Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>O1CCCC1>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:3][N:4]=1)(=[O:11])[CH3:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ncc(N)cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
To a solution of N-(5-aminopyrimidin-2-yl)acetamide (450 mg, 2.96 mmol) and pyridine (0.718 ml, 8.87 mmol) in tetrahydrofuran (10 ml) was added 2,2,2-trichloroethyl chloroformate (0.612 ml, 4.44 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling and then at room temperature for 2 hours, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (88.3 mg, 9.1%) as a solid.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:24][N:23]([C:25]([C@H:27]4[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29][CH2:28]4)=[O:26])[CH2:22]3)[CH:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>C(Cl)Cl>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:22][N:23]([C:25]([CH:27]4[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]4)=[O:26])[CH2:24]3)[CH:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1
Reactant: O=C([C@H]1CC[C@@H](O)CC1)N1CC(Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCC(C(=O)N2CC(Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl](cis-4-hydroxycyclohexyl)methanone (60 mg) in methylene chloride (1.2 mL) was added a Dess-Martin reagent (53 mg) under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium bicarbonate solution, the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to obtain 4-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl]carbonyl}cyclohexanone (20 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([OH:23])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[Cl:31][C:32]1[C:33]([F:49])=[C:34]([C@H:38]([NH:40][C:41]([C@@H:43]2[CH2:48][C@@H:47]3[C@@H:45]([CH2:46]3)[NH:44]2)=[O:42])[CH3:39])[CH:35]=[CH:36][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:31][C:32]1[C:33]([F:49])=[C:34]([C@H:38]([NH:40][C:41]([C@@H:43]2[CH2:48][C@@H:47]3[C@@H:45]([CH2:46]3)[N:44]2[C:21](=[O:23])[CH2:20][N:13]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:8]([NH2:9])=[O:10])=[N:12]2)=[O:42])[CH3:39])[CH:35]=[CH:36][CH:37]=1
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1)c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(N)=O)c2ccncc21)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid trifluoroacetate salt (2.65 g, 7.94 mmol, prepared as described in Scheme A26) in DMF (30 mL) were added successively (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid, [(R)-1-(3-chloro-2-fluoro-phenyl)-ethyl]-amide trifluoroacetate salt (3.00 g, 7.56 mmol), HBTU (3.44 g, 9.07 mmol) and DIPEA (5.28 mL, 30.2 mmol). The reaction mixture was stirred at RT for 16 h and then was concentrated under vacuum. The residual oil was partitioned between CH2Cl2 and a sat. aq. NaHCO3 solution. A solid precipitated from the resulting emulsion and was filtered off, washed with water and dried under vacuum. The solid was suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. MS (LC/MS): 485 [M+H]+; tR (HPLC conditions c): 3.54 min.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl.O>CCOC(C)=O>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114, 1624-35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ 7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s, 1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s, 1H); APCI−MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46 H2O.0.2 EtOAc: C, 47.41, H. 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[OH:32][C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH:36]3[NH:43][CH3:44])[CH2:34]1)[CH2:40]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([N:43]([CH:36]2[CH:37]3[CH2:38][CH:39]4[CH2:40][C:33]([OH:32])([CH2:34][CH:35]2[CH2:41]4)[CH2:42]3)[CH3:44])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(C(=O)c1cccc(OCC2CCCCC2)c1)C1C2CC3CC1CC(O)(C3)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
3-Cyclohexylmethoxy-benzoic acid (300 mg, 1.3 mmol), HOBT (294 mg, 1.9 mmol), EDC (245 mg, 1.3 mmol), and 1-hydroxy-4-methylaminoadamantane (232 mg, 1.28 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.6 mmol) was added. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was purified directly by Preparative HPLC to give 199 mg of the title compound as a mixture of two isomers.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.[CH2:23](OC(OCC)OCC)C>C(O)(C)C>[C:1]([C:3](=[CH:23][NH:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2]
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccsc1
Solvent: CC(C)O
Product: COc1cc(NC(=O)C(C#N)=CNc2ccsc2)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 25.6 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (1.57 g, 6.06 mmol) in 200 mL of iso-propanol was added 3-aminothiophene (600 mg, 6.06 mmol). This mixture was heated to reflux and triethylorthoformate (6.5 mL, 39.1 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. Additional 3-aminothiophene (214 mg, 2.16 mmol) was added and the reaction mixture was heated at reflux for 5 hours. Additional 3-aminothiophene (100 mg, 1.01 mmol) was added and the reaction mixture was heated at reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with iso-propanol to give 572 mg (26%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(thien-3-ylamino)prop-2-enamide as a tan solid, mp >250° C.; MS 366.0, 368.2 (M−H)−
Reaction SMILES: [NH2:1][C:2]1C(C=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C([C:12]([CH2:19][CH3:20])([C:16]([O-:18])=O)[C:13]([O-:15])=[O:14])C.N1CCC[CH2:23][CH2:22]1>>[O:18]=[C:16]1[C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[CH:19][C:20]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1]1
Reactant: C1CCNCC1
Reactant: Nc1ncccc1C=O
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Product: CCOC(=O)c1cc2cccnc2[nH]c1=O
Temperature: 120 °C
Yield: 90.6 %

