly in part (b).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -15 °C
Yield: 91.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 mL) at −20 to −30° C. was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at −10 to −20° C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ˜600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.27 (m, 1H), 3.44-3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1H), 2.15 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:19]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=2)=[CH:18][CH:17]=[CH:16][N:15]=1.I[CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH3:13][C:14]1[C:19]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH2:38][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[N:24]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(C)(=O)=O)cc1
Reactant: C[Si](C)(C)CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9 mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M solution in hexane, 4.6 mmol) at 0° C. The solution was stirred at this temperature for 5 minutes and cooled to -78° C. with a dry ice/isopropanol bath. A solution of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 44) (1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes and the reaction mixture was stirred at −780° C. for 1 hour. (Iodomethyl)trimethylsilane (1.23 g, 57 mmol) was added dropwise and the reaction mixture was warmed to room temperature and was stirred overnight. The reaction was quenched with 50 mL of 1 N HCl and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a white solid (74%): mp(DSC) 155-157° C. Anal. Calc'd. for C21H24F3N3O2SSi: C, 53.94; H, 5.17; N, 8.99; S, 6.86. Found: c, 53.77; H, 4.94; N, 8.75; S, 6.98.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C.O[Li].O.CS(C)=O>C1COCC1.O>[N:22]([C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([OH:25])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3])=[N+:23]=[N-:24]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1O)[C@@H]2C(=O)O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII) (845 mg, 2.45 mmol) in THF (21 mL) and H2O (6 mL) was added LiOH.H2O (411 mg, 9.8 mmol) and the mixture was stirred at 23° C. for 18 h. The benzyl alcohol was extracted with ether, the aqueous layer acidified with 1 M KHSO4 -sol., saturated with solid NaCl, extracted with EtOAc (4×50 mL) and dried over MgSO4. After removal of the solvent under vacuum crude (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (XI) (581 mg, quant.) was obtained as white solid, sufficiently pure for further transformations. 1H-NMR (250 MHz, DMSO) □1.75 (1H, t, J=3.5 Hz), 1.84 (1H, m), 1.92-2.07 (2H, m), 2.15 (1H, dd, J=12.5, 7 Hz), 3.87 (1H, btJ=7 Hz); MS[ISN] 226 [(M-H)-]; mp 124-128° C.; □D20 -61.48° (c=0.90, H2O).
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].CCOCC>Br.C(O)(=O)C>[C:1]([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH2:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)SC(CCCN)C(=O)O

Procedure:
A solution of 2-acetylthio-5-benzyloxycarbonylaminopentanoic acid (1.6 g.) in 2 N hydrobromic acid in acetic acid (10 ml.) is kept at room temperature for thirty minutes. Ether is added to maximum precipitation and the supernatant is decanted. The residue is dissolved in water and applied to a column of Dowex 50 in the hydrogen cycle. The column is washed with water, and 2-acetylthio-5-aminopentanoic acid is eluted with M pyridine-acetic acid buffer pH 6.5.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:38]2[N:39]=[C:40]([NH:43]C=O)[S:41][CH:42]=2)[C:9]([NH:11][CH:12]2[C:36](=[O:37])[N:14]3[C:15]([C:33]([OH:35])=[O:34])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][OH:29])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl>CO.O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:38]2[N:39]=[C:40]([NH2:43])[S:41][CH:42]=2)[C:9]([NH:11][CH:12]2[C:36](=[O:37])[N:14]3[C:15]([C:33]([OH:35])=[O:34])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][OH:29])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=NO)C(=O)O)CS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=NO)C(=O)O)CS[C@H]23)cs1

Procedure:
A solution of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (1.1 g) and conc. hydrochloric acid (0.12 g) in methanol (10 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 2.5 hours. After removal of organic solvents under reduced pressure, the residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was adjusted to pH 7.5. The aqueous solution was washed with ethyl acetate (15 ml) and then adjusted to pH 3.0 with 10% hydrochloric acid to give precipitates which were filtered and washed with water to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazole-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([S:16][C:17]#[N:18])C.BrBr.[OH-].[Na+]>C(O)(=O)C>[NH2:18][C:17]1[S:16][C:7]2[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCSC#N
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc2nc(N)sc2c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Ethyl 4-aminophenylacetate (18 g) was dissolved in acetic acid (120 ml) and ethyl thiocyanate (29.3 g) was added thereto. Under ice cooling, bromine (6.2 ml) was added dropwise thereinto over 45 minutes while maintaining the reaction temperature at about 10° C. After the completion of the addition, the resultant mixture was stirred at room temperature for 1.5 hr and then at 80° C. for about 2 hr until the reaction was completed. Then the reaction solution was poured into ice water, basified with an 8 N aqueous solution of sodium hydroxide, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (22.23 g) as orange crystals (yield: 93.66%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])(=O)=O.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(OCC)C.C(Cl)(Cl)Cl>CO>[CH3:6][CH:5]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCOc2ccccc2)cc1
Reactant: C1CCNCC1
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(CCOc1ccccc1)N1CCCCC1
Yield: 75 %

