Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]2(OC)[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC1(c2ccc(Br)c(Cc3ccc4c(c3)CCCO4)c2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: Brc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCCO2
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 6-[2-bromo-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-benzyl]-chroman (900 mg, 1.05 mmol) in acetonitrile:dichloromethane (1:1 mixture, 6 mL) was added triethylsilane (0.34 mL, 2.1 mmol) and boron trifluoride diethyletharate complex (0.19 mL, 1.58 mmol), at 0° C. After stirring for 2 h, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (2×10 mL). The organic layers were combined and dried over sodium sulfate then concentrated to a residue which was purified by silica gel column chromatography to furnish 6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (600 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH2:26][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH3:17]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Yield: 69.6 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.34 g (1.3 mmol) 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After ionic exchange purification, 0.273 g (70% of yield) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:10]=[C:9]([C:11]([Cl:3])=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.5 ml of thionyl chloride and 2 drops of dimethylformamide were added to a mixed solution comprising 1.0 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and 10 ml of toluene, followed by reflux with heating for one hour, and thionyl chloride and toluene were distilled off to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1>C(Cl)Cl>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][CH:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Solvent: ClCCl
Product: Cc1ccc2c3c(ccc2n1)OCC(CO)O3
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline (0.30 g, 0.94 mmol) in CH2Cl2 (8 mL) being cooled in an ice-bath, FeCl3 (0.77 g, 4.7 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 4 h. CH2Cl2 (30 mL) and 1N NaOH (25 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCl3:iPrOH gave 0.15 g (68%) of the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[C:38]([F:39])=[CH:37][C:36]([NH:40][C:41]([C:43]3([C:46]([NH:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)=[O:47])[CH2:45][CH2:44]3)=[O:42])=[C:35]([F:56])[CH:34]=2)[CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]([CH3:9])[C:6]([NH:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:34]=[C:35]([F:56])[C:36]([NH:40][C:41]([C:43]3([C:46](=[O:47])[NH:48][C:49]4[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=4)[CH2:45][CH2:44]3)=[O:42])=[CH:37][C:38]=2[F:39])[CH:29]=[CH:28][N:27]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)O
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)O[C@@H](C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of (S)-2-Acetoxy-propionic acid (300 mg, 2.278 mmol) and N-methylmorpholine (341 mg, 3.41 mmol) in anhydrous CH2Cl2 was added drop wise isobutyl chloroformate (457 mg, 3.41 mmol). The resultant mixture was stirred at 25° C. for 1 h. N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg, 0.578 mmol) was added and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate (180 mg, 55.9% yield) which was without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].Br[CH2:12][C:13]([C:15]1([CH3:18])[CH2:17][CH2:16]1)=O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:12]=[C:13]([C:15]3([CH3:18])[CH2:17][CH2:16]3)[NH:6]2)=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cc(N)ccc1C
Reactant: CC1(C(=O)CBr)CC1
Agent: Cl
Solvent: CCO
Product: COc1cc2[nH]c(C3(C)CC3)cc2cc1C
Yield: 54.6 %

Procedure:
A solution of 3-methoxy-4-methylaniline (2.26 g) in ethanol (7 mL) was heated under reflux while stirring. To the solution was added slowly a solution of 2-bromo-1-(1-methylcyclopropyl)ethan-1-one (885 mg) in ethanol (3 mL), and this mixture was heated under reflux for 3 hours while stirring. The reaction mixture was left to be cooled. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (588 mg).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]3[C:12]([CH2:13][O:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[N:23]=2)[CH2:18][CH2:17]1>CC(O)(C)C>[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]3[C:12]([CH2:13][O:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:29])=[O:1])[N:23]=2)[CH2:20][CH2:21]1
Reactant: [OH-]
Reactant: N#Cc1cccc(N2CCC(c3nnc4n3-c3ccc(Cl)cc3COC4)CC2)n1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cccc(N2CCC(c3nnc4n3-c3ccc(Cl)cc3COC4)CC2)n1
Temperature: 100 °C
Yield: 54 %

Procedure:
Powdered potassium hydroxide (46 mg, 81 mmol) was added to a solution of the carbonitrile of example 20 (110 mg, 0.27 mmol) in 2-Methyl-propan-2-ol (6 ml). The mixture was heated at 100° C. for 18 hours before evaporation under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound (62 mg), as an off-white solid.
