Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.C([Sn]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(CCCC)CCCC)CCC>O1CCOCC1.C(OCC)(=O)C.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>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:6]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) in dry dioxane (3 mL) was added a solution of Methyl(1RS,2RS,3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooled to room temperature, diluted with ethyl acetate (5 ml) and the resulting solution washed sequentially with brine and water. The organic layer was dried (MgSO4 anhydrous), filtered through a short pad of silica gel and concentrated in vacuo to yield an oil. The product was purified by flash column chromatography (silica gel, gradient elution from hexanes to 10% ethyl acetate/hexanes) to afford the title compound as a white solid. (92 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+].[C:15]([C:17]1([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](Cl)=[O:24])[CH2:19][CH2:18]1)#[N:16]>O1CCCC1>[C:15]([C:17]1([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[CH3:8])=[O:24])[CH2:18][CH2:19]1)#[N:16]
Reactant: Cc1ccc(O)cc1N
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a two-layer solution of 3-amino-4-methylphenol (5.92 g, 48.0 mmol) in tetrahydrofuran (40 mL )/1N aqueous sodium hydrogen carbonate solution (54 mL) was added a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. Since the pH of the reaction mixture was 4-5, sodium hydrogen carbonate (900 mg, 10.7 mmol) was added to the mixture to adjust the pH to 8-9, and the reaction mixture was further stirred at room temperature for 1 hr. The aqueous layer was separated, and extracted with ethyl acetate (150 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (25 mL)/hexane (50 mL) was added to the obtained suspension, and the mixture was stirred at room temperature for 20 min. The precipitate was collected by filtration, washed repeatedly with diisopropyl ether/hexane (1:1), and air-dried to give the title compound (12.2 g, 87%) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1)[CH3:2].Cl[C:10]1[O:11][C:12]2[C:13](=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[N:14]=1>>[Cl:19][C:17]1[CH:18]=[C:12]2[O:11][C:10]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C@@H:3]3[CH2:1][CH3:2])=[N:14][C:13]2=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=1
Reactant: COC(=O)c1cc(Cl)cc2oc(Cl)nc12
Reactant: CC[C@H]1COCCN1
Product: CC[C@H]1COCCN1c1nc2c(C(=O)OC)cc(Cl)cc2o1

Procedure:
Following general procedure GP-A, (S)-3-ethylmorpholine and methyl 2,6-dichlorobenzoxazole-4-carboxylate were coupled to provide (S)-methyl 6-chloro-2-(3-ethylmorpholino)benzoxazole-4-carboxylate. MS consistent.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([OH:23])=[CH:21][C@H:20]2[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][CH2:25][O:26][CH3:27])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH3:36]>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([O:23][CH2:35][CH3:36])=[CH:21][C@H:20]2[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][CH2:25][O:26][CH3:27])[CH:6]=1
Reactant: CCI
Reactant: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OCOC)CC[C@@H]34)[C@H]2C=C1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC1=C[C@H]2C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]32)C=C1OCOC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
A solution of 3,17β-bis(methoxymethoxy)estra-1,3,5-triene-2-ol (Z. Wang and Cushman, Synzthetic Commun. 28:4431-4437 (1998)) (11.3 g, 27.8 mmol) in anhydrous ethanol (225 ml) containing anhydrous potassium carbonate (38.4 g, 280 mmol) was stirred at room temperature under argon for 10 min. Iodoethane (43.7 g, 280 mmol) was introduced to the reaction mixture. The resulting mixture was stirred at gentle reflux. After 4 hr, another portion of iodoethane (10.92 g, 70 mmol) was introduced and the reflux was continued for another 10 hr. The reaction mixture was cooled to room temperature and filtered. The solid was washed with ether (100 ml), and the filtrates were combined and evaporated to dryness. Chromatography of the residue (silica gel 230-400 mesh, ethyl acetate:hexane 1:7 by volume) gave the pure 2 (10.45 g, 92%) as a colorless oil: 1H NMR (CDCl3) δ6.85 (s, 2 H), 5.18 (s, 2 H), 4.66 (ABq, J=6.6 Hz, Δν=3.4 Hz, 2 H), 4.08 (q, J=7.0 Hz, 2 H), 3.61 (t, J=8.5 Hz, 1 H), 3.52 (s, 3 H), 3.38 (s, 3 H), 2.79 (m, 2 H), 2.30-1.20 (m, 13 H), 0.82 (s, 3 H); CIMS (isobutane) m/z (rel intensity) 405 (MH+, 39), 343 (100). Anal. Calcd. for C24H37O5: C, 71.26; H, 8.97. Found: C, 71.48; H, 9.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][C:8]([CH3:11])(O)[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:8]([CH3:11])([CH3:9])[CH2:7][CH2:6][O:5]2)=[CH:13][CH:14]=1
