Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(=O)C)[N:16]=[CH:15]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)([O-])O.[Na+].C(OC(C)C)(C)C>O>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1ncc2cc(OS(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=S(=O)(Oc1ccc2[nH]ncc2c1)c1cccc(F)c1
Yield: 59.3 %

Procedure:
1H-Indazol-5-yl 3-fluorobenzenesulfonate can be obtained in the following way: a suspension of 193 mg of 1-acetyl-1H-indazol-5yl 3-fluorobenzenesulfonate and of 0.19 ml of hydrochloric acid (d=1.18) in 1.65 ml of distilled water is brought to reflux for 16 hours. After returning to a temperature in the region of 20° C., the reaction medium is basified to a pH in the region of 8 with a saturated aqueous sodium hydrogencarbonate solution and extracted with two times 10 ml of dichloromethane. The pooled organic extracts are dried over calcium chloride, filtered and concentrated by evaporation under reduced pressure. The transluscent oil obtained is taken up with 2 ml of diisopropyl ether and concentrated by trituration. The solid obtained is separated by filtration, washed with two times 1 ml of diisopropyl ether and dried under reduced pressure. 100 mg of 1H-indazol-5-yl 3-fluorobenzenesulfonate are thus obtained in the form of a whiteish solid melting at 104° C. (analysis C13H9FN2O3S, % calculated C, 53.42; H, 3.10; F, 6.50; N, 9.58; O, 16.42; S, 10.97. % found C, 53.5; H, 2.9; F, 6.2; N, 9.6).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][Si](C(C)C)(C(C)C)C(C)C)[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1COCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[CH:39])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: CC(C)[Si](C#Cc1cccc2nc(Cn3nc(-c4cccc(O)c4)c4c(N)ncnc43)n(Cc3ccccc3Cl)c(=O)c12)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc2nc(Cn3nc(-c4cccc(O)c4)c4c(N)ncnc43)n(Cc3ccccc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of compound (19) (107 mg, 0.15 mmol) in DMF (0.50 mL) was added tetrabutylammonium fluoride (190 μL of a 1.0 M solution in THF, 0.19 mmol). After 10 min, the reaction mixture was diluted with water (3.0 mL) and cooled to 0° C. for 30 min. The resulting solid was collected by filtration and purified by flash column chromatography, eluting with 4.5% methanol in DCM, to afford the title compound, Example 1, (70 mg, 85%) as a white solid: m/z 534/536 (M+H)+ (ES+); Rt 3.73 min; 1H NMR (500 MHz, DMSO-d6) δ: 4.42 (1H, s), 5.30 (2H, s), 5.77 (2H, s), 6.16 (1H, d), 6.79 (1H, t), 6.84 (1H, dd), 6.89-6.96 (2H, m), 7.04 (1H, t), 7.14 (1H, d), 7.30 (1H, t), 7.70 (1H, d), 7.75 (1H, d), 7.80-7.87 (1H, m), 8.18 (1H, s), 9.67 (1H, s).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:16]1([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:23]1([N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([N:22]([C:23]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:26]=[CH:25][CH:24]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:9][CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccc3c(c2)Cc2cc(N(c4ccccc4)c4cccc5ccccc45)ccc2-3)c2cccc3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a 2-liter three-neck round bottom flask was added anhydrous toluene (1000 mL) by cannula. 2,7-dibromofluorene (50.0 g) was added to this flask, then stirred until all dissolved. N-phenyl-1-naphthylamine (81.14 g) was then added. The reaction vessel was purged with a strong nitrogen flow for 30 minutes, followed by the addition of sodium tert-butoxide (44.5 g) by funnel. Tris(dibenzylideneacetone)dipalladium(0) (5.65 g) was added to the reaction. Tri-tert-butyl phosphine (3.75 g) in anhydrous toluene (20 mL) was added via syringe. The reaction was heated to reflux for 2 hours and reaction completion was confirmed by thin-layer chromatography. The vessel was removed from heat and allowed to cool to room temperature. The reaction solution was filtered through a celite/silica gel plug and solvent was then removed by rotary evaporation. The crude material was initially purified by flash chromatography, followed by sublimation to yield NMR pure product.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:20][CH3:21])=[C:6]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]#[N:19])[CH:16]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[C:5]([O:20][CH3:21])=[C:6]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]#[N:19])[CH:16]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnn(CC#N)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnn(CC#N)c1
Temperature: 25 °C

