Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:49][CH2:50][CH2:51][NH2:52]>C(Cl)Cl.O>[F:49][CH2:50][CH2:51][NH:52][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ncnc(Cn2cc(C(=O)NCCF)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
See FIG. 16(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (250 mg, 0.84 mmol) was taken in a 100 ml single necked flask equipped with an air condenser connected to nitrogen source. DCM (10 mL) was added to get a suspension. Triethyl amine (1.162 mL, 8.38 mmol) was added to get a clear solution. 1-Propanephosphonic acid cyclic anhydride (1.497 mL, 2.51 mmol) was added followed by the addition of 2-fluoroethanamine hydrochloride (83 mg, 0.84 mmol). The reaction mass was stirred at RT for overnight, suspension was observed. After completion of the reaction, diluted with DCM, added water, and separated the DCM layer washed with brine solution. The DCM layer was dried over sodium sulphate, evaporated and purified the compound by column chromatography. Yield-52%. ES+MS m/z: 344 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.25 (s, 20 H) 3.67 (d, J=5.46 Hz, 7 H) 3.77 (d, J=5.46 Hz, 7 H) 4.50 (t, J=4.90 Hz, 7 H) 4.66 (t, J=4.99 Hz, 7 H) 5.69 (s, 13 H) 7.26 (dd, J=8.29, 4.71 Hz, 7 H) 7.94 (d, J=8.48 Hz, 7 H) 8.28 (s, 7 H) 8.41 (s, 6 H) 8.49 (d, J=4.52 Hz, 7 H) 8.95 (t, J=5.84 Hz, 7 H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:32][N:33]1[CH:37]=[C:36]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:35]=[N:34]1
Reactant: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCC(C(F)(F)F)CC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 31.3 %

Procedure:
A degassed mixture of 6-bromo-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.15 g, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.13 g, 0.60 mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II)(25 mg, 0.03 mmol) in acetonitrile (3 mL) and saturated aqueous sodium carbonate solution (3 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM and water then separated on a hydrophobic frit. The organic phase was evaporated then the resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford a residue which was purified by HPLC (C18 column, 50-98% MeCN in water (plus 20 mM triethylamine) to afford the title compound (46 mg, 31%). 1H NMR (DMSO-D6, 400 MHz): 12.15 (s, 1H), 8.94-8.88 (m, 2H), 8.86 (d, J=1.1 Hz, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.56 (s, 2H), 2.99-2.88 (m, 2H), 2.39-2.19 (m, 1H), 2.00 (t, J=1.5 Hz, 2H), 1.85-1.94 (m, 2H), 1.57-1.38 (m, 2H). LCMS (Method A): RT=5.22 min, M+H+=491.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1Br.[CH2:13]([O:15][C:16]([O:18][CH2:19][CH3:20])=[CH2:17])[CH3:14].C([Li])CCC>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16]1([O:18][CH2:19][CH3:20])[CH2:17][C:2]2[C:3]1=[CH:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=2)[CH3:14]
Reactant: COc1cc(Br)c(Br)cc1OC
Reactant: C=C(OCC)OCC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CCOC1(OCC)Cc2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 30.6 %

Procedure:
2.55 g of 1,2-dibromo-4,5-dimethoxybenzene (8.62 mmol; 2 eq) and 500 mg of 1,1-diethoxyethene (4.31 mmol; 1 eq) in 25 mL of toluene are stirred at 0° C. under argon. 3.5 mL of n-butyllithium (2.5M in hexane, 8.62 mmol; 2 eq) are added dropwise at 0° C. When the addition is complete, the reaction mixture is stirred for 22 hours at ambient temperature. The reaction mixture is then hydrolysed and extracted 3 times with ethyl acetate. The organic phases are dried and evaporated, and the crude product is purified by column chromatography over silica gel (eluant: heptane/ethyl acetate 90/10). There are obtained 333 mg of a yellow oil which crystallises at ambient temperature.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.[OH-].[Na+].[CH2:8](Br)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(O)(=O)C.C(O)C>[C:1]([O:4][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC(=O)c1ccccc1