Procedure:
2-Amino-3-pyridine carboxaldehyde (1.0 g, 8.19 mmol) was suspended in diethylmalonate (6.2 ml, 41.0 mmol) in a screw cap pressure tube. Piperidine (1.6 ml, 16.4 mmol) was added and the tube was sealed. The mixture was heated to 120° C. for 3.0 hours. The mixture was allowed to cool. The precipitate formed was filtered and washed with Et2O to yield 1.62 g (91%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[N:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([CH3:29])[N:28]=2)[CH:25]=1.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Br:19][C:20]1[N:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([CH3:29])[N:28]=2)[C:25]=1[Cl:30]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cn2cc(Br)ncc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cn2c(Cl)c(Br)ncc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Into a 1-neck round-bottom flask N,N-diisopropylamine (0.50 mL, 3.6 mmol) was dissolved in tetrahydrofuran (4.0 mL) and cooled at −78° C. 1.6 M n-butyllithium in hexane (1.9 mL, 3.1 mmol) was added. The reaction was stirred at −78° C. for 30 min and 6-bromo-2-methylimidazo[1,2-a]pyrazine (from Ark Pharm, 0.500 g, 2.36 mmol) in tetrahydrofuran (6.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 45 min and hexachloroethane (0.72 g, 3.1 mmol) was added. The resulting mixture was stirred at −78° C. for 1 h. The reaction was quenched with NH4Cl solution and then partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried (MgSO4), and stripped in vacuo. The residue was chromatographed on silica gel eluting with 40% EtOAc in hexanes to give the desired product (0.25 g, 43%). LCMS calculated for C7H6BrClN3 (M+H)+: m/z=245.9. Found: 245.9. 1H NMR (CDCl3, 400 MHz) δ 8.72 (1H, s), 7.68 (1H, s), 2.56 (3H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[C:33]1(=[O:38])[O:37][CH2:36][CH2:35][CH2:34]1.[Na].C[Si](C)(C)N[Si](C)(C)C>O1CCCC1>[OH:38][CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:21])[NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=4)[CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1)=[O:37]
Reactant: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Reactant: O=C1CCCO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(CCCO)Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
30 mg (0.068 mmol) of 1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea were dissolved in 2 ml of dry tetrahydrofuran and 15 μl (0.34 mmol) of γ-butyrolactone were added. The reaction mixture was cooled to 0° C. and a solution of 680 μl (0.68 mmol) of hexamethyldisilazane sodium salt 1M in THF in 2 ml of the same solvent were added dropwise. The mixture was maintained at 0° C. for 6 hours and at room temperature overnight, then partitioned between dichloromethane and water. The organic phase was dried over sodium sulphate and evaporated. The crude was finally purified by preparative HPLC in reverse phase conditions (basic eluant), giving 20 mg (59%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCC1CCCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 290 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>C(OCC)C>[C:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: CCOCC
Product: CC(C)OB(OC(C)C)C(C)(C)C
Temperature: -78 °C

Procedure:
The reaction was conducted as described in Example 1 with tert-butyllithium (30.9 mL, 51 mmol) which was added to triisopropoxyborane (9.59 g, 51 mmol) in 51 mL ethyl ether cooled to -100° C. instead of -78° C. Solvents were removed at 0° C. and 15 mm Hg. The oil bath was maintained at 50° C. to furnish tert-butyldiisopropoxyborane: 8.44 g (45.3 mmol, 89%), bp 136-138 (754 mm Hg); proton NMR (neat) δ4.50 (septet, J=18 Hz, 2H) 1.12 (d, J=18 Hz, 12H), 0.95 (s, 9H); boron NMR (neat) δ+29.5 ppm (s).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH:1]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:6]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1C(=O)OC)C(=O)C(OCC)OCC
Yield: 116.3 %

Procedure:
To a mixture of methyl 2-formylbenzoate (4.92 g), ethyl 4,4-diethoxyacetoacetate (7.2 g) and acetic acid (0.36 g) in benzene (15 ml) was added portionwise each one third portion of a solution of piperidine (306 mg) in benzene (5 ml) for each 20 minutes' interval, and the mixture was heated to reflux for 3 hours under removing off azeotropically the resulting water. After cooling, the reaction mixture was diluted with additional benzene (25 ml), washed three times with water and successively with diluted aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give reddish oil (12.7 g) of crude ethyl 2-(2-methoxycarbonylbenzyliden)-4,4-diethoxyacetoacetate which was used in the following reaction without any further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:53][CH2:54][CH2:55][O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CCOC(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:53][CH2:54][CH2:55][O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(OCCCOCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 90.8 %