Procedure:
A mixture of [4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl]acetonitrile (0.10 g, 0.33 mmol), ammonium acetate (0.254 g, 3.29 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.82 mL, 0.82 mmol) in methanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C15H15ClN3O (M−NH2)+: m/z=288.1. found: 288.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br>C(O)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(F)c(C(=O)O)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)ccc1F
Temperature: 140 °C

Procedure:
To 2-fluoro-5-methoxybenzoic acid (5.00 g, 29.4 mmol) was added 49% aqueous HBr (50 mL) and glacial acetic acid (40 mL). The mixture was heated overnight at 140° C., cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield 2-fluoro-5-hydroxybenzoic acid. MS m/z=157 [M+1]+. Calc'd for C7H5FO3: 156.11.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[C:18]([Si](C)(C)C)[N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH2:33][C:34]2[N:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH:38]=2)=[CH:27][CH:26]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(O)(=O)C>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:26]=[CH:27][C:28]([CH2:31][NH:32][CH2:33][C:34]2[N:35]=[N:36][N:37]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[CH:38]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5CC(Cn6cc([Si](C)(C)C)nn6)OC5=O)cc4F)cc3)nn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5C[C@H](Cn6ccnn6)OC5=O)cc4F)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
A solution of 3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (SC-167-63-2, 0.22 g, 0.343 mmol) in an 1 M solution of tetrabutylammonium fluoride in THF (TBAF, 1.4 mL, 1.4 mmol, 4.0 equiv) was treated with acetic acid (HOAc, 5.0 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was treated with H2O (30 mL) at room temperature and the resulting mixture was stirred at room temperature for 1 h. The solids were collected by filtration, washed with H2O (2×10 mL) and 20% EtOAc/hexane (2×20 mL), dried in vacuo. The crude, desired (5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (SC-167-71, 0.17 g, 0.195 g theoretical, 87%) was obtained as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For SC-167-71: 1H NMR (300 MHz, DMSO-d6) 3.73 and 3.75 (two, s, 4H), 3.94-3.97 (m, 1H), 4.29 (t, 1H), 4.85 and 4.87 (dd, 2H), 5.15-5.20 (m, 1H), 5.48 (s, 1H), 6.91 and 6.94 (d, 2H), 7.28-7.58 (m, 10H, aromatic-H), 7.78 (s, 1H, triazole-H), 7.98 (s, 1H, triazole-H), 8.19 (s, 1H, triazole-H); C30H29FN8O3, LCMS (EI) m/e 568 (M++H).
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:22]([OH:24])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:26])[CH2:6]1)(=O)C.[ClH:27]>>[ClH:27].[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:22]([OH:24])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:26])[CH2:6]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(C)=O)C3)nc21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21

Procedure:
A mixture of 7-(3-acetylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.81 g) in 20% hydrochloric acid (20 ml) was heated under reflux for 3 hours with stirring. The mixture was concentrated to dryness under reduced pressure and then ethanol was added to the residue. After cooling the mixture, the resulting solid was collected and recrystallized from ethanol-water to yield 1.64 g of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (Compound 1), m.p. 285°-290° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[F:1][C:2]1[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)c([N+](=O)[O-])c1F
Temperature: 70 °C

