Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.IC1C=CC=C([N+:51]([O-:53])=[O:52])C=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[N+:51]([C:3]1[CH:4]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:7][CH:2]=1)([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3cccc([N+](=O)[O-])c3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Compound TTT in Example 83 above). In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) was coupled with 1-iodo-3-nitrobenzene (175 mg, 0.70 mmol) (Aldrich) using CuI (13 mg, 0.068 mmol) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) as catalyst in 3 mL DMF and 3 mL triethylamine at 70° C. for 13 hours to give (Z)-1,3-dihydro-5-(3-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 148 mg, 65%)
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[C:8]1[C:9]2[NH:16][N:15]=[C:14]([CH3:17])[C:10]=2[N:11]=[CH:12][N:13]=1>O>[CH3:17][C:14]1[C:10]2[N:11]=[CH:12][N:13]=[C:8]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]=2[NH:16][N:15]=1
Reactant: CCCCCN
Reactant: Cc1n[nH]c2c(Cl)ncnc12
Solvent: O
Product: CCCCCNc1ncnc2c(C)n[nH]c12

Procedure:
When n-pentylamine (7 g) was added to 7-chloro-3-methylpyrazolo[4,3-d]pyrimidine (6.13 g, 36 mmol), an exothermic reaction took place and the mixture heated itself to boiling. The cooled reaction mixture was triturarted with water (100 ml). The crude product crystallized and was filtered, washed with water and air-dried to give a quantitative crude yield of slightly yellow crystals. Recrystallization from ether and treatment with charcoal afforded the product, yield 5.0 g (63%), m.p. 157.5°-158.5°. An additional 1.24 g was recovered from the mother liquor as the maleinate. Total yield, 73.6%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OC([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH:23]=2)=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: Nc1ncc(I)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(C=O)c3)cn2)CC1
Temperature: 25 °C

Procedure:
150 mg (0.605 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 413 mg (1.089 mmol) of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate are dissolved in 2.3 ml of N,N-dimethylformamide in a nitrogen-filled microwave vessel, and 1.7 ml (3.4 mmol) of 2M sodium carbonate solution and 35 mg (0.030 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature and filtered. The filtrate is evaporated to dryness. The oily residue is purified by means of RP-HPLC, giving tert-butyl 4-[4-(6-amino-5-formylpyridin-3-yl)pyrazol-1-yl]-piperidine-1-carboxylate; HPLC-MS [M+H]+ 372.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:40](CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:40][N:6]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: NN(C(=O)CCN1CCCC1)c1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2nnc(CCN3CCCC3)n2c1
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Intermediate 1a (400 mg) was dissolved in THF (20 mL) and cooled in an ice/water bath. Triphenylphosphine (643 mg, 2.45 mmol) was added followed by triethylamine (682 μL, 4.90 mmol) and hexachloroethane (581 mg, 2.45 mmol). The reaction mixture was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH then eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (292 mg, 1.16 mmol, 52%). 1H NMR (400 MHz, CDCl3): 1.80-1.87 (4H, m), 2.60-2.68 (4H, m), 3.00-3.10 (2H, t, J 7.3), 3.24-3.34 (2H, t, J 7.3), 7.13-7.21 (1H, ddd, J 9.9, 7.6, 2.3), 7.70-7.77 (1H, dd, J 9.8, 4.5), 8.00-8.04 (1H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (7.8 g), methyl iodide (1.7 ml), potassium carbonate (2.9 g) and N,N-dimethylformamide (14 ml) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with diethyl ether-hexane to give the title compound (6.85 g, yield 85%) as colorless needle crystals.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[CH3:18]O>>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:18])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (19.4 g, 164.85 mmol) was added to a solution of 4-amino-3-nitrobenzoic acid (20 g, 109.89 mmol) in methanol (200 mL) at 0° C. The resulting mixture was then refluxed for 12 h. The reaction mixture was allowed to cool to room temperature. The yellow solid precipitated was filtered and dried to afford the title compound (22 g, yield: 100%) as a solid. 1H-NMR (CDCl3, 300 MHz): δ 8.85 (d, 1H), 7.99 (dd, 1H), 6.83 (d, 1H), 6.40 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:27])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][C:35]([F:50])([C:46]([F:49])([F:48])[F:47])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[S:38](F)(=[O:40])=[O:39]>CN(C=O)C>[F:43][C:37]([F:42])([S:38]([O:27][C:9]1[CH:8]=[C:7]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:40])=[O:39])[C:36]([F:44])([F:45])[C:35]([F:50])([F:34])[C:46]([F:49])([F:48])[F:47]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(O)ccc1O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Reaction time: 0.17 h