Reaction SMILES: OP(O)(O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]([O:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O>O>[Br:6][C:7]1[CH:15]=[C:11]2[C:12](=[O:14])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([I:23])[CH:21]=3)[O:16][C:10]2=[N:9][CH:8]=1
Reactant: O=C(O)c1cc(Br)cnc1Oc1ccc(I)cc1
Agent: O=P(O)(O)O
Solvent: O
Product: O=c1c2cc(I)ccc2oc2ncc(Br)cc12
Temperature: 117.5 °C
Reaction time: 17 h
Yield: 85.3 %

Procedure:
A 3-neck 12 L flask equipped with an overhead stirrer, thermometer, condenser and nitrogen inlet was charged with NaH (186.1 g, 4.653 mol) and DMF (1500 mL). The slurry was cooled to 0° C. and a solution of 4-iodophenol (488.6 g, 2.221 mol) in DMF (1500 mL) and added. The temperature of the reaction mixture was maintained below 25-30° C. during this addition. After complete addition, the cooling bath was promptly removed and the mixture continued to stir at RT for 1 h. 5-Bromo-2-chloronicotinic acid (500 g, 2.115 mol) was then added to the slurry portion wise. The reaction mixture was heated to 115° C. overnight. The dark brown reaction mixture was cooled to 20° C. and diluted with water (2 L). The reaction mixture was acidified using HOAc (845 ml). The black homogenous solution (pH=5) was allowed to stir for 1 h at RT and poured slowly onto ice-water (20 L). The slurry was filtered at RT, washed with water (2×2 L) and dried in air to give 765 g of 5-Bromo-2-(4-iodophenoxy)-nicotinic acid as light orange solid. Step 2: A 5 L 3-neck flask equipped with an overhead stirrer, a thermometer and nitrogen inlet was charged with PPA (4 Kg, 1942 mL) (115% H3PO4) and heated to 115-120° C. 5-Bromo-2-(4-iodophenoxy)nicotinic acid (400 g, 952 mmol) was charged portion wise to the hot PPA. The viscous mixture was then allowed to stir overnight (16-18 h) at 115-120° C. The dark viscous mixture was cooled to 60-65° C. and poured slowly onto a mixture of ice (3000 g) and water (2000 mL) under mechanical stirring. The light brown slurry was allowed to stir overnight and filtered at RT. The wet cake was washed with water (2×1000 mL) followed by IPA (1500 mL) and hexane (2×1000 mL). The solid was dried to obtain 326.4 g of 3-Bromo-7-iodo-5H-chromeno[2,3-b]pyridine-5-one as a grey solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>CN(C=O)C.O>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]=2[N:20]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of pyridin-3-ol (0.048 g, 0.500 mmol) in DMF (1.67 ml) was added NaH (0.027 g, 55% dispersion in mineral oil, 0.630 mmol) at 0° C. After stiffing for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture. After stiffing for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 70%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.46 (1H, dd, J=8.0 and 4.8 Hz), 7.66-7.69 (1H, m), 7.86 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=4.4 Hz), 8.65 (1H, d, J=2.8 Hz), 8.80 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([O-])=O>CCOC(C)=O>[O:19]1[CH2:20][CH2:21][N:16]([C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:9][C:4]=2[NH2:1])[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCOCC1
Solvent: CCOC(C)=O
Product: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4,4′-(2-nitro-1,4-phenylene)dimorpholine (5.6 g, 19 mmol) in EtOAc (90 mL) was added stannous chloride, dihydrate (18 g, 95 mmol). The reaction was stirred at rt for 10 min and at reflux for 90 min. After this time the reaction was cooled to rt and a precipitate formed. The precipitate was collected and washed with 1N NaOH (40 mL), water (50 mL) and brine (50 mL) and dried under vacuum overnight. After this time the solid was dissolved in EtOAc (200 mL) and washed with 1N NaOH (30 mL) and brine (50 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to give 2,5-dimorpholinoaniline.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][NH2:58])=[CH:53][CH:52]=1.Cl>C1COCC1>[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][NH:58][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:6]([O:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[N:7][CH:8]=2)=[CH:53][CH:52]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccco2)c1
Reactant: NNc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(NNc1ccc(F)cc1)c1cnc(OC2CCC2)c(-c2ccco2)c1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In a 5 mL round-bottomed flask the above prepared 6-cyclobutoxy-5-furan-2-yl-nicotinic acid (0.050 g, 174 μmol, Eq: 1.00) was combined with THF (2 mL) to give a colorless solution. TBTU (83.6 mg, 260 μmol, Eq: 1.5) and N,N-diisopropylamine (112 mg, 152 μL, 868 μmol, Eq: 5) were added. The reaction mixture was stirred for 10 min at RT before (4-fluorophenyl)-hydrazine hydrochloride (33.9 mg, 208 μmol, Eq: 1.2) was added and the reaction allowed to proceed at RT overnight. The mixture was poured into 15 mL 1 M HCl and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 1 M NaOH, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) to yield 40 mg of the title compound as white solid; MS (EI) 368.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([CH3:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[C:11]([C:17](OCC)=[O:18])=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.Cl>C(OCC)C>[CH:1]1([C:4](=[O:5])[CH2:6][C:17]([C:11]2[C:10]([Cl:9])=[CH:15][C:14]([Cl:16])=[CH:13][N:12]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ncc(Cl)cc1Cl
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C1CC1)c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