Procedure:
Five grams of acetic acid are added to 25 mls. of water in a suitable vessel and carefully neutralized with 10% aqueous sodium hydroxide. A few drops of acetic acid are then added until the solution is just acid to litmus paper. Fifty milliliters of ethanol and 5 grams of phenacyl bromide are then added and the mixture is refluxed for 1 hour. If a solid separates during refluxing additional ethanol is added to dissolve the same. The solution is allowed to cool and the phenacyl acetate is recovered by filtration and purified by recrystallization from ethanol, m.p. 47°-48° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[NH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[CH2:11]([N:10]1[CH2:2][CH2:3][N:4]([CH2:8][CH2:7][OH:6])[C:5]1=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: O=C1OCCN1CCCl
Reactant: CCCCN
Solvent: O
Product: CCCCN1CCN(CCO)C1=O
Yield: 72 %

Procedure:
6.17 g of 3-(2-chloroethyl)oxazolidin-2-one and 6.45 g of 1-aminobutane were stirred together for 30 hours at room temperature and then at reflux for 6 hours. The cooled reaction mixture was diluted with water and extracted with ether. The organic extracts were dried and concentrated to give 5.53 g (70%) of crude 1-butyl-3-(2-hydroxyethyl)imidazolidin-2-one. A dry 250 ml flask equipped with nitrogen inlet, refluxcondenser and stirring bar was charged with 1.34 g of hexane washed 60% NaH/oil and 40 ml of dry DMF. To this was slowly added 5.23 g of 1-butyl-3-(2-hydroxyethyl)imidazolidin-2-one in 10 ml of THF. After the initial reaction had subsided the reaction mixture was heated at 60° C. for 2 hours. 3.1 ml ofiodoethane was injected dropwise into the reaction mixture and it was refluxed for 16 hours. The reaction mixture was cooled and quenched with dilute HCl and ether. The ether layer was washed with brine, dried and concentrated to give 5.15 g (85.5%) of crude product. Kugelrohr distillation at 120°-125° C./0.2 mm gave colorless oil.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH3:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].[CH2:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH3:16].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH:10]([C:9](=[O:14])[CH3:8])[C:11](=[O:13])[CH3:12])=[CH:19][CH:18]=1)[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: CCc1ccc(C=O)cc1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CC#N
Product: CCc1ccc(CC(C(C)=O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A suspension of sodium iodide (15.0 g) in acetonitrile (100 ml) was cooled to 0° C. under argon atmosphere, and thereto were added dropwise chlorotrimethylsilane (12.7 ml), 2,4-pentanedione (2.05 ml) and 4-ethylbenzaldehyde (2.68 g), successively. The reaction mixture was stirred at room temperature for 17 hours, and further stirred at 60° C. for 10 hours. The reaction mixture was cooled to room temperature and poured into an aqueous sodium thiosulfate solution. The mixture was extracted with diethyl ether, and the extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3-(4-ethylphenylmethyl)-2,4-pentanedione (2.72 g) as pale yellow oil. APCI-Mass m/Z 219 (M+H).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:8](=[O:7])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 472 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:43][CH:44]=1)[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN(C)Cc3ccccc3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1ncccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
To a solution of 3-bromo-2-pyridinecarboxylic acid (available from Fluorochem Ltd, 0.81 g, 4.03 mmol) in DMF (10 ml) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.53 g, 4.03 mmol) and DIPEA (2.11 ml). The mixture was stirred at room temperature for 10 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (0.5 g, 2.01 mmol) was added and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to 5 ml which was added to 2×50 g aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The solvent was removed in vacuo to give a brown oil that was placed in the vacuum oven overnight. DCM was added to the oil and a precipitate occurred, which was collected by filtration to give the title compound (0.58 g) as a cream solid.
Reaction SMILES: Cl[CH:2]([CH3:24])[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:23])[CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[O:16])=O.O1CCC[CH2:26]1>CN(C)C1C=CN=CC=1>[CH2:24]([CH:2]1[C:3]2=[N:5][C:6]3[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=3[C:13]([OH:23])=[C:14]2[C:15](=[N:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[O:16]1)[CH3:26]
Reactant: C1CCOC1
Reactant: CC(Cl)C(=O)Nc1c(F)cccc1C(=O)CC(=O)Nc1nccs1
Agent: CN(C)c1ccncc1
Product: CCC1OC(=Nc2nccs2)c2c1nc1c(F)cccc1c2O

