Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[N:5]=[C:4]2[S:12][C:13]([Br:16])=[C:14]([CH3:15])[C:3]=12.C1(OC2C=CC=CC=2)C=CC=CC=1>CO>[Br:16][C:13]1[S:12][C:4]2[N:5]=[C:6]([CH3:11])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:14]=1[CH3:15]
Reactant: Cc1nc2sc(Br)c(C)c2c(N)c1C(=O)O
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(N)c2c(C)c(Br)sc2n1
Temperature: 200 °C
Yield: 56.9 %

Procedure:
A mixture of 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylic acid (Description 61) (720 mg, 2.391 mmol) and diphenyl ether (3.80 mL, 23.91 mmol) was heated to 200° C. for 48 h. The mixture was then cooled to RT, taken-up in MeOH (10 mL) and purified on silica, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM. Further purification by SCX, eluting with 0-100% 2M NH3 in MeOH in MeOH afforded the title compound (350 mg). LCMS (A) m/z: 257/259 [M+1]+, Rt 1.10 min (basic).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:30]([F:37])=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([F:37])=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1F
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 3-chloro-2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=499.0 (M+H)+
Reaction SMILES: [SiH](CC)(CC)CC.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:26])=[C:13]([CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)=O.B(F)(F)F.CCOCC>ClCCCl.CC#N>[CH3:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:14][C:13]2[CH:25]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=2[Cl:26])=[CH:21][CH:20]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a stirred solution of Et3SiH (400 mL, 2.51 mol and 5-bromo-2-chloro-4′-ethoxybenzophenone (390 g, 1.15 mol) in 900 mL of a 1:2 mixture 1,2-dichloroethane/MeCN at 10° C. was added BF3.Et2O (150 mL, 1.58 mol) at such a rate that the temperature did not exceed 20°. Caution a moderate exotherm insues during the addition. After stirring overnight at 20° C., HPLC revealed the reaction to be 90% complete. After adding an additional 40 mL Et3SiH and 15 mL of BF3.Et2O, the reaction was heated to 50° for 3 hr. (Note elevated temperatures increase formation of the Ritter reaction product N-acetyl 5-bromo-2-chloro-4′-ethoxydiphenylmethylamine). Upon cooling, the reaction was quenched with 120 g of KOH in 300 mL of H2O. After stirring 2 hr, the layers were separated. The aqueous layer was extracted 2× with CH2Cl2; the combined organic layers were washed 1× with 300 mL portions of 2M KOH, 2× with H2O containing 10% brine to aid phase separation and with brine 2× prior to drying over Na2SO4. After removal of the volatiles, the residue was recrystallized from absolute EtOH to yield 230 g of 5-bromo-2-chloro-4′-ethoxydiphenylmethane as a white solid.
Reaction SMILES: O[CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].C(N)C.COCCN(S(F)(F)[F:38])CCOC>C(Cl)Cl>[F:38][CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Agent: CCN
Solvent: ClCCl
Product: CC(F)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a cooled mixture of {(2R,5S)-5-[2-(1-hydroxyethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile (8.0 mg, 0.023 mmol) in methylene chloride (0.2 mL) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-44)-sulfanyl)ethanamine (4.7 μL, 0.026 mmol) (Deoxo-Fluor). The resulting mixture was warmed to room temperature and stirred overnight. Additional Deoxo-Fluor (5 μL) was added. After 6 h, the reaction was quenched with a few drops of water then concentrated. The residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 1.6 mg (20%) of the desired product. LCMS calculated for C17H18FN4OS (M+H)+: m/z=345.1. Found: 345.0.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1[OH:36])=[O:6])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O>ClCCl>[CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][C:8]1=[O:36])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)C1C(=O)Cc2cc(Cl)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)cc21
Reaction time: 10 h

