Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl>[F:24][C:21]([F:22])([F:23])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[CH2:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:31][CH:30]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)([OH:29])[C:25]([F:28])([F:26])[F:27]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2-(4-((4-(4-Aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.336 mmol, 150 mg) and 2-phenylacetyl chloride (0.504 mmol, 0.067 mL, 78 mg) were combined in dichloromethane (3 mL) and cooled to 0° C. Triethylamine (0.672 mmol, 0.093 mL, 68.0 mg) was added and the mixture allowed to stir at 0° C. for 2 hours before allowing to warm to room temperature and stirring overnight. The reaction was diluted with dichloromethane and washed with water. The mixture was filtered through a hydrophobic frit and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane-10% methanol/dichloromethane gradient) to afford the title compound (124.4 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH2:18](I)[CH3:19]>>[CH2:18]([O:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:19]
Reactant: CCI
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Product: CCOCC1(CO)c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
The target product as white crystal was prepared from 9,9-bis(hydroxymethyl)fluorene and ethyl iodide through the same procedure as described above. Yield: 51%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCOCC1.O>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Glycine ethyl ester hydrochloride (31.39 g, 225.0 mmol) is dissolved in dioxane (150 mL) and water (150 mL), triethylamine (69.0 mL, 495.0 mmol) is added, and the solution is cooled to 0° C. To this solution is added 4-methoxybenzenesulfonyl chloride (51.15 g, 248.0 mmol) over 10 minutes. The reaction is warmed to room temperature and stirred overnight. The next day the mixture is reduced to one-half volume by evaporating solvent, diluted with 1N sodium hydroxide, and extracted well with ether. The combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/ethyl acetate/hexanes to give ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=383.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:14]([NH:16][CH3:17])[CH3:15])[N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Na+].[Na+].C1COCC1>O.CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C@H:14]([N:16]([CH3:17])[C:19](=[O:20])[O:21][CH3:22])[CH3:15])[N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CN[C@H](C)c1nc(-c2ccc(I)cc2)cn1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(C)[C@H](C)c1nc(-c2ccc(I)cc2)cn1C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a 250 mL round bottom flask was added (R)-1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)-N-methylethanamine (3.1 g, 9.1 mmol), methyl chloroformate (0.84 mL, 10.9 mmol), Na2CO3 (1.15 g, 10.9 mmol), and THF (100 mL). The reaction was stirred for 2 hours, followed by the addition of EtOAc (50 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give 1.50 g (41%) of (R)-methyl 1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl(methyl)carbamate as an off-white solid (M+H (m/z)=400).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21]C)[CH3:19].ClC(OC1C=CC=CC=1)=[O:27].N1CCCC1>O1CCCC1>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21]([N:20]3[CH2:23][CH2:24][CH2:19][CH2:18]3)=[O:27])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCCC1
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
2-Amino-4-(4-nitrophenoxy)pyridine (490 mg) was dissolved in tetrahydrofuran (10 ml) under a nitrogen atmosphere, and then triethylamine (0.886 ml) and phenyl chloroformate (0.798 ml) were added dropwise, followed by stirring for 20 min. To the reaction mixture was added pyrrolidine (1.42 ml), followed by stirring for 40 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:3). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (639 mg, 91.8%) as a brown solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11]2.CN([CH:24]=[O:25])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([F:20])([F:18])[F:19])=[C:11]2[CH:24]=[O:25]