Reactant: CC(C)(O)CCOc1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC1(C)CCOc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of 4-(3-bromo-phenoxy)-2-methyl-butan-2-ol (5.741 g, 22.2 mmole) in 45 mL of nitromethane was added dropwise to a suspension of aluminum chloride (4.019 g, 30.1 mmole) in 45 mL of nitromethane. The reaction mixture was stirred at room temperature for two hours and then poured onto 300 mL of ice-water. The pH was adjusted to 2.0 with 10% HCl and the product was extracted with three 100 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a purple oil. The product was purified by flash chromatography (SiO2, 1% ethyl acetate in hexanes) to yield 4.667 g of 7-bromo4,4-dimethyl-chroman as a colorless oil, which contained about 16% of 5-bromo-4,4-dimethyl-chroman.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.C1C=C[NH+]=CC=1.[Br:27][Br-]Br>O>[Br:27][CH2:17][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:19])([F:20])[F:8])[CH:11]=1)=[O:18]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CBr)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
To a toluene solution (423 mL) of commercially available 3′-trifluoromethylacetophenone (79.6 g, 0.423 mol) was added pyridinium bromide perbromide (135.4 g, 0.423 mol) under ice cooling and stirred for 5 hours while heating up to room temperature. The reaction liquid was ice cooled again, followed by dropwise adding 400 mL of distilled water to stop reaction and fractionation. A toluene layer was washed with 400 mL of a saturated aqueous solution of sodium bicarbonate, followed by drying with magnesium sulfate anhydride and concentration under reduced pressure and distillation under reduced pressure to obtain an objective compound (92.35 g, 81.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.[C:18](Cl)(=[O:20])[CH3:19].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:13][C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2n[nH]c3nc(N)sc23)cc1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: COc1ccc(-c2n[nH]c3nc(NC(C)=O)sc23)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a vial charged with 3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (100 mg, 0.306 mmol), PS-DMAP (Argonaut resin, 1.2 g, 6 equiv.), and a stirring bar was added THF (3 mL) and acetyl chloride (110 μL, 1.53 mmol). The reaction mixture was stirred at 70° C. for 1 hour, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 1.1 g, 20 equiv.) for 1 hour. The resin was filtered, washed with THF and the solvent was evaporated. The resulting crude was suspended in MeOH and treated with hydrazine monohydrate (0.06 mL) for 30 minutes. The precipitate was filtered, and the filtrate was directly purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 12.5 mg (14% yield) of N-[3-(4-methoxy-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-acetamide as an off-white solid. 1H-NMR (d6-DMSO) δ: 13.4 (broad s, 1H), 12.3 (broad s, 1H), 7.66 (broad s, 2H), 7.09 (broad s, 2H), 3.80 (s, 3H), 2.18 (s, 3H); HPLC/MS m/z: 289.0 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][C:20]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[S:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][CH:28]4[CH2:27][CH2:26][N:25]([C:23]5[S:22][N:21]=[C:20]([CH3:19])[N:24]=5)[CH2:30][CH2:29]4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3,4-difluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one. The title compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I>O>[F:1][C:2]1[N:3]=[C:4]([I:15])[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: II
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(F)nc1I