Procedure:
Using the procedure of Step B of Example 6, 8.5 g of the product of Step E in 85 ml of tetrahydrofuran and 3.37 g of 4-dimethylamino-pyridine were reacted to obtain 6.5 g of 1,3-dihydro-3-ethyl-1-[(2-thiazolyl)-imino]-5-fluoro-furo[3,4-b]quinoline-9-ol melting towards 210° C.
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl>C1COCC1.[Fe](Cl)(Cl)Cl.CC(OC)(C)C>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: BrC1CCCC1
Agent: Cl[Fe](Cl)Cl
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 2.5 °C
Reaction time: 0.38 h

Procedure:
To a 50 L three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet, was added dry THF (35 L) and cooled to 0-5° C. To the flask was added Iron (III) chloride (2.7 kg, 0.15 eq) portion wise over 30-60 min. and stirred for 15-30 min. resulting in a clear greenish solution. Under a nitrogen atmosphere in a dry 100 gallon glass lined reactor was added THF (87.5 L) and magnesium turnings (4.05 kg, 1.5 eq), and cooled to 0-5° C. To the THF and magnesium mixture was added the solution of FeCl3 in THF at a rate to maintain the internal temperature below 10° C. To the resulting yellow/green mixture was added TMEDA (15.5 kg, 1.2 eq) at a rate to maintain the internal temperature below 20° C. The resulting reaction mixture was heated to 40-45° C. for 1 hour and a mixture of 1 bromo-2-(trifluoromethyl)benzene (25 kg, 1.0 eq) and bromocyclopentane (19.9 kg, 1.2 eq) was added to the reaction mixture at a rate to maintain an internal temperature below 25° C. The resulting reaction mixture was allowed to stir at room temperature overnight and subsequently cooled to an internal temperature of 0-5° C. To the resulting mixture was added 6 N HCl (100 L, 1.5 h) at such a rate as to maintain the internal temperature below 15° C. (caution, very exothermic). After the quench, MTBE (200 L) was added and the reactor contents was stirred for 30 min. The phases were separated and the aqueous layer back extracted with MTBE (75 L). The combined organic layers were washed with H2O (50 L), brine (50 L) and dried (MgSO4). The mixture was filtered through an in-line (1 micron) filter cartridge followed by an additional in-line (0.45 micron) filter cartridge into a clean dry reactor. The solvent was evaporated under vacuum (jacket≦30° C.) and co-evaporated with heptanes (2×25 L) to provide a viscous liquid. The viscous liquid was dissolved in heptanes (100 L) and passed through a silica plug (25 kg). The silica plug was eluted with heptanes (TLC, Rf˜0.8, silica gel, heptanes) and the fractions containing the product were evaporated to provide the title compound as a yellow liquid, 11.7 kg (49.2%), purity as determined by HPLC was 94.1%. 1H NMR conforms to reference standard.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([C:3]1[C:4]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1cccc(C=O)c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C=O)c1OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of 5.0 g of methyl 3-formyl-2-hydroxybenzoate, 11.7 g of 4-nitrobenzyl bromide, 11.7 g of potassium carbonate and 70 ml of dimethylformamide is stirred at room temperature for 1 hour. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to remove solvent to give 8.70 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate as colorless powder.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH2:43][C:44]3[CH:48]=[CH:47][NH:46][N:45]=3)[CH:40]=[CH:39][C:38]=2[C:49]([CH3:52])([CH3:51])[CH3:50])=[O:35])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4].Cl>CO.[C].[Pd]>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH2:43][C:44]3[CH:48]=[CH:47][NH:46][N:45]=3)[CH:40]=[CH:39][C:38]=2[C:49]([CH3:52])([CH3:51])[CH3:50])=[O:35])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(Cc3cc[nH]n3)ccc2C(C)(C)C)c(-c2cccc(OCCCOCc3ccccc3)c2)c2cccnc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(Cc3cc[nH]n3)ccc2C(C)(C)C)c(-c2cccc(OCCCO)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A suspension of N-[1-butyl-4-[3-[3-(benzyloxy)propoxy]phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(1-pyrazolylmethyl)phenyl]urea (1.86 g, 2.6 mmol), 10% palladium carbon (180 mg), conc. hydrochloric acid (0.21 ml, 2.6 mmol) in methanol is stirred under hydrogen atmosphere at room temperature for 8 hours. The mixture is filtered on celite, and the solvent is concentrated under reduced pressure. The resultant is dissolved in chloroform, and thereto are added water and aqueous ammonia. The mixture is stirred and the chloroform layer is dried over anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound (1.53 g, 2.46 mmol) as colorless amorphous.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ncn1)Oc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
According to the procedure described in Example 113B, 6-(trifluoromethyl)pyrimidin-4-amine (480 mg, 2.94 mmoles) was dissolved in 20 mL of tetrahydrofuran. To this solution was added potassium carbonate (528 mg, 3.82 mmoles), followed by phenyl chloroformate (598 mg, 3.82 mmoles). An additional equivalent of phenyl chloroformate was added after stirring overnight and the reaction heated to 60° C. for 2 days. The crude product was purified to afford phenyl 6-(trifluoromethyl)pyrimidin-4-ylcarbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 9.13 (s, 1H), 8.46 (s, 1H), 7.7-7.2 (m, 5H)
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].[CH:9]1[C:19]2[CH:18]=C[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1.O>COCCOCCOC>[F:6][C:2]1([F:7])[CH:18]2[CH:3]1[C:23]1[CH:22]=[CH:21][CH:20]=[CH:16][C:15]=1[C:14](=[O:24])[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:19]=12
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C1c2ccccc2C2C(c3ccccc31)C2(F)F
Yield: 45.1 %