Reactant: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C(F)(F)F)c(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
DMF (1 mL) was cooled to 0° C. and POCl3 (0.25 mL) was added and stirred for 10 min Compound 203 (336 mg, 1.69 mmol) in DMF (2 mL) was added drop-wise over 10 min. The solution was stirred for an additional 1 h warming to rt then heated to 85° C. and allowed to react for an additional 4 h. The solution was poured into ice-cold 1 N NaOH (40 mL) and stirred for 30 minutes in an ice-bath resulting in the formation of a precipitate. The precipitate was collected, washed with cold H2O and dried overnight at 40° C. in a vacuum desiccator to yield a cream-colored solid. The sample was further purified by chromatography (7% to 20% EtOAc/hexanes) to obtain a white solid (178 mg, 43%): mp 236-239° C. TLC Rf 0.51 (30% EtOAc/hexanes). 1H NMR (600 MHz, d4-MeOH) δ 10.22 (s, 1H), 7.79 (d, 1H, J=2.46 Hz), 7.45-7.43 (d, 1H, J=9 Hz), 7.06-7.04 (dd, 1H, J1=8.94 Hz, J2=2.52 Hz), 3.86 (s, 3H). 13C NMR (150 MHz, d4-MeOH) δ 186.2, 159.0, 132.0, 127.1, 123.4, 121.6, 118.2, 117.2, 114.8, 104.1, 56.2. 19F NMR (376 MHz, CDCl3) δ −58.7 (s, 3F). Elemental analysis calculated for C11H8F3NO2: C, 54.33; H, 3.32; N, 5.76. Found: C, 54.53; H, 3.32; N, 5.76.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 2.53 g, 63.1 mmol) was added portionwise to a stirring solution of 5-bromoindole (8.25 g, 42.1 mmol) in DMF (80 mL) at 0° C. under a nitrogen atmosphere over a period of 10 min. The mixture was then warmed up to room temperature. After the reaction mixture was stirred at room temperature for 1 hour, 4-methylbenzyl bromide (12.0 g, 63.1 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and diluted with water. The aqueous phase was extracted with ethyl acetate. The organic extract was washed with water and brine, then dried over anhydrous magnesium sulfate. This mixture was concentrated to give a crude oil (14.1 g, 71%). Crystallization from petroleum ether afforded the title compound as a white solid, m.p: 56-57° C. Mass spectrum (APCI, [M+H]+) m/z 300. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.53 (s, 1H), 7.40 (d, 1H, J=8.9 Hz), 7.18 (d, 1H, J=10.5 Hz), 7.09 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.2 Hz), 6.45 (s, 1H), 5.35 (s, 2H), and 2.22 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]2=[O:27])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[F:30][C:2]([F:1])([F:31])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:27])=[CH:28][CH:29]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a stirring solution of tert-butyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (3.05 mmol, 1.39 g) in dichloromethane (15 mL) was added trifluoroacetic acid (30.5 mmol, 3.47 g) and the mixture allowed to stir at room temperature for 5 hours. The reaction mixture was concentrated and the resulting residue purified by strong cation exchange column chromatography to afford the title compound (932 mg). MS (ESI) m/z 357.0 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)N1CCS(=O)(=O)CC1

Procedure:
A solution of 1.17 g (5 mmol) (4-Bromo-phenyl)-acetyl chloride (CAS 37859-24-8) in 25 ml CH2Cl2 is added dropwise to a solution of 710 mg (5.25 mmol) thiomorpholine 1,1-dioxide in 25 ml CH2Cl2. After complete addition, the reaction mixture is partitioned between water and CH2Cl2. The aqueous phase is re-extracted twice with CH2Cl2. The combined organic solution is washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a light yellow residue.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[N:30]=[CH:31][CH:32]=[CH:33][N:34]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-pyrimidin-2-yl-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.18 (d, 1H), 10.94 (s, 1H), 9.28 (s, 1H), 8.52 (d, 1H) 8.08 (d, 1H), 7.99 (d, 1H), 7.84 (d, 1H), 7.6 (d, 1H), 7.13 (d, 1H), 7.06 (m, 1H), 7.01 (m, 1H),; APCI-MS m/z 449 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=1Br)[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:32]=[C:33]([C:15]2[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:14]=2[CH2:13][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:11][CH3:12])[C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(C(C)(C)O)ccc1Br)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(C)(C)O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2-bromo-5-(1-hydroxy-1-methyl-ethyl)-benzyl]-ethyl-carbamic