Procedure:
To a 0.5 L stirred round bottom, purged with nitrogen, charge in order: [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-(4-hydroxybenzoyl)-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (13.58 mmol), acetonitrile (250 mL), and potassium carbonate (67.92 mmol). To this stirred solution, at room temperature, add 3-bromopropoxymethylbenzene (27.2 mmol) and heat at 60° C. for 16 hours under nitrogen. Dilute with EtOAc (200 mL) and filter. Concentrate the filtrate and purify by flash chromatography (330 g silica gel) eluting with 2-40% EtOAc/chloroform. Concentrate the product containing fractions to give the title compound (9.0 g. 90.79%): mass spectrum (m/z): 730.4 (M+H).
Reaction SMILES: [H-].[Na+].[H][H].[I-].[CH3:6][S+](C)C.[CH2:10]([O:26][CH2:27][CH:28]([CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[O:56])[CH:50]=1)[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CS(C)=O.O1CCCC1.O>[CH2:10]([O:26][CH2:27][CH:28]([CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]2[O:56][CH2:6]2)[CH:50]=1)[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C[S+](C)C
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C=O)c1)OCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C2CO2)c1)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A suspension of sodium hydride (3.23 g. of a 57 wt. % dispersion in mineral oil, 67 mmoles) in dimethylsulfoxide (117 ml.) was heated under a nitrogen atmosphere at 70° to 75° C. until hydrogen evolution stopped (45 min.). Tetrahydrofuran (88 ml.) was added and the mixture cooled to 0° to 5° C. Trimethylsulfonium iodide (13.67 g., 67 mmoles) was then added in portions, followed by rapid addition of a solution of 1,2-di-O-(n-hexadecyl)-3-O-(3-formylbenzyl)-glycerol (7.0 g., 10.6 mmoles) in tetrahydrofuran (58 ml.). The resulting mixture was stirred for 16 hours at room temperature, poured into water (200 ml.) and extracted with ether (3×180 ml.). The combined ether extract was washed with water (2×100 ml.) and saturated aqueous sodium chloride solution (100 ml.), dried (MgSO4), filtered and evaporated in vacuo to an oil (7.0 g., 98% yield), which was sufficiently pure to be used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2].[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([OH:22])=O>B(F)(F)F.CCOCC>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([OH:16])[CH:18]=2)[C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2]
Reactant: CCc1c(O)cc(O)cc1CC(=O)OC
Reactant: COc1ccc(C(=O)O)cc1O
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)c(O)c2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
Methyl 2-ethyl-3,5-dihydroxyphenylacetate (2.0 g, 9.7 mmol) obtained in Example 7, Step 2 was suspended in boron trifluoride diethyl etherate (40 mL), and 3-hydroxy-4-methoxybenzoic acid (1.7 g, 11 mmol) was added thereto, followed by stirring at 80° C. for 5 hours. After cooling to room temperature, the reaction mixture was added dropwise to ice-cold water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-9/1) to obtain methyl 2-ethyl-3,5-dihydroxy-6-(3-hydroxy-4-methoxy-benzoyl)phenylacetate (2.2 g, 65%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:41]>>[CH2:21]([CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:41])[CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1ccc(F)c(C)c1)CCNCC2
Yield: 87.3 %

Procedure:
The title compound (34 mg) was prepared according to Example 183 using 59 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 19 mg of 4-fluoro-3-methylphenylboronic acid. MS (ESI): exact mass calculated for C19H26FN3, 315.21; found, m/z 316.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.27-7.18 (m, 3H), 4.69-4.65 (m, 1H), 3.93-3.89 (m, 1H), 3.50-3.27 (m, 5H), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.87 (m, 2H), 1.83-1.76 (m, 2H), 0.81-0.68 (m, 6H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[H-].[Na+].C(O)(=O)C>CN(C=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccnc(Nc2ccc(F)cc2)c1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a mixture of 2-fluoro-isonicotinic acid (Aldrich, 423 mg, 3.0 mmol) and 4-fluoroaniline (555 mg, 5.0 mmol) in DMF (18 mL) at rt was added NaH (500 mg of 60% in oil), and the mixture was heated at 85° C. for 75 min. Acetic acid (0.7 mL) was added to the reaction mixture and it was concentrated in vacuo. To the residue were added EtOAc (100 mL) and water (20 mL), stirred for 20 min and the solid was filtered, washed with EtOAc and dried to obtain the desired product (600 mg, 50%) as a tan solid. 1H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.04 (d, 1H, J=4.9 Hz), 7.69 (dd, 2H, J=8.8, 4.9 Hz), 7.24 (s, 1H), 7.05 (dd, 2H, J=8.2, 6.0 Hz); MS(ESI+) m/z 233.3 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.C(N([CH2:28][CH3:29])CC)C>C1C=CC=CC=1.CC(C)=O>[C:4]([C:29]1[CH:28]=[CH:12][C:8]([C:9]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([NH:22][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][C:5]([C:4]([O:3][CH3:2])=[O:14])=[CH:6][CH:7]=3)[CH:16]=2)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:2])=[O:14]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1cccc(N)c1
Reactant: CCN(CC)CC
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)Nc2cccc(NC(=O)c3ccc(C(=O)OC)cc3)c2)cc1

Procedure:
The following are reacted in accordance with the instruction given in Example A: 180 g of terephthalic acid monomethyl ester monochloride (0.9 mol) dissolved in 1.8 liters of benzene, with 48.6 g of m-phenylenediamine (0.45 mol) and 126 ml of triethylamine in a mixture of 450 ml of benzene and 450 ml of acetone.