Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[C@:26]([CH3:44])([C:40]([F:43])([F:42])[F:41])[O:27][CH2:28][C@:29]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[C:34](Br)[N:33]=3)([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[NH2:45][C:46]1[C:51]([C:52]#[N:53])=[CH:50][CH:49]=[CH:48][N:47]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[C@:26]([CH3:44])([C:40]([F:43])([F:42])[F:41])[O:27][CH2:28][C@:29]([C:32]3[N:33]=[C:34]([NH:45][C:46]4[N:47]=[CH:48][CH:49]=[CH:50][C:51]=4[C:52]#[N:53])[CH:35]=[CH:36][C:37]=3[F:38])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1cccnc1N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)CO[C@@]2(C)C(F)(F)F)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Nc4ncccc4C#N)ccc3F)CO[C@@]2(C)C(F)(F)F)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
To a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine (250 mg, 0.372 mmol) in toluene (3.72 ml) was added 2-amino-3-pyridinecarbonitrile (221 mg, 1.859 mmol), Pd2(dba)3 (6.81 mg, 7.43 μmol), BINAP (9.26 mg, 0.015 mmol) and sodium tert-butoxide (50 mg, 0.520 mmol). The reaction mixture was degassed for 5 min and the microwave vial was sealed and stirred at 100° C. for 9 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried with Na2SO4. The residue was purified by chromatography (silica gel; eluent DCM/MeOH+NH4OH) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.[I:33]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[I:33][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Ic1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C

Procedure:
10 g (24 mmol) of 2-bromo-9,10-diphenylanthracene was put in a 500 mL three neck flask, the atmosphere in the flask was substituted by nitrogen, and then 150 mL of tetrahydrofuran (THF) was added thereto and dissolved well. This solution was stirred at −78° C. Then, 19 mL of n-butyllithium solution (1.6 mmol/L) was dropped into this solution, with a syringe and stirred for 1 hour at −78° C., so that a white solid substance was precipitated. After reaction, a solution in which 12 g (49 mmol) of iodine was dissolved into 80 mL of tetrahydrofuran was dropped into this reacted mixture using a funnel for dropping. After dropping, the mixture was stirred for 1 hour at −78° C. and for 12 hours at room temperature. After reaction, a sodium thiosulfate solution was added into the reaction solution, and was stirred for 1 hour at room temperature. Ethyl acetate was added into this mixture for extraction. An aqueous layer and an organic layer were separated, and the organic layer was washed with sodium thiosulfate and saturated brine in this order. The aqueous layer and the organic layer were separated and the organic layer was dried with magnesium sulfate. This mixture was subjected to suction filtration so that the magnesium sulfate was removed. The obtained filtrate was concentrated, so that a solid substance was obtained. Methanol was added into this solid substance and washed by ultrasonic wave irradiation, so that a solid substance was precipitated. This solid substance was collected by suction filtration, so that 9.9 g of a light yellow powdered solid substance was obtained in a yield of 90%.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]([C:12]([F:15])([F:14])[F:13])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]([C:12]([F:13])([F:14])[F:15])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of (±)-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine (100 mg, 0.30 mmol) in 1.5 mL ethyl acetate was added 10% Pd—C (42 mg). The reaction mixture was then purged with nitrogen and then purged with hydrogen. A hydrogen balloon was then inserted through a septum into the reaction mixture and allowed to stir for 3 hours at room temperature. The solution was then filtered through a pad of celite and rinsed with ethyl acetate. The solvent was evaporated under reduced pressure to give a crude brown oil which was purified via flash chromatography (2:1 hexanes:EtOAc) to afford 85 mg (93%) (±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine. 1H NMR (400 MHz, CDCl3) 6.68 (d, 1H, J=8.4), 6.32–6.28 (m, 2H), 4.56 (dd, 1H, J=12.0, 0.96), 4.16–4.00 (m, 2H), 3.84–3.69 (m, 2H), 3.60–3.32 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][C@H:33]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][C@H:33]([CH2:37][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Yield: 92.3 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.14 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 0.560 g of potassium t-butoxide and 1.86 g of (S)-4-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)morpholine were reacted in 25 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.97 g (yield 92%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1(/[CH:8]=[CH:9]\[CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CC#CC2(O)CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2C/C=C\C2(O)CCCCC2)cc1

