Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[CH2:30])[CH3:27])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[C:5]1([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:28][CH2:29][CH3:30])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: C=CCN(C)CCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(C)CCCCCc1cc2c(cc1F)N(C(=O)Oc1ccccc1)CC2
Yield: 57.9 %

Procedure:
Hydrogenolysis at atmospheric pressure of 5 mg (0.013 mmol) 5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester in 0.5 ml AcOH in the presence of 5 mg 10% Pd/C during 12 hrs, followed by filtration, evaporation of the AcOH, distribution of the residue between Et2O and 0.5 M NaOH, drying of the organic layer with Na2SO4, evaporation of the solvent and chromatograpy on silica gel with EtOAc/MeOH/NEt3 10:1:0.1 gave 3 mg (64%) of 6-Fluoro-5-[5-(methyl-propyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid phenyl ester as a yellow oil, MS: 399 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:32]=[N:33][N:34]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:30])[C:23](=[N:28][OH:29])[C:24](=O)[CH2:25]Cl)[C:19](=[O:31])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1.[NH2:35][C:36]([NH2:38])=[S:37].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:3]2[N:4]([N:32]=[N:33][N:34]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:30])[C:23]([C:24]4[N:35]=[C:36]([NH2:38])[S:37][CH:25]=4)=[N:28][OH:29])[C:19](=[O:31])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]3SC2)nn2nnnc12
Reactant: NC(N)=S
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4cc(N)c5nnnn5n4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-7-(4-chloro-2-hydroxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (5.12 g; 0.01 mole) was dissolved in anhydrous N,N-dimethylacetamide (25 ml). Thiourea (0.76 g; 0.01 mole) was added, and the mixture was stirred at room temperature for 3 hours. The resulting solution was dropped under stirring into ethyl acetate (250 ml). A gummy material precipitated; the supernatant mother liquors were discarded and the residue was carefully triturated with fresh ethyl acetate until a powder was obtained. The powder was collected by filtration and dried. There was thus obtained a N,N-dimethylacetamide solvate of the hydrochloride salt of the desired product. This material was dissolved in aqueous NaHCO3 and washed five times with ethyl acetate, then with diethyl ether. Nitrogen was bubbled in for 15 minutes, charcoal was added, the charcoal was filtered off and the solution made acidic with 2 N HCl. The crystalline precipitate was collected and thoroughly washed with water and then with ethyl alcohol, yielding 3.8 g of the title compound, identical by TLC, IR, NMR to the product prepared in Example 7.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of phosphorus tribromide (2.1 mL, 6.0 g, 22.1 mM) in 30 mL of carbon tetrachloride was slowly added dropwise to solution of 2-benzylbenzyl alcohol (1.98 g, 10 mM) in 70 mL of carbon tetrachloride at 0° C. The mixture was stirred at 0° C. for 2 hours, then at room temperature for 2 hours. The solvent was removed in vacuo and the residue diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 2.6 g (99%) of 2-benzylbenzyl bromide as a yellow solid. 1H NMR (DMSO-d6) δ 7.5-7.0 (m, 9H), 4.7 (s, 2H), and 4.15 (s, 2H). IR (CHCl3, cm−1) 3065, 1601, 1495, and 1453. MS (FD) m/e 260, 262.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:19]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[CH:7][CH:6]=2)[OH:20])[CH:21]=1
Reactant: CCc1cccs1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)ccc2OC)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of 2-ethylthiophene (3.00 g) in tetrahydrofuran (36 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.56 M hexane solution, 17.1 ml). The mixture was stirred at the same temperature for 30 minutes, and cooled to −78° C., and thereto was added dropwise a suspension of 5-bromo-2-methoxybenzaldehyde (5.74 g) in tetrahydrofuran (60 ml). The mixture was stirred at the same temperature for 2 hours, warmed to 0° C., and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-85:15) to give 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol (5.99 g) as a pale yellow syrup. APCI-Mass m/Z 309/311 (M+H−H2O).
Reaction SMILES: [BH3-]C#N.[Na+].[CH:5]([CH:18]1[CH2:23][C:22](=[O:24])[CH:21]=[CH:20][O:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH:5]([C@H:18]1[CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20][O:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1C=COC(C(c2ccccc2)c2ccccc2)C1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Yield: 68 %

Procedure:
NaCNBH3 (0.75 g, 12 mmol) was added portionwise to a mixture of 2-diphenylmethyl-2,3-dihydro-4H-pyran-4-one 2 (1.05 g, 4 mmol) and boron trifluoride etherate (1.99 g, 14 mmol) in dry THF (50 ml) cooled to −78° C. The reaction mixture was allowed to reach room temperature and the reaction was quenched with saturated aqueous NaHCO3 (30 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl ether (3×20 ml). The organic phases were combined and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure, and purification by flash chromatography (hexane/ethyl acetate 7:3) first afforded trans-2-benzhydryl-tetrahydropyran-4-ol 3a (0.73 g, 68% yield).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.7 %

