Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O-:25])=[O:24])=[CH:15][C:14]=2[CH:26]=1.Cl.O1CCO[CH2:31][CH2:30]1>>[Cl:9][C:10]1[C:11]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:30][CH3:31])=[O:24])=[CH:15][C:14]=2[CH:26]=1
Reactant: C1COCCO1
Reactant: OCC(F)(F)F
Reactant: O=C([O-])C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1=Cc2cc(Cl)c(OCC(F)(F)F)cc2OC1C(F)(F)F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
A solution of 2,2,2-trifluoroethanol(1.3 g, 13 mmol) in 1,4-dioxane (2 mL) was added to a slurry of NaH (0.5 g, 13 mmol) in 1,4-dioxane (2 mL). The reaction was stirred for 10 minutes then a solution of 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (1.61 g, 5.0 mmol) in 1,4-dioxane (5 mL) was added and the reaction was heated to 85° C. for 22 hours. The reaction mixture was acidified with 3N HCl, extracted with ethyl acetate, washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated in vacuo, to give a brown oil which was passed through a column of silica gel with 10% ethyl acetate/hexanes to give a white solid (0.37 g, 18%): 1H NMR (CDCl3/300 MHz) 7.62 (s, 1H), 7.28 (s, 1H), 6.58 (s, 1H), 5.69 (q, 1H, J=6.6 Hz), 4.42 (m, 2H), 4.31 (m, 2H), 1.34 (t, 3H, J=7.1 Hz). 19F NMR (CDCl3/282 MHz) −74.2 (t, 3F, J=8.0 Hz), −78.9 (d, 3F, J=6.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH2:26]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Br)=[O:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCCCc1ccc(C(=O)Br)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)OC)C(C)C)C4=O)cc2)cc1
Yield: 52 %

Procedure:
The compound of example 324 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-(n-pentyl)benzoyl bromide. The compound of example 324 was used directly without isolation, for the preparation of compound of example 325.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][NH:8][C:9](=[O:16])[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)([O-])=O.C(OC(C)C)(=O)C.[H][H].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>O.[Pd]>[C:40]1([O:39][C:37](=[O:38])[NH:1][C:4]2[CH:19]=[CH:18][CH:17]=[C:6]([CH2:7][NH:8][C:9]([O:10][C@H:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[O:16])[CH:5]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: [H][H]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)O[C@H]1CCOC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=C(Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1)Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixture of 2c (50 g, 1.00 equivalent), 5% Pd/C (0.75 g, 50% water, 0.75 wt %) and isopropyl acetate (400 ml, 8 volumes) was added to a hydrogenation vessel under nitrogen and heated to 60° C. The vessel was pressurized with hydrogen (1.00 bar overpressure) and the mixture stirred at 60° C. The reaction was complete within 3 hours. The pressure was released and the vessel purged with nitrogen. The mixture was filtered through a pad of Celite® and then the hydrogenation vessel and pad were rinsed with isopropyl acetate (100 ml, 2 volumes). The solution of 2d in isopropyl acetate was then combined with a solution of sodium sulfate (29.3 g, 1.10 equivalents) in water (150 ml, 3 vol) and then the mixture was heated to 70° C. Phenyl chloroformate (25.7 ml, 1.10 equivalents) was then added to the mixture while maintaining a temp. of 70° C. The reaction was stirred for 30 min after the end of addition and then the stirring was stopped. The phases were allowed to separate and the aqueous phase was removed. Water (150 ml, 3 vol) was then added and the mixture stirred for an additional 30 min before the stirring was stopped. The phases were allowed to separate and the aqueous phase removed. The mixture was then distilled at atmospheric pressure to azeotropically remove water from the organic phase. Compound 2e precipitated from solution when all of the water was removed. Distillation continued until there were 4 volumes of solvent remaining. The mixture was cooled to 20° C. over 5 hours then filtered to isolate the solid. The reactor and filter cake were washed with isopropyl acetate (2 vol) then the cake was dried under vacuum at 50° C. to afford 61.1 g (91%) of 2e.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].C([O:18][C:19]([C:21]1[C:25]([NH2:26])=[N:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:22]=1)=O)C>CCO>[CH2:6]([O:5][C:3]([C:2]1[C:1]([OH:9])=[N:26][C:25]2=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH:22]=[C:21]2[C:19]=1[OH:18])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2nn(Cc3ccc(OC)cc3)cc2c1O

Procedure:
To a solution of diethyl malonate (9.6 g, 60 mmol) in a freshly prepared solution of NaOEt in EtOH (from 2.52 g of 60% oil dispersion NaH and 40 mL of EtOH) was added a solution of 5-amino-2-p-methoxybenzyl4-pyrazolecarboxylic ethyl ester (4.2 g, 15 mmol) in EtOH (60 mL) at rt. The resulting solution was refluxed for 20 h. The mixture was concentrated and the residue was dissolved in H2O (250 mL) and washed with EtOAc (60 mL). The aqueous layer was acidified with AcOH to pH 5. The product (5.1 g) was collected by filtration and dried under high vacuum. LC: 3.47′ (Gradient 1); MH+: 344
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:9])[CH:4]=[C:3]1[C:24]([O:26]C)=[O:25].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:9])[CH:4]=[C:3]1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.3 %