Procedure:
4-{3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (4.0 g., 0.01 mole) is dissolved in ethyl acetate (50 ml.) and hydrogenated at 25° C. and one atmosphere pressure over 1.0 g. of a 5% palladium on charcoal catalyst. The theoretical amount (0.01 mole) of hydrogen is absorbed in 110 minutes. The catalyst is removed by filtration and the solvent evaporated. The residual oil is chromatographed on 60 g. of silica gel with elution by 2% methanol is chloroform. The chromatographed product crystallizes and is recrystallized from butyl chloride to yield 1.4 g. of the title product, m.p. 118°-120° C.; pmr (CDCl3) δ5.14 (1H, m, --CH2 --CH=), 5.60 (1H, d, ##STR46##
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:38][CH3:39])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([C:34]([O:36]C)=[O:35])[CH2:23]1.[Li+].[OH-].O.Cl>C1COCC1>[C:30]([O:29][C:27]([N:25]1[CH2:26][C@@H:22]([O:21][C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:38][CH3:39])=[CH:4][CH:5]=3)[N:10]=[C:9]([N:12]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[N:13]3)[CH:8]=2)[CH2:23][C@H:24]1[C:34]([OH:36])=[O:35])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a stirred solution of compound 112 (650 mg, 1.13 mmol) in THF (12 mL) was added LiOH (82 mg, 3.41 mmol) and water. The reaction mixture was stirred at room temperature for 16 hrs and was acidified with 1N HCl to pH 5-6. Aqueous layer was extracted with EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 113 as a pink solid in 95% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7](=[O:19])[C:6]=2[N:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:7](=[O:19])[C:6]3[N:20]=[C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)[CH:3]=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: O=C1c2nc(Br)ccc2OCN1Cc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cc3)CO4)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (110 mg, 0.33 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (149 mg, 0.30 mmol) and K3PO4.3H2O (237 mg, 0.89 mmol) in dioxane/H2O (5 mL/0.2 mL) were added Pd2(dba)3 (13 mg, 0.02 mmol) and X-phos (14 mg, 0.03 mmol) under N2. The mixture was stirred at 110° C. for 1 hour. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (DCM:MeOH=100:1) to afford the product of 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (170 mg, yield: 82%). 1H-NMR (CDCl3, 400 MHz) δ 7.94˜7.97 (m, 3H), 7.75˜7.77 (m, 1H), 7.62 (s, 1H), 7.42˜7.45 (m, 1H), 7.33˜7.36 (m, 2H), 7.19 (t, J=7.6 Hz, 2H), 7.05 (t, J=7.6 Hz, 2H), 6.05 (br s, 1H), 5.22 (s, 2H), 4.78 (s, 2H), 3.22 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.93 (s, 3H). MS (M+H)+: 633.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]([F:24])[C:21]([Cl:25])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)ccc2C(=O)O)cc1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 87.1 %

Procedure:
2-(4-tert-Butyl-benzenesulfonylamino)-4-fluoro-benzoic acid (23 g, 65.5 mmol) was added to 230 mL of stirring acetic acid in a 500 mL round bottom flask. N-chlorosuccinimide (17.5 g, 131 mmol) was then added and the mixture heated to 80° C. under a N2 atmosphere. The reaction was determined to be complete in seven hours according to LCMS analysis. The heat bath was subsequently removed and the reaction was quenched via the addition of 250 mL of a 50% solution of sodium metabisulfite. The mixture immediately formed a thick white slurry which was allowed to stir for approximately 15 minutes. Vacuum filtration of the slurry resulted in a white solid that was washed with a small amount of water and dried in vacuo to generate 22 g of 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-4-fluoro-benzoic acid (white solid, 87% yield): HPLC retention time=2.87 minutes; MS (ES) M+H expected 386.0, found 386.0.
Reaction SMILES: O=[C:2](C1SC=CC=1)[CH2:3]C#N.[C:11]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH3:12].CC1SC=C(C(=O)CC#N)C=1>>[C:11]([O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])([O:19][CH2:20][CH3:21])[CH2:12][CH2:2][CH3:3]
Reactant: N#CCC(=O)c1cccs1
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1cc(C(=O)CC#N)cs1
Product: CCCC(OCC)(OCC)OCC