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A 125 mL pressure flask was charged with 2-fluoro-5-hydroxypyridine (5.0374 g, 45 mmol), 50 mL water, a stirbar, and sodium carbonate (4 ml, 89 mmol). The slurry was stirred and heated using a heat gun until homogenous. The solution was cooled to room temperature, and treated with iodine (2 ml, 45 mmol). The flask was sealed, and the reaction was stirred overnight at room temperature. The slurry was filtered through a 0.22 μm PTFE membrane, and the precipitate was washed with water (3×30 mL). The precipitate was dried at <1 mm Hg and 60° C. for 12 h, and then heated into 20 mL dry DCE. The cloudy solution was filtered hot, and allowed to cool. The filtrate was acidified to pH 3 with 2 M HCl, during which a precipitate had formed. The precipitate was isolated using a 0.22 μm PTFE membrane, washed with water (3×30 mL), and dried under a stream of nitrogen overnight. The solids were washed with hexanes (3×50 mL), DCM (3×50 mL), and then dried under a stream of nitrogen for 1 h to afford 6-fluoro-2-iodopyridin-3-ol (2.88 g, 27% yield). 1H NMR (400 MHz, acetone) δ ppm 6.93 (ddd, J=8.56, 3.57, 0.29 Hz, 1H) 7.38 (ddd, J=8.58, 6.58, 0.39 Hz, 1H) 9.39 (br. s., 1H). 19F NMR (377 MHz, acetone) δ ppm −78.17 (s, 1 F). 13C NMR (101 MHz, acetone) δ ppm 103.81 (d, J=15.17 Hz, 1 C) 110.35 (d, J=39.45 Hz, 1 C) 127.81 (d, J=7.37 Hz, 1 C) 154.14 (d, J=4.33 Hz, 1 C) 156.76 (d, J=234.95 Hz, 1 C). HPLC-MS: 1.39 min (>99%@215 nm; >99% @254 nm; m/z=239.9, calculated for C5H3FINO+H+=239.9).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH2:28]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH:28][C:2]1[C:3]2[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=2)[N:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2F)c(N)c1
Product: Cc1ccc(Sc2ccccc2F)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (200 mg, 1.12 mmol) was reacted with the product from Example 89b (260 mg, 1.12 mmol) for 72 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (180 mg, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.32 (s, 3H), 2.62 (s, 3H), 6.11 (br-s, 1H), 6.95-7.45 (m, 8H), 8.26 (br-s, 1H), 8.55-8.70 (m, 1H), 9.08 (br-s, 1H); MS (ESI+) m/z 376 (M+H)+, (ESI−) m/z 374 (M−H)−.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1)=O>>[C:40]([CH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:34][CH:35]=1)([OH:42])=[O:41]
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Yield: 93.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (296 mg) and (4-formylphenyl)acetic acid (360 mg) according to an analogous synthetic method to Example 212,the title compound (375 mg) was obtained.
Reaction SMILES: [CH2:1]([N:5]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])(=O)=O>C1C=CC=CC=1>[CH2:1]([N:5]([C:14]1[C:18]([Cl:23])=[CH:17][N:16]([CH3:19])[N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)C1CCCCC1)c1ccn(C)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCN(C(=O)C1CCCCC1)c1nn(C)cc1Cl
Reaction time: 12 h

Procedure:
N-Butyl-N-(1-methylpyrazol-3-yl) cyclohexane carboxamide (1.3 g, 0.0049 m) in dry benzene (15 cc) was cooled at 0° C. while sulphuryl chloride (0.67 g, 0.0049 m) was added slowly. The cooling bath was then removed and the solution was kept at room temperature for 12 hours. The solvent was then evaporated and the residue crystalled from ether/petrol (40°-60° C.) as white prisms, 1.0 g, m.p. 110°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[I:8].[Br-].[CH2:17]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH3:19].CC(C)([O-])C.[K+].O>C1COCC1>[CH:17](=[C:12]1[CH2:13][CH2:14][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:10][CH2:11]1)[CH2:18][CH3:19]
Reactant: O=C1CCC(c2ccc(I)c(F)c2)CC1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC=C1CCC(c2ccc(I)c(F)c2)CC1
Temperature: -10 °C

Procedure:
44.95 g of 4-(3-fluoro-4-iodophenyl)cyclohexanone and 55.4 g of propyltriphenylphosphonium bromide were introduced into 250 ml of THF, and the mixture was cooled to -10° C. with stirring and under nitrogen. A solution of 15.8 g of potassium tert-butoxide in 150 ml of THF was then added dropwise at -10° C. with stirring, and the mixture was then stirred at room temperature for a further 2 hours. The yellow suspension was then cooled to 10° C., and 500 ml of water were added. The organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methyl tert-butyl ether. The combined organic extracts were washed once with 100 ml of water, dried using sodium sulfate, filtered and evaporated to a residue. The residue was then purified by means of a silica-gel frit, and the eluate was evaporated to a residue, giving 4-(4-propylidenecyclohexyl)-2-fluoro-1-iodobenzene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:6]=2[CH:23]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>CS(C)=O.C(N(CC)CC)C.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>[NH2:22][C:18]1[N:17]=[C:16]([N:7]2[C:6]3[CH:23]=[C:2]([C:33]#[C:32][C:30]([C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)([OH:34])[CH3:31])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:21]=[CH:20][N:19]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC(F)(F)F)n(-c4ccnc(N)n4)c3c2)no1