Procedure:
A solution of 5-chloro-2-hydroxy-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide (230 mg, 0.35 mmol) in dichloromethane is treated with pyridinium chlorochromate (29 mg, 1.0 mmol), stirred for 10 hours, and treated with water. Organic layer is separated, dried over sodium sulfate, filtered, and evaporated. Purification by chromatography using ethyl acetate/hexane as eluent gives 5-chloro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indan-2-one carboxylic acid isopropylamide as solid; LC/MS: 540/542 (M+1)+; m.p.: 198-199° C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:38]3[CH:37]=[C:36]4[C:31]([N:32]=[CH:33][CH:34]=[N:35]4)=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:35]1[C:36]2[C:31](=[CH:30][C:29]3[O:28][CH2:27][C:20]4([C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]4=[O:39])[C:38]=3[CH:37]=2)[N:32]=[CH:33][CH2:34]1
Reactant: O=C1Nc2ccccc2C12COc1cc3nccnc3cc12
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)N(Cc1ccccn1)CC=N3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7H-spiro[furo[2,3-g]quinoxaline-8,3′-indolin]-2′-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (93%) as a pale orange solid: mp 232-233° C.; 1H NMR (300 MHz, CDCl3) δ8.64 (m, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77-7.67 (m, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 5.56 (d, J=16.5 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.91 (d, J=16.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.5, 155.9, 149.4, 144.9, 142.3, 142.1, 139.8, 139.8, 136.9, 132.6, 132.4, 128.8, 123.3, 123.2, 122.6, 121.9, 121.4, 116.6, 109.6, 82.6, 57.7, 46.5; MS (ES+) m/z 381.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][C:30]2[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (Step 9.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.72 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 521 [M+H]+ (LC-MS 2); Rf=0.16 (EtOAc).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][O:7][CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-:12].[Na+].[Na+]>O>[CH:8]([O:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2][OH:12])([CH3:10])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OCCC=CCCl
Agent: [Na+]
Solvent: O
Product: CC(C)OCCC=CCO

Procedure:
8.13 g (0.05 mol) of 1-chloro-5-isopropoxy-2-pentene are added to a solution of 6.5 g of sodium carbonate in 60 cc of water and the mixture is heated to 95°-98° during 18 hours. After cooling the organic parts are extracted with benzene, the benzene extract is washed with saturated salt solution and dried with sodium sulphate. The solvent is distilled off and then it is distilled at reduced pressure. According to gas-chromatography pure 5-isopropoxy-2-penten-1-ol distils at 102°-104°/15 mm. nD20 = 1.4363.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: COC/C=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COC/C=C/c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 85 mg of (E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na2CO3 aqueous solution and 1 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 5-50% EtOAc/hexane to yield 2-chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (87 mg, 68%). 2-Chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (40 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 29.1 mg of 334. MS (Q1) 408.1 (M)+
Reaction SMILES: [C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])[S:13][C:8]=2[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1)(=O)[CH3:2].B(F)(F)F.CCOCC.CO.[ClH:31]>C1COCC1>[ClH:31].[CH2:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([S:14](=[O:16])(=[O:17])[NH2:15])[S:13][C:8]=2[S:7](=[O:18])(=[O:19])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1
Yield: 27 %

Procedure:
4-Acetyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepin-1,1-dioxide (200 mg, 0.62 mmol) was dissolved in dry THF (10 mL), boron trifluoride etherate (0.15 mL) was added and the reaction mixture was refluxed for 0.5 hour. Borane dimethyl sulfide complex (0.7 mL) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled and methanol and isopropanolic HCl were added. This solution was refluxed for 0.5 hours and the solvents removed. The residue was chromatographed on silica gel eluting with 10% methanol-methylene chloride. Appropriate fractions were combined, isopropanolic HCl added and the solvents evaporated to give 110 mg (27%) of the title compound as its hydrochloride salt. Recrystallization from isopropanol afforded analytically pure material as the hydrochloride salt solvated with one equivalent of isopropanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[C:20](/[CH:37]=[CH:38]\[CH3:39])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20](/[CH:37]=[CH:38]\[CH3:39])[CH:19]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:17])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.1 %

Procedure:
tert-Butyl (Z)-4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazine-1-carboxylate (67 mg, 0.119 mmol) was dissolved in dichloromethane (2.0 mL). Under ice-cold conditions, trifluoroacetic acid (200 μL) was added and stirred at room temperature for 0.5 hours. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform). The title compound (77 mg (yield >99%)) was obtained as a white pink oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][P:21]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:15])[C:5]2=[O:39].[CH2:40]([NH:42][C:43](=[O:63])[NH:44][C:45]1[N:50]=[CH:49][C:48](B(O)O)=[C:47]([C:54]2[S:55][CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[N:58]=2)[CH:46]=1)[CH3:41].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:48]3[CH:49]=[N:50][C:45]([NH:44][C:43](=[O:63])[NH:42][CH2:40][CH3:41])=[CH:46][C:47]=3[C:54]3[S:55][CH:56]=[C:57]([C:59]([F:62])([F:60])[F:61])[N:58]=3)=[CH:11][N:10]=2)[C:5](=[O:39])[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][P:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:22])=[O:15])=[CH:7]1)[CH3:13]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCn1cc(C(=O)OCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(=O)c2cc(Br)cnc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn3CC)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
3-{[Bis(benzyloxy)phosphoryl]oxy}propyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 26, 750 mg, 1.21 mmol) was dissolved in dimethylformamide (25 mL) and the solution was purged with argon. Tetrakis (triphenylphosphine) palladium (145 mg, 0.12 mmol) followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 645 mg, 1.46 mmol) was added and the mixture was stirred for 20 min at room temperature. Sodium carbonate solution (516 mg, 4.87 mmol) (dissolved in minimum amount of water) was added to reaction mixture and it was heated to 90° C. for 3 h. The reaction mixture was passed through celite bed and the celite was washed with dimethylformamide. The dimethylformamide layer was poured into water (100 mL) and a precipitate formed. The solid was filtered and dried then purified by flash column chromatography over silica gel (100-200 mesh). The product was eluted with gradient of MeOH/CHCl3 (0-6%) to afford 650 mg (65%) 3-{[bis(benzyloxy)phosphoryl]oxy}propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate as white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1>CN(C)C=O.FC1C=CC(CN)=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH2:6][C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNCc1ccc(F)cc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-fluorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[S:15](=[O:18])(=[O:17])[NH2:16])=[O:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:10][C:9]=1[S:15](=[O:18])(=[O:17])[NH2:16])=[O:6]
Reactant: COC(=O)CC(=O)Nc1ccc(N)cc1S(N)(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O