Procedure:
A 25-mL flask was charged with (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (577.53 mg, 1.581 mmol), cesium carbonate (566 mg, 1.739 mmol), and DMF (7903 μL). The resulting mixture was stirred for 10 min, then the vial was submerged in an ice-bath for 10 min. nonafluorobutanesulfonyl fluoride (306 μL, 1.739 mmol) was added dropwise over 2 minutes. Stirred for 2 hours before the mixture was quenched with saturated aqueous ammonium chloride (10 mL). The mixture was partitioned between water (15 mL) and EtOAc (15 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on an 80-g Redi-Sep column, eluting with 0-50% of a 90:10 mixture of DCM/MeOH in DCM to give (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccnc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5.6 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.26 mmol), 3-Pyridinecarboxaldehyde (26.4 uL, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 5.5 mg (6%) of the title compound. (300 MHz, DMSO-d6) 13.50 (s, 1H), 9.31 (s, 1H), 8.66 (d, J=5 Hz, 1H), 8.45 (d, J=8 Hz, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.59 (q, J=13 Hz, 6 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.24 (s, 1H), 6.42 (m, 1H), 6.37 (m, 1H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.80 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=381 (M+H), HPLC: 1.69 min. (G Method)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]2[CH2:27]O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:40]([NH2:43])[C:41]#[CH:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]2[CH2:27][NH:43][CH2:40][C:41]#[CH:42])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: C#CCN
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: C#CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 47, 5-chloro-2',6'-difluoro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with p-toluenesulfonyl chloride followed by propargylamine, to give 5-chloro-2',6'-difluoro-2-[3-[[(2-propynyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O1CCN(C2C=CC(C=O)=CC=2)CC1.S1C=CC=C1[Mg]Br.[CH3:41][O:42][C:43]([O:47][Si](C)(C)C)=[C:44]([CH3:46])[CH3:45]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:45][C:44]([CH3:46])([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:8][CH:9]=1)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:43]([O:42][CH3:41])=[O:47]
Reactant: OC(c1ccc(N2CCOCC2)cc1)c1cccs1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Br[Mg]c1cccs1
Agent: O=Cc1ccc(N2CCOCC2)cc1
Product: COC(=O)C(C)(C)C(c1ccc(N2CCOCC2)cc1)c1cccs1
Yield: 82.3 %

Procedure:
In a similar manner to Preparation 1, Step 2, the reaction of (4-morpholinophenyl)-(thiophen-2-yl)methanol (675 mg, 2.45 mmol), prepared from 4-morpholinobenzaldehyde and thiophen-2-ylmagnesium bromide, and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (2.48 ml, 12.3 mmol) in the presence of titanium tetrachloride (1M in DCM, 5.40 ml. 5.40 mmol) afforded methyl 2,2-dimethyl-3-(4-morpholinophenyl)-3-(thiophen-2-yl)propanoate (725 mg, 82.5% yield).). 1H NMR (400 MHz, CDCl3): δ 1.15 (s, 3H), 1.20 (s, 3H), 3.06 (m, 4H), 3.51 (s, 3H), 3.78 (m, 4H), 4.59 (s, 1H), 6.76 (d, 1H, J=8.5 Hz), 6.83 (m, 1H), 6.87 (m, 1H), 7.06 (m, 1H), 7.20 (d, 1H, J=8.5 Hz). HPLC Rt: 3.181 min.
Reaction SMILES: CN(C)C=O.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])(=O)C.S(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:21][CH3:22])[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1O
Temperature: 25 °C
Yield: 92 %

Procedure:
Dimethylformamide (0.5 ml) was added to a solution of 7-(acetoxy)-6-methoxyquinazolin-4-(3H)-one (2.0 g, 8.5 mmol) in thionyl chloride (32 ml) and the reaction mixture was heated at reflux for 1.5 hours. Upon cooling to ambient temperature, the thionyl chloride was removed in vacuo and azeotroped twice with toluene. The residue was diluted with dichloromethane (15 ml), a solution of 10% ammonia in methanol (80 ml) added and the mixture heated at 80° C. for 10 minutes. Upon cooling to ambient temperature, the solvent was evaporated to almost complete dryness, water was added and the pH adjusted to 7 with dilute hydrochloric acid. The resultant precipitate was collected by filtration and dried in vacuo at 35° C. for 18 hours to yield 4-chloro-7-hydroxy-6-methoxyquinazoline (1.65 g, 92% yield):
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14]1.I[CH3:31]>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]1[CH2:18][C@@H:17]([O:19][CH3:31])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:14]1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H](CN2C(=O)c3ccccc3C2=O)C1
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.6 %