acid benzyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:28](=[O:30])[CH3:29])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline (0.22 g, 0.51 mmole) (prepared as described in Example 29-preparation of starting materials) was dissolved in a mixture of methylene chloride (4 ml), pyridine (1 ml) and diisopropylethylamine (0.17 ml) under a nitrogen atmosphere. Acetic anhydride (0.1 ml, 1.0 mmole) was added and the mixture stirred at ambient temperature for 3 hours. The mixture was then partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the expected product were evaporated and triturated with diethylether. The solid was filtered and dried under vacuum to give the title product as a white solid (0.12 g: 55%); 1H NMR Spectrum: (DMSO d6) 1.95-1.98 (m, 3H); 2.14-2.40 (m, 2H); 3.53-3.70 (m, 3H); 3.91 (m, 4H); 5.12-5.21 (m, 1H); 7.15-7.30 (m, 2H); 7.4-7.60 (m, 2H); 7.70-7.90 (m, 1H); 8.36-8.37 (d, 1H); 9.60-9.62 (m, 1H); Mass Spectrum: (M+H)+ 431.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:19][C:12]1[CH:11]=[C:10]([CH3:20])[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[N:7][CH:6]=2)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.35 g) in a mixed solvent of THF (8.40 mL)-water (2.80 mL) were added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.53 g), potassium carbonate (0.66 g) and tetrakis(triphenylphosphine)palladium(0) (0.14 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.35 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](OC)(=[O:19])[C:15]([O:17][CH3:18])=[O:16].C[O-].[Na+]>CO.C(Cl)Cl>[F:13][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12]
Reactant: COc1c(F)cc(C(C)=O)cc1F
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3,5-fluoro-4-methoxyacetophenone from Step 1 (6.46 g, 34.70 mmol) and dimethyl oxalate (6.15 g, 52.05 mmol) in methanol (80 mL), was added sodium methoxide solution (13.4 mL of 25% solution, 58.99 mmol) in one portion and the reaction stirred overnight. The crude reaction was diluted with methylene chloride, washed with potassium bisulfate (0.1N solution), brine, dried over MgSO4, filtered, and concentrated in vacuo yielding methyl 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate as an off white crystalline solid which was used as is. A mixture of 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate and 4-sulfonamidophenylhydrazine hydrochloride salt (7.76 g, 34.70 mmol) dissolved in methanol was warmed to reflux for 9 hours. Upon allowing the clear reaction to cool to room temperature, a crystalline precipitate formed which was collected by vacuum filtration yielding 5.45 g, (37% based upon the 3,5-difluoro-4-methoxyacetophenone) of methyl 1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate as an off-white solid: mp 185°-190° C.; 1H NMR (CDCl3/300 mHz) 7.95 (d, J=8.86, 2H), 7.49 (d, J=8.86, 2H), 7.02 (s, 1H), 6.77 (m, 2H), 4.99 (s, 2H, 4.04 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3/300 mHz) −126.66. Anal. Calc'd for C17H13F2N3O3S: C, 51.06; H, 3.57; N, 9.92. Found: C, 51.06; H, 3.54, N, 9.99.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[NH2:41][CH2:42][C:43]([NH:45][C@H:46]([C:68]([NH2:70])=[O:69])[CH2:47][S:48][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:44].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:41][CH2:42][C:43]([NH:45][C@H:46]([C:68]([NH2:70])=[O:69])[CH2:47][S:48][C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:44])=[O:20])=[O:14])=[CH:30][CH:31]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
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
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
559 mg (0.99 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 415 mg (0.99 mmol) of the compound from example 18A, 173 μl (0.99 mmol) N,N-diisopropylethylamine and 376 mg (0.99 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 70 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1 to dichloromethane/methanol 5/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 860 mg (0.69 mmol, 70% of theory) of the desired product.