Procedure:
mesylating the N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV), via addition of methanesulfonyl chloride to a suspension of N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV) and pyridine to form the intermediate compound N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (V).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[I-].[CH3:12][S+](C)C.[OH-].[K+].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[CH2:12][O:5]1
Reactant: C[S+](C)C
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Clc1cccc(C2CO2)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 2,3-dichlorobenzaldehyde (0.314 mmol) in acetonitrile (1 ml) was added solid trimethylsulfonium iodide (0.314 mmol, 64 mg), potassium hydroxide (0.628 mmol, 35 mg), and water (0.079 mmol, 1.4 μl). The heterogeneous mixture were heated in a capped test tube at 60° C. for 3 h. The suspension was then diluted with ethyl acetate (1 ml) and washed with saturated sodium bicarbonate (1×1 ml) and water (3×0.5 ml). The tube was concentrated by vacuum centrifuge over 1 hour and the resulting 2,3-dichlorophenyloxirane used without further purification
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:22]([O:26][C:27]([NH:29][C:30]1([C:33](=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:22]([O:26][C:27]([NH:29][C:30]1([C:33]([CH:34]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]3)=[O:4])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:40])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)(F)F
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NCC(F)(F)F)nc12)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.5 %

Procedure:
A mixture of 2-bromo-1-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)ethanone (616) (700 mg, 1.93 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604, 629 mg, 2.32 mmol) and K2CO3 (668 mg, 4.83 mmol) in DMF (7.0 mL) was stirred at RT for 45 min. The reaction mixture was treated with a saturated solution of NH4Cl (aq.) and EtOAc was added and the layers were separated. The organic layer was washed with brine (25 mL), and dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by chromatography on an ISCO Combiflash RF (40 g SingleStep column, eluted using a gradient of 0-90% EtOAc in hexanes) affording ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-4-oxobutanoate (890 mg, 1.611 mmol, 83% yield) as a light orange viscous oil. m/z (ESI, +ve ion) 553.3 (M+H)+. The light orange viscous oil was added to a sealed tube with EtOH (4 mL). AcOH (2 mL) and NH4OAc (1192 mg, 15.46 mmol) were added and the mixture was stirred at 60° C. for 12 h. The reaction mixture was concentrated. The residue was treated with EtOAc and water. The layers were separated and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by chromatography on an ISCO Combiflash RF (40 g Thomson SingleStep column, eluting with a gradient of 0-70% EtOAc in hexanes) to provide the title compound (970 mg, 1.81 mmol, 94% yield) as yellow crystalline solid. 19F NMR (376 MHz, CDCl3) δ ppm −71.24 (3F, s). m/z (ESI, +ve ion) 534.2 (M+H)+.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:20]CC[CH2-].C(=O)=O.CC(C)=O.CI>C1COCC1>[C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[C:14]([CH3:20])=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1cc(C2CC2)on1)Oc1ccccc1
Reactant: [CH2-]CCC
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)Oc2ccccc2)noc1C1CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(5-Cyclopropyl-isoxazol-3-yl)-carbamic acid phenyl ester (0.368 g, 1.51 mmol) is dissolved in THF (10 mL) and cooled to −78° C. and flushed with nitrogen. N-butyllithium (2.17 mL, 3.47 mmol) is then added. The mixture is stirred in the dry ice/acetone bath for 30 minutes. Methyl iodide (0.10 mL, 1.66 mmol) is added neat and the reaction is stirred for 2 hours at −78° C. The reaction is quenched (0° C.) with 20 mL of a saturated solution of ammonium chloride, diluted with ethyl acetate and the organic layer is removed, dried (sodium sulfate) and concentrated to an oil that is purified via FCC (0-40% ethyl acetate:heptanes) to give the title compound as an oil. MS (ESI) m/z 259.20 (M+1).