Yield: 38.7 %

Procedure:
A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (120 mg, 0.31 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol) and bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) in dimethylsulfoxide (2 mL) and triethylamine (1 mL) kept in a 10-mL vial under nitrogen was irradiated with microwave radiation for 2 h at 70° C. The reaction mixture was concentrated in vacuo. The crude product (120 mg) was purified by preparative HPLC to give 55 mg (39%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (400 MHz, DMSO) delta 8.45 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.17 (s, 2H), 6.86 (d, J=5.2 Hz, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 5.37-5.30 (m, 2H), 2.41 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=+459 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH3:10].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([F:9])[C:3]=1[CH3:10]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(F)ccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)cc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
To 2,3,6-trifluorotoluene (55 g) is added conc. sulfuric acid (366 ml) and the mixture is cooled to 0° C. Thereto a solution of potassium nitrate (44 g) in conc. sulfuric acid (120 ml) is added dropwise at below 10° C. and then the mixture is stirred for 15 minutes. The mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off to give 2,3,6-trifluoro-5-nitrotoluene (68.25 g), as yellow oil.
Reaction SMILES: Cl.Cl[C:3]1C=C(NN)C=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Cl)[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20]2)[CH:15]=[CH:16][C:17]=1F>>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:23]([C:24]3[CH:25]=[C:26]([CH3:3])[CH:27]=[C:28]([F:30])[CH:29]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(C)cc(F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 20A and 3-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 1.75 g of the title compound are obtained.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]=[C:10]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11]1.CI>C1COCC1>[CH3:2][C:12]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:10](=[CH2:9])[CH2:11]1
Reactant: C=C1CC(C(=O)OCC)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=C1CC(C)(C(=O)OCC)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
To a stirred solution of LDA (60 mL, 54 mmol, 1.0 M in THF (150 mL) at −78° C., was added ethyl 3-methylenecyclobutanecarboxylate (5.0 g, 35.7 mmol) and the reaction mixture was slowly allowed to warm to 0° C. and stir for 20 min. The reaction mixture was again cooled to −78° C. and MeI (8.92 mL, 143 mmol) was added and the reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl and the aqueous layer was extracted with diethyl ether (3×5 mL). The combined organic layer was washed with an aqueous solution of 1.5N HCl, brine, then dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 1% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 258A as a pale yellow liquid (3.5 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.83-4.93 (m, 2H), 4.18 (q, J=7.18 Hz, 3.12-3.24 (m, 2H), 2.41-2.55 (m, 2H), 1.45 (s, 3H), 1.23-1.36 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH:14]=[CH:13]N=C1)=[S:9].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:13][CH2:14][NH:10][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:9]
Reactant: S=C(Nc1ccccn1)n1ccnc1
Reactant: NCCc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccccc1Cl)Nc1ccccn1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
A solution of 1-[(2-pyridyl)thiocarbamoyl] imidazole (1.02 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.21 g (14%) of the titled product as a yellow solid:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].I[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Cc1ccc(I)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 195 °C

Procedure:
11.2 g of 2-nitrobromobenzene are mixed with 15 g of 4-iodotoluene and the mixture is heated to 195° C. and stirred at this temperature for 3 and a half hours. After returning to RT, it is taken up with DCM and heated to the reflux point, the hot solution is filtered on Celite® and the DCM is then evaporated off.