Procedure:
Methyl 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-pyrrole-2-carboxylate (5.0 g, 12.43 mmol) prepared in the capping step was dissolved in THF/H2O (200 ml/100 ml), 1N LiOH (30 ml) was added thereto, and the mixture was stirred for 4 days at room temperature. The reaction solution was acidified to pH 2.0 by 1N HCl and then extracted with EA and water. The organic layer was washed with aqueous NaCl solution and dried over anhydrous MgSO4. The solvent contained therein was removed to give a white solid, which was then recrystallized from EA and n-hexane to give 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxy carbonylamino]-1H-pyrrole-2-carboxylic acid (3.20 g, 66.29%) of a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1[C:28](=[O:43])[C:29]2C(C=1C1C=CC=CC=1)=C[CH:32]=[C:31](O)[CH:30]=2.O1CCCC1CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:32][CH:31]4[CH2:30][CH2:29][CH2:28][O:43]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: OCC1CCCO1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCC3CCCO3)cc21
Reaction time: 17 h
Yield: 7 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, (tetrahydrofuran-2-yl)methanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 17 h, and being purified by prep. HPLC (20% H2O/CH3CN and 30% H2O/CH3CN) to provide the title compound (7%).
Reaction SMILES: [I-:1].OC1C=CC=CC=1C=[N:6][C@@H:7]1[C:37](=[O:38])[N:9]2[C:10]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:11]([CH2:14][N+:15]3[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][S:13][C@H:8]12.[ClH:43]>O1CCCC1.C(O)C>[ClH:43].[I-:1].[NH2:6][C@@H:7]1[C:37](=[O:38])[N:9]2[C:10]([C:21]([O:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:22])=[C:11]([CH2:14][N+:15]3[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][S:13][C@H:8]12
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=Cc3ccccc3O)[C@H]2SC1
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of benzhydryl 7β-(2-hydroxybenzylideneamino)-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (1 g) in tetrahydrofuran (20 ml) and ethanol (3 ml) was added conc. hydrochloric acid (0.14 ml) at ambient temperature. After stirring at the same temperature for 1 hour, the mixture was poured into tetrahydrofuran (20 ml). The resulting precipitates were collected by filtration to give hydrochloric acid salt of benzhydryl 7β-amino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (0.65 g).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]=[C:19]=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:11]([N:18]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][N:10]=[C:19]1[S:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: BrCc1ccccc1
Reactant: S=C=NCc1ccccc1
Product: c1ccc(CSc2nnc(-c3ccccc3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using benzoic acid hydrazide, benzyl isothiocyanate and benzyl bromide as the starting materials. (M+H)+−358.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzylamine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].O>CS(C)=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][N:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add sodium azide (12.5 g, 193 mmol) to a rapidly stirred solution of methyl 5-bromovalerate (25.08 g, 129 mmol) in DMSO (200 mL, anhydrous). Stir at room temperature overnight under N2. Add water (400 mL) and stir for 30 minutes. Extract with Et2O (×3) and wash combined Et2O layers with brine (×3). Dry organic layer over MgSO4 and concentrate to give the title compound (20.3 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:14]1.Cl.Cl.NC1C=CC(N2CCC[C@@H](C(N3CCCC3)=O)C2)=NC=1N.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:20])[CH2:14]2)[N:7]=1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Agent: Cl
Agent: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-nitropyrimidin-4-amine (670 mg, 3.84 mmol, 80% pure), (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (prepared by the method described in Steps 1 and 2 of Intermediate 1, 560 mg, 2.56 mmol) and triethylamine (0.761 mL, 5.46 mmol) in dimethylsulfoxide (5 mL) was heated to 100° C. for 5 h. The mixture was diluted with ethyl acetate (80 mL), washed with water and brine, dried over sodium sulfate and concentrated. The crude material was purified via flash chromatography (ethyl acetate/heptane: 40-70-100%) to afford (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as a yellow solid (420 mg). 1H NMR (500 MHz, DMSO-d6) δ 1.45 (t, 1H), 1.62 (d, 1H), 1.72-1.82 (m, 4H), 1.88 (d, 4H), 2.56 (br s, 1H), 2.90-3.04 (m, 2H), 3.28 (t, 2H), 3.37-3.62 (m, 2H), 4.59-4.87 (m, 2H), 8.00 (br s, 1H), 8.16 (br s, 1H), 8.90 (s, 1H); MS (ES+) (M+H) 321.2.
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])C[C:8]2=[O:13].I[CH3:16].[C:17](#N)[CH3:18]>>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[C:17]([CH3:18])([CH3:16])[C:8]2=[O:13]
Reactant: CC#N
Reactant: CI
Reactant: O=C1CC(=O)c2c(Cl)cccc21
Agent: [F-]
Agent: [K+]
Product: CC1(C)C(=O)c2cccc(Cl)c2C1=O
Temperature: 25 °C