Procedure:
To cis-phenylmethyl (3RS,5SR)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-hydroxy-1-piperidinecarboxylate (380 mg, 0.96 mmol) in 5 mL of CH2Cl2 was added iodomethane (1 mL, 16.1 mmol) and Ag2O (1.15 g, 5.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 48 h. The reaction mixture was filtered through a pad of Celite® which was washed with 25 mL CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using a 10-100% EtOAc/hexanes gradient to provide the desired compound (210 mg; 53%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][N:31]1[CH2:32][CH2:33][CH:28]([C:26](=[O:27])[C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=2)[CH2:29][CH2:30]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A solution of ((R)-1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.0 mmol), (4-fluoro-phenyl)-piperidin-4-yl-methanone (0.414 g, 2.0 mmol) and sodium triacetoxyborohydride (0.638 g, 3.0 mmol) in tetrahydroftiran (20 ml) is stirred at ambient temperature for 24 hours. The solvent is evaporated and the residue redissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The dichloromethane is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethylacetate:hexane, 3:1 elution) to afford {(R)-1-benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}carbamic acid tert-butyl ester. [MH]+441.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[N:9]=1)[CH3:2].Cl[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29].N1C=CC=CC=1>C(OCC)C>[C:28](=[O:29])([O:30][CH2:31][CH2:32][O:33][CH3:34])[O:24][C:22]1[CH:23]=[C:18]([N:5]2[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:19]([F:26])=[CH:20][C:21]=1[Cl:25]
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: COCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(=O)OCCOC)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone and 2-methoxyethyl chloroformate with pyridine in diethyl ether there is obtained {5-[2-ethoxy-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-2-chloro-4-fluorophenyl} 2-methoxyethyl carbonate, 1H-NMR (CDCl3, 400 MHz): 7.39 ppm (d,1H), 7.26 ppm (d,1H), 6.64 ppm (s,1H), 4.39°-4.56 ppm (m,4H), 3.70 ppm (m,2H), 3.43 ppm (s,3H), 1.30 ppm (t,3H):
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[N:17]=[C:16]2[CH2:18][O:19][C:20](=O)[C:15]2=[CH:14][CH:13]=1.Cl>C1COCC1>[CH3:11][C:12]1[N:17]=[C:16]2[CH2:18][O:19][C:20](=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[C:15]2=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1ccc2c(n1)COC2=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
A solution of 1,3-dihydro-indol-2-one (200 mg, 1.5 mmol.) in THF (2 mL) is placed under an argon atmosphere and cooled in an ice bath. A solution of Li bis(trimethylsilyl)amide (4.0 mL of a 1M solution in THF, 4.0 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is then removed and a solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (150 mg, 1.00 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and then poured into 10% aqueous HCl solution (50 mL). After 10 min at room temperature, the reaction is heated to ˜90° C. for 45 min followed by stirring at room temperature for 36 h. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH, EtOAc, Et2O and dried under vacuum to give the title compound as a yellow solid (78 mg, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:29]=[N:30][C:31]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[N:32][CH:33]=1>CN(C=O)C>[F:45][C:42]([F:43])([F:44])[O:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:31]2[N:30]=[CH:29][C:28]([CH2:27][O:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[C:7](=[O:9])[O:8][C:4]=4[CH:3]=3)=[CH:33][N:32]=2)=[CH:40][CH:39]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2cc(O)ccc21
Reactant: FC(F)(F)Oc1ccc(Nc2ncc(CCl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)oc2cc(OCc3cnc(Nc4ccc(OC(F)(F)F)cc4)nc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To a solution of 6-hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (0.093 g, 0.329 mmol) in DMF (4 mL) was add cesium carbonate (0.322 g, 0.988 mmol) and 5-(chloromethyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (0.1 g, 0.329 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate, and washed with 10% NaOH solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using 20 to 80% ethyl acetate in hexanes to give 6-((2-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as an white solid (0.07 g, 39%). LCMS: RT 2.216 min; 529.2 [M−H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:26][C@H:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH3:25])[N:3]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 47.3 %

Procedure:
2.4 g of 2,4,6-trichloropyrimidine was dissolved in 24 ml of tetrahydrofuran, and 2.0 ml of triethylamine was added at room temperature, and a solution of 2.0 g of (S)-(−)-1-(4-fluorophenyl)ethylamine in 12 mL of tetrahydrofuran was added dropwise, and then the mixture was stirred at room temperature for 9.5 hours. The reaction mixture was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 1.77 g of the objective compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]O[CH2:3][CH2:2]1.[NH:38]1CCNCC1>>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[CH:17]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:6][CH2:5][NH:38][CH2:3][CH2:2]1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Reactant: C1CNCCN1
Product: O=C(CN1CCNCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Yield: 17 %

Procedure:
The title compound (0.047 g, 17%) was prepared from the product of Example 47 Step 1 and piperazine using the method of Example 47 Step 2; MS(ES+) m/e 485 [M+H]+.