Procedure:
To a N,N-dimethylformamide (DMF) (15 ml) solution of (4-tert-butylphenoxy)acetic acid (312 mg, 1.50 mmol) and N-[4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (451 mg, 1.80 mmol), 1-ethyl-3-(3′-dimethylaminopr6pyl)carbodiimide hydrochloride (EDC) (518 mg, 2.70 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol) and triethylamine (607mg, 6.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=100/1 to furnish 350 mg (58% yield) of the title compound as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].Cl[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>[Cu]I>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:23][CH:24]=1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(Cl)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Product: Cc1ccc(N2CCCC2=O)cc1
Temperature: 140 °C
Reaction time: 42 h
Yield: 62.4 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (20 mg, 0.105 mmol, 5.1 mol %), K2CO3 (600 mg, 4.34 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (26 μL, 0.217 mmol, 11 mol %), 2-pyrrolidinone (155 μL, 2.04 mmol) and 4-chlorotoluene (1.0 mL, 8.44 mmol) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 140° C. for 42 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 3:7; 20 mL fractions). Fractions 10-20 provided 223 mg (62% yield) of the product as white crystals. The 1H NMR spectrum was in accord with that reported by Boeyens et al. Billing, D. G.; Boeyens, J. C. A.; Denner, L.; Du Plooy, K. E.; Long, G. C.; Michael, J. P. Acta Cryst. (B) 1991, B47, 284.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>>[CH:11]1([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1cnc(C2CCCCC2)nc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cnc(C2CCCCC2)nc1
Yield: 22.1 %

Procedure:
A solution of 2-cyclohexyl-pyrimidine-5-carboxylic acid methyl ester (0.97 g, 4.39 mmol) and aqueous LiOH (1 M, 4.39 mL) MeOH (6 mL) is stirred at room temperature overnight. MeOH is evaporated in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The resulting precipitate is filtered off, washed with water and dried in vacuo to afford 2-cyclohexyl-pyrimidine-5-carboxylic acid (0.2 g, 22%) as a solid. MS: 207 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][OH:24])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:6])([F:25])[F:26])[CH:9]=1)(=[O:15])=[O:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCCCC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
Methanesulfonyl chloride (1 eq), dissolved in methylene chloride (2 ml/mmol) was added dropwise to a cooled solution (0° C.) of (1-(3-(trifluoromethyl)phenyl-sulfonyl)piperidin-2-yl)methanol (1.1 eq) in methylene chloride (4 ml/mmol) and triethylamine (2.5 eq). When the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature until, according to thin layer chromatography control, the reaction was complete. Hydrogen chloride solution (0.5 mol/l, 2 ml/mmol) was added, the mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield: 43%
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:7]([CH3:23])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:23])[C:8]=1[NH:10][C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC)ccc1Nc1cc(C(C)(C)C)nn1C
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(OC)ccc1Nc1c(Br)c(C(C)(C)C)nn1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxy-benzoic acid methyl ester (Example 155, 1.34 g, 4.22 mmol) in acetic acid (27 mL), was added dropwise a solution of Br2 (6.74 g, 4.22 mmol) in acetic acid (5 mL). The reaction was stirred for 5 min, and then water (100 mL) was added. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with water, and then with NaHCO3 (10% aqueous solution) 10 times. The organic layer was then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 5 to 10% EtOAc in hexane) to give the title compound as a light yellow solid. (1.49 g, 89%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.66 (s, 3H), 3.78 (s, 3H), 4.05 (s, 3H), 6.32 (d, 1H), 7.06 (dd, 1H), 7.48 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:48]3[CH2:50][CH2:49]3)=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:48]3[CH2:49][CH2:50]3)=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K33) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (353 mg, 72%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:20])[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[OH:28][CH2:29][CH2:30][NH2:31]>>[OH:28][CH2:29][CH2:30][NH:31][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][S:24](=[O:27])[CH2:25][CH2:26]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:20])[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: NCCO
Product: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-[N-methyl-N-(3-picolyl)-amino]-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 154°-156° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:21](OC)=[O:22])[C:8]2=[O:25])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH2:21][OH:22])[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)cn(Cc2ccc(Cl)cc2)c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: COc1ccc(-c2cc(CO)c(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
According to Scheme 18: To a solution of methyl 1-(4-chlorobenzyl)-5-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1 eq, 0.52 mmol, 0.20 g) in Et2O (7 mL) at −78° C. was added DIBAL (3 eq, 1.60 mmol, 1.11 g). The reaction was stirred at −78° C. for 30 minutes and 0° C. for 1 hour. The reaction was then allowed to warm to room temperature and quenched with saturated aqueous NH4Cl solution. The aqueous phase was extracted 3 times with AcOEt and the combined organic fractions were washed twice with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked 50 g column SiO2) using CH2Cl2/AcOEt 80/20 as eluent which was then recrystallized from pentane/Et2O to afford the title compound (0.04 mmol, 16.0 mg, 9%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=[O:23])=[CH:4][C:5]2[C:10](=[O:11])[O:9][CH2:8][N:7]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[CH3:19])[C:6]=2[C:20]=1[F:21].[F:25][C:26]1[C:31](OC(=O)C(F)(F)F)=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[F:25][C:26]1[C:31]([O:23][C:22]([C:3]2[C:2]([F:1])=[C:20]([F:21])[C:6]3[N:7]([C:12]4[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=4[CH3:19])[CH2:8][O:9][C:10](=[O:11])[C:5]=3[CH:4]=2)=[O:24])=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42]
Reactant: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)O)c(F)c(F)c21
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c(F)c21
Reaction time: 4 h
Yield: 83 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid (0.3 g, 0.67 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.127 mL, 0.74 mmol) and pyridine (0.60 mL, 0.74 mmol). After stirring for 4 hours the reaction mixture is diluted with ethyl acetate and washed 3 times with 1.0 M HCl solution, 3 times with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester as a dark orange oil (0.34 g, 83.1%). To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester (0.33 g, 0.54 mmol) in freshly distilled THF (10 mL) is added methylamine hydrochloride (0.037 g, 0.54 mmol) and N,N-diisopropylethylamine (0.019 mL, 1.08 mmol). After stirring for 17 hours, the reaction mixture was diluted with ethyl acetate and washed 2 times with water and 2 times with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide as a yellow solid (0.19 g, 76.9%); mp 219–223° C.; 1NMR (400 MHz; DMSO-d6) 8.40 (s, 1H), 8.06 (d, 1H, J=6.8), 7.74 (s, 1H), 7.50 (d, 1H, J=8.4), 6.87 (d, 1H, J=8.0), 5.61 (s, 2H), 2.76 (d, 3H, J=4.4), 2.25 (s, 3H); MS(APCI)m+1=459; Anal.calcd/found for C17H13F2IN2O3 C 45.00/45.39, H 3.01/3.16, N 6.05/5.88.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH:6]([Cl:8])[Cl:7].C(=O)([O-])[O-].[K+].[K+].N#N.[CH2:26](Br)[CH:27]=[CH2:28]>CC(C)=O>[CH2:28]([N:4]([C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[C:3]1[CH:10]=[C:11]([C:14]([F:16])([F:15])[F:17])[CH:12]=[CH:13][C:2]=1[Cl:1])[CH:27]=[CH2:26]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)C(Cl)Cl
Reactant: C=CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C(=O)C(Cl)Cl)c1cc(C(F)(F)F)ccc1Cl
Yield: 83.4 %