Procedure:
Potassium fluoride on Celite® [loading wt: 50% purchased from Sigma-Aldrich Co.] (17.4 g, ˜150 mmol) is heated at 135° C. for 2 hours under vacuum (<20 torr). The solid is then permitted to cool to room temperature and placed under a nitrogen atmosphere, at which time a solution of 4-chloro-indan-1,3-dione (CAS#20926-88-9, 5.6 g, 31.0 mmol), which can be prepared as described by Smith, H.; et al. Journal of Medicinal Chemistry, 1973, 16, 1334-1339, in acetonitrile (45 mL) is added. Iodomethane (5.4 mL, 90 mmol) is then added to the mixture. The reaction is heated in a sealed vessel at 70° C. overnight. The reaction mixture is cooled to room temperature and filtered through a pad of Celite®. The eluent is concentrated and the reaction mixture is cooled to room temperature and filtered through a pad of Celite®. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:9) to furnish 4-chloro-2,2-dimethyl-indan-1,3-dione; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (s, 6 H), 7.74-7.82 (m, 2 H), 7.91 (dd, J=7.1, 1.5 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[C:35]([CH2:37]Cl)[N:36]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[C:35]([CH2:37][O:3][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]4[CH:17]=[CH:16][N:15]=[CH:14]4)=[CH:6][CH:5]=3)[N:36]=2)=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)cc1
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
Sodium hydride (440 mg) was added, at room temperature, to a solution of 1-[3-(4-hydroxyphenyl)propyl]imidazole (2.02 g) in N,N-dimethylformamide (50 ml). The mixture was stirred for 1.5 hour, to which was added 2-(4-benzyloxyphenyl)-4-chloromethyloxazole (3.60 g). The mixture was stirred for further 3 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with ethyl acetate-methanol (50:1, v.v) was recrystallized from ethanol to give 2-(4-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (2.88 g, 62%) as colorless prisms, mp 133-134° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@H]1C(=O)O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c(c3ccccc3n2Cc2ccc(F)cc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
The acid 2 (20.0 g, 63.2 mmol) in DMF (630 mL) was degassed and the flask was cooled in ice water bath. NaH (60% in mineral oil; 7.8 g, 196.0 mmol) was slowly added portionwise over 45 min at 0° C. and stirred for 1 hr. 4-fluorobenzyl bromide (8.7 mL, 69.5 mmol) was added dropwise over 45 min at 0° C. and stirred for 1.5 hr. The reaction quenched with water. The mixture diluted with water (1.8 L) and washed with EtOAc (1 L). The aqueous layer was acidified to pH 3-4 with solid citric acid. The mixture extracted with EtOAc (3×300 mL). The combined organic extracts were washed with water (900 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using 0-30% EtOAc/Hexane to give a solid. The solid was washed with 10% CH2Cl2/hexane to afford the acid 3 (19.5 g, 72%) as a white powder. 1H NMR (300 MHz, DMSO-d6): δ 12.81 (br s, 1H), 7.48-7.42 (m, 2H), 7.13-6.97 (m, 6H), 5.41-5.28 (m, 2H), 5.14-5.03 (m, 1H), 4.66-4.58 (m, 1H), 4.42-4.27 (m, 1H), 3.32-3.28 (m, 1H), 3.06-2.96 (m, 1H), 1.40 (s, 9×½H), 1.39 (s, 9×½H); LC-MS [M+H+ 425].
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1.C(N(CC)CC)C.C(#N)C>O>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:1]([O:2][C:3]4[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=4)=[O:12])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC4)nc(N)n2)CC1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
4-Nitrophenyl carbonochloridate (0.14 g, 0.69 mmol) was added to 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (0.30 g, 0.69 mmol) and triethylamine (0.38 mL, 2.8 mmol) in acetonitrile (8.0 mL, 150 mmol) at 0° C. After 1 h., the mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dicloromethane (0-10%) to afford the desired product (0.32 g, 94%). Analytic LCMS (M+H)+: m/z=490.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CC(C=CC(=O)O)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(CCC(=O)O)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1

Procedure:
12D, in solution in tetrahydrofuran, was placed on a Parr shaker and treated with hydrogen (40 psi hydrogen pressure, Parr shaker, 10% palladium-on-charcoal catalyst) to give 4-(4-(2-amino-4-(trifluoromethyl)phenylamino)phenoxy)pentanoic acid (12E), as an oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:24]3[N:25]=[CH:26][C:27]([C:30]([OH:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:37])([F:38])[F:36])=[CH:28][N:29]=3)[C@@H:12]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:11]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)s1)N1CCN[C@@H](CC2CCOCC2)C1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CC2CCOCC2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A mixture of (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (190 mg, 0.464 mmol, Example 133, Step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (156 mg, 0.557 mmol, Intermediate D), and potassium carbonate (128 mg, 0.928 mmol) in DMF was heated at 100° C. and stirred for 16 h. The mixture was diluted with water (20 mL) and EtOAc (20 mL). The layers were separated and the organics were washed with water (20 mL) and brine (20 mL). The organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give (S)-2-(2-(4-(5-bromothiophen-2-ylsulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (140 mg).