Procedure:
3.5 g (0.02 mol) of 2,4,5-trifluorobenzoic acid are introduced into a mixture of 6.8 ml of concentrated sulphuric acid and 8 ml of 98% strength nitric acid at 5°-10° C., and the mixture is then stirred without cooling. The temperature increases to 70° C. The mixture is heated for 5 hours at 80°-90° C., a further 8 ml of 98% strength nitric acid are added, and the mixture is heated at 80° C. for 2 hours. The mixture is then introduced into 100 ml of ice water, extracted thoroughly with dichloromethane, dried using sodium sulphate and concentrated. The oil remaining crystallizes. If is stirred with light petroleum, and the solid product is filtered off under suction and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:25])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].C[N:32]([CH:34]=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:25])[NH:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[CH:6][C:34]([NH2:32])=[CH:4][CH:3]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(Br)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-(3-Bromo-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (201 mg, 0.5 mmol), 6-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1 eq., 108 mg), Pd[P(Ph)3]4 (5 mol %, 20 mg), in methanol (6 mL), NaHCO3 (sat. aq., 900 uL) and DMF (1.5 mL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 26 mg. MS: 440.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 10.1 (s, 1H), 7.9 (m, 1H), 7.5-7.0 (m, 12H), 5.0 (m, 2H), 4.4 (m, 1H), 3.5 (m, 1H), 2.2 (m, 1H), 1.9 (m, 3H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[NH:21]N.C(O)C.Cl>O>[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[N:21]1[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Reactant: CN(C)/C=C/C(=O)c1cccnc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3nccc3-c3cccnc3)c(F)c2)C(=O)O1
Yield: 42.5 %