Procedure:
In a sealed tube, 10 g of the 4-phenoxy-2-butyl tosylate was reacted with 11.2 g of piperidine in 60 ml of absolute methyl alcohol for one hour at 125° C. After the reaction solution was condensed under reduced pressure, 100 ml of diethyl ether was added into the solution, and then the solution was separated into the diethyl ether solution and 20% aqueous sodium hydroxide solution. After the ether layer was dried over anhydrous sodium sulfate, ether was removed under reduced pressure therefrom. The residue thus obtained was subjected to an alumina-column chromatography using chloroform as the developing solvent to give 5.46 g of 1-(1-methyl-3-phenoxypropyl)piperidine in a yield of 75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:45])[C:9]([C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:32])=[O:31])([CH3:29])[CH3:28])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)=[CH:4][CH:3]=1.[CH3:46][Mg]I>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:45])([C:9]([C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:31])=[O:32])([CH3:28])[CH3:29])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)[CH3:46])=[CH:4][CH:3]=1
Reactant: CC(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)(C(=O)c1ccc(F)cc1)c1ccc(S(C)(=O)=O)cc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(F)cc1)C(C)(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 21 °C
Reaction time: 12 h

Procedure:
To a solution of Example 19 (93 mg, 0.144 mmol) in CH2Cl2 (4 mL) at −78° C. was added methyl magnesium iodide (3M, Et2O, 0.24 mL, 0.8 mmol) dropwise. The resulting reaction mixture was stirred at 21° C. for 12 h, then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with dichloromethane/methanol, 99:1, 2×), then stirring vigorously the resulting residue in hexane/ethyl acetate/ether for 1 h and then filtration afforded the title compound as a white powder (mixture of diastereoisomers; 1:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)=[CH:13]3)=[N:8]2)[CH:2]=1.[CH3:24][O:25][CH2:26][CH2:27][C:28]1(Br)[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36].C1CN2C(=NCCC2)NC1.C(#N)C>CO.C(O)(=O)C>[CH:12]([O:16][CH:17]([CH3:22])[CH3:18])([CH3:13])[CH3:11].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][N:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[N:8]=4)[CH:13]=3)=[CH:18][CH:19]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Oc1ccc(Oc2ccc3nn(-c4cccnc4)cc3c2)cc1
Agent: C1CN=C2NCCCN2C1
Solvent: CC(=O)O
Solvent: CO
Solvent: CC#N
Product: CC(C)OC(C)C
Product: COCCC1(Oc2ccc(Oc3ccc4nn(-c5cccnc5)cc4c3)cc2)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.7 %

Procedure:
A mixture of 4-(2-Pyridin-3-yl-2H-indazol-5-yloxy)-phenol (0.05 grams, 0.17 mmol), 2-methoxyethylbromobarbiturate (0.06 grams, 0.2 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene (0.22 grams) and acetonitrile (1.5 mL) was shaken for 48 hours at room temperature. The mixture was treated with a solution of acetic acid in methanol (1:4 v/v), shaken for 20 minutes, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with an ethyl acetate-hexanes gradient (0-100% ethyl acetate). Trituration of the purified product with iso-propyl ether afforded 5-(2-Methoxy-ethyl)-5-[4-(2-pyridin-3-yl-2H-indazol-5-yloxy)-phenoxy]-pyrimidine-2,4,6-trione (0.009 grams) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.[CH3:18][C:19]([CH3:21])=[O:20].BrC1C=CC=CC=1C=O>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:18][C:19](=[O:20])[CH3:21])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=Cc1ccccc1Br
Solvent: CCOCC
Product: CC(=O)C=Cc1ccc(Br)cc1
Yield: 80 %

Procedure:
The p-bromobenzaldehyde (1 mmol) and the L-proline (30 mol %) are dissolved in N,N′-dimethylimidazolium methyl H-phosphonate (1 ml). The acetone (1 ml) is added. The mixture is stirred at room temperature until disappearance of the bromobenzaldehyde (followed by Thin Layer Chromatography). 4-(4-bromophenyl)but-3-en-2-one is isolated by extraction with ether (3×5 ml). The product is purified by column chromatography (0.96 g; yield=80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:9])=[N:4][CH:5]=[N:6][C:7]=1I.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[NH2:14].O>CN1CCCC1=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]2[C:2]([NH2:1])=[C:3]([I:9])[N:4]=[CH:5][N:6]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1
Reactant: Nc1c(I)ncnc1I
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1c(I)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 81 %

Procedure:
A solution of 5-amino-4,6-diiodopyrimidine (3.83 g) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.78 g) in 1-methyl-2-pyrrolidone (30 mL) was stirred at 70° C. for 14 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=1:4→2:3→1:1) to give the title compound (4.21 g) as brown powder crystals.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)=[CH:14][C:13]1=[O:29])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=3)=[CH:14][C:13]2=[O:29])[C:3]([OH:30])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.520 g, 0.001 mol) in tetrahydrofuran-water (3:1, 20 mL) was added lithium hydroxide (153 mg, 0.006 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (380 mg, 76%) as a light yellow solid.