Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added cyclohexanecarbonyl chloride (87.8 ml, 0.59 mmol) and saturated-aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (141 mg, 79%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)C1C=CC=CC=1.[CH2:25]([O:32][C:33]([O:35]N1C(=O)CCC1=O)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.CN(C=O)C.O.[OH-].[OH-].[Pd+2]>[CH2:25]([O:32][C:33]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:35])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(NCC1CN(Cc2ccccc2)CCO1)c1ccc(O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1CN(C(=O)OCc2ccccc2)CCO1)c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (Step 1 above) (320 mg) was dissolved in ethanol (20 mL) and hydrogenated at 1 atm over 20% Pd(OH)2/C (250 mg) for 18 h. The catalyst was removed by filtration, washed with ethanol, and the filtrate evaporated, to give a solid. A portion (21 mg) of this material was dissolved in DMF (0.5 mL) and N-(benzyloxycarbonyloxy)succinimide (27 mg) was added. The reaction mixture was stirred for 10 min, one drop of water was added and the solution was purified by preparative reverse phase HPLC to give the 2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine4-carboxylic acid benzyl ester compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CC1(C)C(C)(C)OB([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1
Reactant: Fc1cncc(Cl)c1I
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2c(F)cncc2Cl)CC1
Temperature: 90 °C
Yield: 77.7 %

Procedure:
3-chloro-5-fluoro-4-iodo-pyridine (750 mg, 2.913 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (990.7 mg, 3.204 mmol) and Pd(PPh3)2Cl2 (102.2 mg, 0.1456 mmol) in DME (15 mL) were degassed using 3×vacuum/nitrogen cycles. Na2CO3 (4.370 mL of 2 M, 8.739 mmol) was added followed by further degassing and the reaction heated at 90° C. for 2 hours. The reaction was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 20% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl 3′-chloro-5′-fluoro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate as an off-white solid (708 mg, 78% Yield). MS (ES+) 313.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].[F:15][C:16]([F:27])([F:26])[C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC>CN(C=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:17]([C:16]([F:26])([F:27])[F:15])[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]2[C:10]([F:13])([F:12])[F:11]
Reactant: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A yellow solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (1.32 g, 4.94 mmol, Intermediate 8, step b) and 1,1,1-trifluoro-3-phenylpropan-2-one (0.980 g, 5.21 mmol) in DMF (4.95 mL) was treated with tributylamine (1.23 mL, 5.19 mmol) and stirred at 130° C. under air (capped) for 2 hours. The homogeneous orange solution was then cooled to room temperature and partitioned with ether (8 mL) and 1 M NaH2PO4 (8 mL). The organic layer was washed with 1 M NaH2PO4 (1×8 mL), dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a heptane to 30% DCM/heptane gradient to yield the title compound as a nearly colorless oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]3[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(OCc3ccc(CO)cc3)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(OCc3ccc(C=O)cc3)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (2.6 equivalents) in dry DCM, cooled to −78° C. under N2 was added oxalyl chloride (1.1 equivalents) in DCM drop-wise. The solution was stirred at −78° C. for 5 minutes before a solution of 4-[4-(4-methylpiperazin-1-yl)phenoxymethyl]benzyl alcohol (1 equivalent) in DCM was added drop-wise, and allowed to stir at −78° C. for another 30 minutes. Triethylamine (2.5 equivalents) was slowly dripped in before allowing the solution to reach ambient temperatures. The solution was washed with aqueous NaHCO3 and brine, dried over MgSO4 and concentrated to provide the crude 4-[4-(4-methylpiperazin-1-yl)phenoxymethyl]benzaldehyde which was converted to thiosemicarbazones according to Scheme 2.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH3:24])[N:23]=2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:19]([O:18][C:16]([N:15]1[C:14]2[CH:13]=[CH:12][N:11]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:10]3[C:9]=2[CH:32]=[C:31]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Nc1ccn2cc(C)nc2c1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(-c2ccccc2)cc2c1ccn1cc(C)nc21
Reaction time: 0.08 h
Yield: 10.8 %