Procedure:
(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (58 mg, 0.327 mmol) and (S)—N-((3-(3-fluoro-4-hydrazinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (94 mg, 0.327 mmol) were combined with a solvent, ethanol (3 mL), and then the mixture was slowly heated to reflux, followed by addition of concentrated hydrochloric acid (40 μL). The reaction mixture was maintained under reflux until completion of the reaction as monitored by TLC. Then, the reaction mixture was poured into water and then was extracted with dichloromethane. The dichloromethane layer was rotary evaporated. The residue was purified with column chromatography to afford 55 mg light yellow solid, with a yield of 40.7%, melting point: 83.7-85.9° C., HPLC: 98.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.N>CO.[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5% palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70% yield, mp 132-133° C.). GC/MS (EI, M+) m/Z=178.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[CH:19]=[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.[Pd].ClC1[C-](P)C(C2C=CC=CC=2)=C(C2C=CC=CC=2)C=1Cl.[CH-]1C=CC=C1.[Fe+2]>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:22]2[CH:23]=[CH:18][CH:19]=[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)Cc1cccc(-c2ccc(O)cc2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
10 g of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenol and 12.5 g of methyl 3-bromophenylacetate were dissolved in 150 ml of 1,2-dimethoxyethane, then 14 g of potassium carbonate and 920 mg of dichlorodiphenyl phosphinoferrocene palladium were added thereto, and the mixture was stirred overnight at 70° C. in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 10.336 g of the title compound in the 2:1 hexane-ethyl acetate fraction.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([CH2:10][C:11]3[C:12]([CH3:30])=[C:13]([F:29])[C:14](OS(C(F)(F)F)(=O)=O)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:33](C([Sn])=C(CCCC)CCCC)[CH2:34]CC.[Cl-].[Li+].[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]([CH2:10][C:11]3[C:12]([CH3:30])=[C:13]([F:29])[C:14]([CH:33]=[CH2:34])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C)c1F
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (11.8 g), tributylvinyltin (11.9 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.88 g), lithium chloride (7.84 g) and DMF (240 mL) was stirred at 90° C. for 1.5 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was 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 (7.98 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([O:16][CH2:26][CH2:25][O:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: OCCOC1CCCCO1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(OCCOC2CCCCO2)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a suspension of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol (0.150 g, 0.547 mmol), 2-(Tetrahydro-pyran-2-yloxy)-ethanol (0.0960 g, 0.657 mmol), and Triphenylphosphine (0.230 g, 0.876 mmol) in Methylene chloride (6 mL) cooled to 0° C. on an ice bath was slowly added Di-tert-butyl azodicarboxylate (0.202 g, 0.876 mmol), at which time a solution formed. The reaction mixture was stirred at rt overnight. The reaction did not go to completion so equal amounts of 2-(Tetrahydro-pyran-2-yloxy)-ethanol, Triphenylphosphine, Methylene chloride, and Di-tert-butyl azodicarboxylate were added as were at the start of the reaction and stirred. The reaction mixture was then concentrated and dissolved in minimal amounts of DCM. It was then purified by silica gel chromatography (ISCO, 0-30% EtOAc) to give (2,5-Dichloro-pyrimidin-4-yl)-{2-fluoro-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-amine as a clear oil (98 mg, 44%). 1H-NMR (CDCl3): 8.17 (s, 1H), 7.22 (m, 1H), 6.93 (s, 1H), 6.82 (m, 2H), 4.63 (s, 1H), 4.22 (m, 2H), 3.98 (m, 1H), 3.74 (m, 2H), 3.47 (m, 1H), 1.67 (m, 2H), 1.55 (m, 2H) 1.49 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:14])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c(=S)oc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-1,3-benzoxazole-2(3H)-thione (375 mg, 2.27 mmol) was dissolved in THF (2.0 mL), and iodomethane (1610.8 mg, 11.35 mmol) and potassium carbonate (627.36 mg, 4.54 mmol) were added. This reaction mixture was stirred vigorously at rt overnight. The reaction mixture was filtered and the solid was rinsed with additional THF. The filtrate was concentrated in vacuo to a yellow solid. The solid was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried with MgSO4, and concentrated. The solid was dried for 1 h in a 50° C. oven. The product 6-methyl-2-(methylsulfanyl)-1,3-benzoxazole was obtained as yellow solid (145 mg, 35.6%). 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, 1 H), 7.20 (s, 1 H), 7.10 (d, 1 H), 2.78 (s, 3 H), 2.42 (s, 3 H); LC-MS ret. time 2.90 min (method 2), m/z 180.1 (MH+).
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.Cl[S:12]([C:15]1[N:25]=[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([Cl:23])[N:17]2[N:16]=1)(=[O:14])=[O:13].[NH2:26][C:27]1[C:28]([C:35]([F:38])([F:37])[F:36])=[N:29][N:30]([CH2:33][CH3:34])[C:31]=1[CH3:32]>C(#N)C>[CH2:33]([N:30]1[C:31]([CH3:32])=[C:27]([NH:26][S:12]([C:15]2[N:25]=[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([Cl:23])[N:17]3[N:16]=2)(=[O:14])=[O:13])[C:28]([C:35]([F:37])([F:36])[F:38])=[N:29]1)[CH3:34]
Reactant: CCn1nc(C(F)(F)F)c(N)c1C
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Cl)nc2c1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CC#N
Product: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)cc(Cl)n3n2)c1C
Reaction time: 18 h

Procedure:
Pyridine (0.31 g (3.9 mmol)) and dimethyl sulfoxide (0.03 g (0.4 mmol)) were added to a solution of 1.0 g (3.9 mmol) of 2-chlorosulfonyl-5-chloro-7-methyl-[1,2,4]triazolo[1,5-a]pyridine and 0.76 g (3.9 mmol) of 4-amino-1-ethyl-5-methyl-3-(trifluoromethyl)pyrazole in 15 mL of acetonitrile at ambient temperature with stirring. After 18 hours, the volatiles were removed by evaporation under reduced pressure and the residue was partitioned between dichloromethane and water, stirring for 10 min before separation. The solids were recovered by filtration and washed with ether. They were then resuspended in water and the mixture stirred for 30 min. The solids were recovered by filtration, washed with ether, and dried under reduced pressure at 40° C. overnight. The resulting 1.24 g (68 percent of theory) of white powder melting at 224°-226° C. was the title compound.