Procedure:
The general procedure of Example 11 is repeated but replacing the β-oxo-2-thiophenepropionitrile and triethyl orthoacetate employed in that example with equivalent amounts of 5-methyl-β-oxo-3-thiophenepropionitrile and triethyl orthobutyrate whereby there is obtained the title compound in equally good yield.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
The mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.59 mmol), 4-methoxyphenyl methylbromide (0.094 mL, 0.65 mmol), potassium carbonate (244 mg, 1.77 mmol) in DMF (10 ml) was stirred at room temperature for 2 hours. The reaction was quenched with water and the solid formed was filtered and dried over to yield the desired product (270 mg, 99.7%). LCMS calculated for C2OH BrN6O2: 459.1. found 460.1.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C.CCOC(C)=O>O>[Br:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18]([OH:19])=[N:20][C:3]([C:2]([F:13])([F:1])[C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=3)=[N:15]2)=[CH:21][CH:22]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: NC(=O)c1ccc(Br)cc1N
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (2.05 g, 9.62 mmol) and 2-amino-4-bromobenzamide (1.89 g, 8.75 mmol) was added trimethylsilyl polyphosphate (˜15 mL) and the mixture was stirred overnight at 120° C. Equal volumes of EtOAc and water were added and the resulting solution was stirred for 1 h. The EtOAc layer was washed with brine, dried over Na2SO4 and then concentrated under reduced pressure. Et2O was added and evaporated. Trituration of the residue with hexanes, followed by collection of the solid by filtration afforded 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (2.49 g, 77%). 1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.76 (s, 1H), 7.97-8.07 (m, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.69-7.81 (m, 2H);
Reaction SMILES: C([O:8][C:9](=[O:51])[CH2:10][C@@H:11]([N:34]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)=[CH:41][CH:40]=2)=[CH:35]1)[C:12]([NH:14][C@H:15]1[CH2:31][C:30]2=[CH:32][N:23]([C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH:17][C:16]1=[O:33])=[O:13])C1C=CC=CC=1.C(O)=O.CC(O)=O>CCOC(C)=O.CCO.C1COCC1.[Pd]>[O:33]=[C:16]1[C@@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:34]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[CH:41][CH:40]=3)=[CH:35]2)[CH2:10][C:9]([OH:51])=[O:8])[CH2:31][C:30]2=[CH:32][N:23]([C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH:17]1
Reactant: O=C(C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a solution of N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12,14,1 6-tetraen-9(S)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (185 mg, 0.280 mmol) in EtOAc/EtOH/THF was added in succession 10% palladium on carbon (50 mg) and 88% formic acid (0.1 mL). After 1.5 hours, HOAc (1 mL) was added. After 16 hours, more 10% palladium on carbon (25 mg), 88% formic acid (0.1 mL), and HOAc (1 mL) was added. At 24 hours, more 10% palladium on carbon (25 mg) was added. After 25 hours total elapsed time, the catalyst was filtered off. The filtrate was concentrated to a crude solid. The product dissolved in a minimal amount of MeOH/EtOAc, and inorganic particulates were filtered away. The filtrate was concentrated to a solid that was triturated with CH2Cl2/hex to give 76 mg (46%) of N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9(S)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp >172° C. (d).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.Cl[C:15]1[C:16](=[O:29])[NH:17][C:18]2[C:23]([N:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2>CN1C(=O)CCC1>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[C:15]1[C:16](=[O:29])[NH:17][C:18]2[C:23]([N:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C[C@H]1CN(c2ccccn2)CCN1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of (S)-3-methyl-1-(pyridin-2-yl)piperazine (748 mg, 4.22 mmol) in NMP (5 ml), was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1 g, 4.19 mmol). After stirring 1 h at 140° C., the resulting solution was quenched by the addition of water (100 ml) and filtered to give (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (1.07 g, 67%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[F:22][C:23]([F:40])([F:39])[C:24]1[N:29]=[CH:28][C:27]([NH:30][NH:31]C(OC(C)(C)C)=O)=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:30]([C:27]3[CH:28]=[N:29][C:24]([C:23]([F:22])([F:39])[F:40])=[CH:25][CH:26]=3)[N:31]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)nc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 47.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.350 g), tert-butyl 2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate (Intermediate-61, 0.350 g), DCM (20 mL) and TFA (5.0 mL) to afford 0.250 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:46])/[C:18](/[NH:42][C:43](=[O:45])[CH3:44])=[CH:19]\[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:30][C:29](=[O:31])[NH:28][S:27]2(=[O:33])=[O:32])=[C:22]([O:34]CC2C=CC=CC=2)[CH:21]=1>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3](=[O:47])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:46])[CH:18]([NH:42][C:43](=[O:45])[CH3:44])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:30][C:29](=[O:31])[NH:28][S:27]2(=[O:32])=[O:33])=[C:22]([OH:34])[CH:21]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)/C(=C\c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)C(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)NC(C)=O

Procedure:
A solution of 2-(4-{(E)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acryloylamino}-butoxy)-6-hydroxybenzoic acid methyl ester (300 mg) in 16 mL of EtOH/HOAc (1:1) is hydrogenated 1 atm over 10% Pd/C (70 mg) for 4 h. The catalyst is filtered, the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC and lyophilization to give the title compound as a white solid. This is converted to its potassium salt by addition of 1 equivalent of KHCO3: (M−1)−=577. HPLC retention time: 0-86 min. (Method A).