Procedure:
The intermediate N-[2'-chloro-5'-trifluoromethylphenyl]-3-chloro-4-chloromethyl-2-pyrrolidinone is prepared as follows: 50 g of 2-chloro-5-trifluoromethylaniline is combined with 34.8 g of triethylamine (TEA) and 200 ml of CH2Cl2. 48.6 g of dichloroacetyl chloride (DCAC) added dropwise while the mixture was kept at about 10° C. The mixture was stirred overnight forming a precipitate. The mixture was brought up to 1800 ml with CH2Cl2 and was washed 3 times (×) with 300 ml water, 3×300 ml 1.0N HCL and 3×300 ml saturated NaHCO3. The precipitate was dried over night with magnesium sulfate (MgSO4) and stripped, yielding 59 g of 2'-chloro-5'-trifluoromethyldichloroacetanilide. 58.3 g of the 2'-chloro-5'-trifluoromethyldichloroacetanilide and 37.2 g of potassium carbonate (K2CO3) were combined with 300 ml acetone and heated with stirring to reflux in a 2 liter flask equipped with a thermal reflux condenser, drop funnel and N2 bubbler. 39.1 g allyl bromide was added via the drop funnel at a constant temperature at 60° C. The mixture was refluxed for 2 hours and then stirred overnight. The mixture was filtered and stripped. 200 ml CH2Cl2 was added to the residue. This mixture was washed 3× with 100 ml H2O and 2× with 100 saturated NaCl solution. The filtrate was dried overnight in MgSO4 and stripped to yield 55 g of N-allyl-2'-chloro-5'-trifluoromethyldichloroacetanilide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[NH:53][N:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:51]2[CH:50]=[C:49]([CH3:48])[NH:53][N:52]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)n[nH]1
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5-methyl-1H-pyrazole-3-carboxylic acid as starting materials in 29% yield. LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c1NCC2
Product: CC(=O)N1CCc2cccc(C)c21
Temperature: 0 °C

Procedure:
A solution of 7-methylindoline (10.2 g) in acetic anhydride (25 ml) was refluxed for 30 min. After cooling, the reaction solution was poured into ice water (250 ml) and the resulting crystal was filtered by means of suction, heated and vacuum dried to yield the end product (11.7 g).