Methyl cyclopropyl ketone (1.65 g) was added to a stirred suspension of sodium hydride (80% dispersion in oil; 0.6 g) in dry diethyl ether at 0° C. under an inert atmosphere. The mixture was stirred at 0° C. for one hour. Ethyl 3,5-dichloropyridine-2-carboxylate (2.16 g) was added and the mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. Hydrochloric acid (2N) was added and the mixture was extracted with diethyl ether. The organic extracts were washed with water, dried (anthydrous magnesium sulphate), filtered and evaporated to give a brown gum which was purified by column chromatography on silica eluted with a mixture of ethyl acetate and hexane to yield 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)propan1,3-dione (1.35 g) as a colourless solid, m.p. 50.2°-52.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([Sn](C)(C)C)[N:11]=[N:10][N:9]=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1
Reactant: C[Sn](C)(C)n1nnnc1-c1ccccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1nnn[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 1.0 g of 5-(2-bromophenyl)-1-(trimethylstannyl)-1H-tetrazole in toluene/THF (10:1) at room temperature is added HCl gas, via a bubbler. Gas addition is continued for 5 minutes after the appearance of a precipitate and the solid is then isolated by filtration and washed with hexanes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13])=[O:7].[I-].[Na+].[CH3:22][O-:23].[Na+]>CO>[CH3:22][O:23][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13])=[O:7]
Reactant: C[O-]
Reactant: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COCCCCC(=O)c1oc2ccc(OC)cc2c1C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution (20 mL) of 5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one (1.93 g) synthesized in Example A120(1) in methanol were added sodium iodide (1.54 g) and sodium methoxide (1.86 g), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (797 mg, 42%) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11].[CH2:12]([O:19][C:20]([C:22]1[CH:28]=[CH:27][C:25]([O-:26])=[CH:24][CH:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[K]>CN(C)C=O>[CH2:12]([O:19][C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:26][C:2]2[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[N:7]=2)=[CH:27][CH:28]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
33.8 g of pentafluoropyridine (0.2 mol) are dissolved in 500 ml of dimethylformamide, the solution is cooled to 0° C. by means of a cryostat, and a solution of 53.3 g of potassium 4-benzyloxycarbonylphenoxide (0.2 mol) in 400 ml of dimethylformamide is then added drop wise over the course of 2 hours. After 24 hours at 0° C., the potassium salt has reacted.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)cc1OCc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2-ol ((5.8 g, 20.7 mmol) in DMF (75 mL) was added Cs2CO3 (8.8 g, 26.9 mmol). A solution of MeI (1.62 mL, 25.9 mmol) in DMF (10 mL) was added dropwise to this mixture. After stirring at room temperature for 3 h, the reaction mixture was concentrated. The residue was taken up in H2O and the aqueous solution was extracted with CH2Cl2 (3×). Combined organic solutions washed with brine (1×), dried over Na2SO4 and concentrated. Purification by flash chromatography (250 g silica gel, 50% EtOAc in hexanes) afforded 4.02 g (66%) of 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.32 (m, 5H), 7.05 (s, 1H), 6.91 (s, 1H), 5.11 (s, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11](=[O:30])(=[O:29])[N:12]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:13]3[S:17][N:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:3]=1.[CH3:38][N:39]1[C:43]([C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2B(O)O)=[CH:42][CH:41]=[N:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][N:12]([C:13]1[S:17][N:16]=[CH:15][N:14]=1)[S:11]([C:7]1[N:6]=[C:5]2[N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:3]=[C:2]([C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:51])[F:52])=[CH:49][C:44]=3[C:43]3[N:39]([CH3:38])[N:40]=[CH:41][CH:42]=3)[C:10]2=[CH:9][CH:8]=1)(=[O:29])=[O:30]
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
A vial was charged with tert-butyl 3-bromo-6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (531.8 mg, 0.871 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (306 mg, 1.132 mmol), potassium phosphate (555 mg, 2.61 mmol), and Pd(AmPhos)2Cl2 (30.8 mg, 0.044 mmol). 1,4-Dioxane (2178 μl) and water (726 μl) were added in sequence. The vial was sealed and heated in a microwave reactor for 30 min at 90° C. The organic layer was removed via pipette, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 50% EtOAc/Heptane) to give tert-butyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (469 mg, 0.621 mmol, 71.2% yield) as a white solid. m/z (ESI) 756.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)C1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 192.9 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (891 mg, 2.81 mmol) in DMF (8.7 mL) and acetic acid (7.0 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (401 mg, 1.40 mmol) in 3 portions over 10 min. The mixture was allowed to stir at −20° C. for 90 min. The reaction was quenched with the addition 5% aqueous K2CO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated to provide 1.07 g (96%) of the desired product. ES-MS m/z 396.06 [M+H]+, HPLC RT (min) 3.05.