Procedure:
A solution of sodium chlorodifluoroacetate (350 g) in diglyme (1400 mL) was added dropwise over 4 to 8 hours, preferably over 6 hours, to a solution of 5H-dibenzo[a,d]cyclo-hepten-5-one (25 g) in diglyme (500 mL), with stirring, and under nitrogen, maintaining the reaction temperature at 160°-165° C. The cooled reaction mixture was poured into water (1.8 L) and extracted with ether (1.8 L). The organic phase was washed with water, dried over sodium sulfate (Na2SO4), and evaporated. The residue was recrystallized from ethanol, then from acetone/hexane to give 14 g of 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6(1H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16]Cl)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>C(#N)C.O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine (500 mg, 1.95 mmol) to a solution of piperidine (0.58 mL, 5.84 mmol) and saturated aqueous NaHCO3 (2.5 mL) in acetonitrile (15 mL). Stir the mixture at room temperature overnight. Dilute the mixture with water (20 mL) and DCM (25 mL), separate the layers and extract the aqueous layer with DCM (3×20 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (547 mg, 92%). MS (APCI+) m/z: 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH3:59])=[CH:54][CH:53]=2)=[CH:4][C:5]([CH:12]2[C@H:17]([O:18]CC3C=CC=CC=3)[C@@H:16]([O:26]CC3C=CC=CC=3)[C@H:15]([O:34]CC3C=CC=CC=3)[C@@H:14]([CH2:42][O:43]CC3C=CC=CC=3)[O:13]2)=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:3]([CH2:51][C:52]2[CH:53]=[CH:54][C:55]([CH2:58][CH3:59])=[CH:56][CH:57]=2)=[CH:4][C:5]([C@H:12]2[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([OH:34])[C@@H:14]([CH2:42][OH:43])[O:13]2)=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC=C3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCCC3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 84 (170 mg, 0.21 mmol) and Pd/C (10 wt. %, 25.5 mg) in THF (2.0 mL) and MeOH (1.0 mL) was stirred at room temperature for 6 hours under atmosphere of H2. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by a prep HPLC to provide the product E023 (28 mg, 28%) as a white solid.