Procedure:
To a mixture of Et3N (10 mL), DMF (75 μL), carbamate 19 (215 mg, 0.72 mmol), PdCl2(PPh3)2 (10 mg, 2 mol %) and phenylacetylene (89 mg, 0.87 mmol) stirred 5 min beforehand, CuI (5 mg, 4 mol %) was added and stirring was continued for another 2 min before flushing with Ar. After stirring for 2 days at 60° C., the mixture was concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with CH2Cl2 (3×30 mL). The organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography using cyclohexane/EtOAc (4/1, v/v) as eluent to afford compound 20 as an oil (24.8 mg, yield: 11%); 1H NMR (400 MHz, CDCl3) δ 1.06 (t, 3H, J=7.1 Hz), 2.48 (s, 3H), 4.25 (q, 2H, J=7.1 Hz), 7.09 (s, 1H), 7.32 (s, 1H), 7.40 (m, 5H), 7.69 (d, 1H, J=7.3 Hz), 7.87 (d, 1H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 13.5, 14.2, 63.6, 103.0, 108.1, 109.5, 115.8, 121.5, 127.8, 127.9, 129.0, 132.3, 133.7, 139.7, 140.4, 141.7, 151.3. Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 72.03; H, 5.42; N, 13.25. Further elution afforded starting material 19 (124 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:13][C:14](OCC)=[O:15]>C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:12]2[CH2:11][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:14](=[O:15])[CH:13]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C=C(CBr)c1ccc(F)cc1
Solvent: CCO
Product: COc1ccc(N2CC(c3ccc(F)cc3)=CC2=O)cc1
Reaction time: 24 h

Procedure:
p-Anisidine (1793 g, 14.6 mol) and ethyl 4-bromo-3-(4-fluorophenyl)-2-butenoate (1393 g, 4.9 mol) are combined in ethanol (6 L), and the mixture is stirred for 24 hr. The precipitate which forms is collected by filtration, washed with ethanol, and dried under vacuum for 24 hr at 60° C. to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=1.CCCCCC>CCO>[Br:19][C:20]1[CH:21]=[N:22][C:23]([N:12]2[CH2:13][CH2:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11]2)=[N:24][CH:25]=1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCCCCC
Solvent: CCO
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncc(Br)cn2)CC1
Temperature: 70 °C
Yield: 51.6 %

Procedure:
To a solution of methyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (0.11 g, 0.42 mmol) in EtOH (5 mL) was added 5-bromo-2-chloropyrimidine (0.09 g, 0.46 mmol) at rt and the reaction mixture heated up to 70° C. for 1 h. After completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 20% EtOAc:hexane to obtain the desired product as a yellow solid (0.09 g, 52% yield). MS: 415.17 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)#[N:54]>CN(C=O)C>[C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=1)#[N:54]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
DIEA (0.015 mL, 0.085 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.021 g, 0.077 mmol) and HATU (0.032 g, 0.085 mmol) in 0.45 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-cyano-biphenyl-3-ylamine (0.015 g, 0.077 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 63% yield: LCMS (ESI) m/z 451 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)=O)(C)(C)C.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][N:25]([CH:35]1[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:38][CH2:37][CH2:36]1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH2:10][CH:9]2[CH2:12][CH2:13][CH2:14][NH:8]2)=[CH:29][CH:28]=1)[CH:35]1[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:38][CH2:37][CH2:36]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCC2CCCN2)cc1)Cc1nc2ccccc2[nH]1
Reaction time: 0.67 h

Procedure:
Using General Procedure B: To a stirred solution of N-(tert-butoxycarbonyl)-D-prolinal (0.121 g, 0.61 mmol) in dry CH2Cl2 (9 mL) was added N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.236 g, 0.59 mmol) at room temperature and the mixture stirred for 40 min. To the resultant mixture was added sodium triacetoxyborohydride (0.174 g, 0.82 mmol) and the mixture stirred overnight at room temperature. Purification and separation of the crude material by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 50:1:1) afforded the more polar mono-alkylated (77 mg, 23%) and the less polar dialkylated (70 mg, 21%) products, both as white foams.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)\[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:38][CH:39]=2)[N:4]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 88.3 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyloxazole (368 mg), ethyl E-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 13 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (770 mg, yield 88%) as a colorless oil from an ethyl acetate-hexane (2:7, v/v)-eluted fraction.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[CH:4][CH:3]=1.Cl.FC1C=C2C(C=C([C@@H](N)C)C(C3C=CC=CC=3S(C)(=O)=O)=N2)=CC=1.[NH2:57][C:58]1[C:63]([C:64]#[N:65])=[C:62](Cl)[N:61]=[CH:60][N:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:57][C:58]1[C:63]([C:64]#[N:65])=[C:62]([NH:24][C@H:22]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:23])[N:61]=[CH:60][N:59]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Reactant: N#Cc1c(N)ncnc1Cl
Agent: C[C@H](N)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
To (S)-tert-butyl (1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-carbamate (440 mg, 1.0 mmol) was added HCl, 4M (1 mL). The resulting mixture was stirred at rt for 1 h. Solvent was removed and the crude (S)-1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethanamine was used without further workup. A solution of (1S)-1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-quinolin-3-yl)ethanamine (100 mg, 290 μmol), 4-amino-6-chloropyrimidine-5-carbonitrile (45 mg, 290 μmol) and DIEA (101 μl, 581 μmol) in DMF (4 mL) was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory. TLC using 3% of MeOH/DCM to afford a white powder of (S)-4-amino-6-((1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-amino)pyrimidine-5-carbonitrile (6.9 mg, 5.1%). 1H NMR (500 MHz, CD3OD) δ ppm 1.51 (d, J=7.09 Hz, 3H) 3.17 (s, 3H) 5.43 (d, J=6.85 Hz, 1H) 7.48 (d, J=2.45 Hz, 1H) 7.60-7.63 (m, 1H) 7.66-7.69 (m, 2H) 7.73 (d, J=1.47 Hz, 1H) 7.81 (s, 1H) 8.07 (dd, J=9.05, 6.11 Hz, 1H) 8.13-8.17 (m, 1H) 8.49 (s, 1H). Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F.O.[NH2:16][NH2:17]>C(O)C>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:16][NH:17]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(O)n[nH]c2c1
Yield: 30.9 %

Procedure:
2-Fluoro-4-nitrobenzoic acid methyl ester (5 g, 25.11 mmol) and hydrazine hydrate (1.34 ml, 27.62 mmol) were dissolved in 250 ml of ethanol and heated under reflux for 11 h. A further 0.26 ml of hydrazine hydrate were added and heated under reflux for a further 6 h, and the mixture was concentrated and ethyl acetate and water were added. The precipitated residue was filtered off with suction and dried. Purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA) resulted in 1.39 g of product, M+H+: 180.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:27]([CH3:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH:27]([CH3:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1
Product: CC(Oc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1)[C@H](C)NC(=O)OC(C)(C)C

Procedure:
Using 2-(4-(benzyloxy)-3-fluorophenyl)-1,3-benzoxazol-6-ol and tert-butyl ((2S)-3-hydroxybutan-2-yl)carbamate, and in the same manner as in Step C of Example 1, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:22]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)N4CCc5ccccc5C4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 1,2,3,4-tetrahydroisoquinoline were processed as described in Example 33C to provide the title compound: MS (APCI) m/z 449 (M+H)+.
Reaction SMILES: [OH-].[K+:2].O.[C:4]([OH:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([OH:14])=[O:13])([C:8]([OH:10])=[O:9])[OH:7]>O>[C:4]([O-:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([O-:14])=[O:13])([C:8]([O-:10])=[O:9])[OH:7].[K+:2].[K+:2].[K+:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 90 °C

Procedure:
An aqueous solution of potassium citrate was prepared by adding 132 grams of potassium hydroxide (KOH, 85% pure) and 210 grams of citric acid monohydrate to 695 grams of distilled water. To this, 15.2 grams of acetaldehyde/diacetyl flavorant was added. After mixing, the mixture was transferred to a Niro spray dryer, which maintained an inlet air temperature of 120° C. and an outlet air temperature of 90° C. The resultant free-flowing powder was hygroscopic and collapsed in storage over night.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].[CH3:10][O:11][C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>CN(C=O)C>[CH3:10][O:11][C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:9][CH2:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: OCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C
Reaction time: 1.25 h
Yield: 59.1 %

Procedure:
To a suspension in DMF (3.5 mL) of sodium hydride (60% in mineral oil, 52 mg, 1.3 mmol) was added 2-thiophenemethanol (0.135 mL, 1.4 mmol) and the reaction mixture was stirred for 1.25 hours. 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (0.35 mL, 1.2 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between water and ether. The aqueous phase was extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (3% ethyl acetate-hexane) gave 4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester (250 mg).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1.C1(C(C2C=CC(F)=CC=2)C(C2C=C[C:50]([OH:53])=CC=2)C(F)(F)F)C=CC=CC=1.ClCOCCl.[OH-].[Na+]>C1C=CC=CC=1>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:53][CH3:50])=[CH:15][CH:14]=2)[C:9]([F:12])([F:11])[F:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C(c2ccccc2)c2ccc(F)cc2)C(F)(F)F)cc1
Reactant: Oc1ccc(C(C(c2ccccc2)c2ccc(F)cc2)C(F)(F)F)cc1
Agent: Cl
Agent: ClCOCCl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCOc1ccc(C(C(c2ccccc2)c2ccc(F)cc2)C(F)(F)F)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A mixture of 18.72 g (50 mmoles) of 1-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propane, prepared as described in Example 19, and 56 g of pyridine hydrochloride is heated at 200° C. for 3 hours, and then processed as described in Example 1. The resulting crude 1-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-2-(4-hydroxyphenyl)-propane is dissolved in 70 ml of benzene, then 6.44 g (80 mmoles) of chloromethylether and 6 g (300 mmoles) of powdered sodium hydroxide are added, and the mixture is boiled for one hour. The reaction mixture is diluted with 100 ml of benzene, washed until neutral with a 20% aqueous ammonium chloride solution, dried and evaporated. The residue is crystallized from isopropanol. 12.54 g (62%) of 1-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-2-[4-(methoxy-methoxy)-phenyl]-propane are obtained; m.p.: 96.5°-99° C.