Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:15]2[C:16]([N+:28]([O-:30])=[O:29])=[CH:17][C:18]([C:24]([F:27])([F:25])[F:26])=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
deprotonating (R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, and reacting the resultant compound with 2-chloro-1,3-dinitro-5-trifluoromethylbenzene to form (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester;
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[Na+]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CNCCCOc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCOc1ccccc1
Yield: 84.7 %

Procedure:
A solution of 486 mg of 11β-fluor-7α-(5-iodopentyl)-estra-1,3,5(10)-triene-3,17β-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 600 mg of methyl-(3-phenoxy-propyl)-amine for 3 hours at a bath temperature of 80° C. Then, the batch is added to saturated sodium chloride solution, extracted with ether, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with methylene chloride/methanol/ammonia. 443 mg of 11β-fluoro-7α-{5-[methyl-(3-phenoxy-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam [α]D=+47° (c=0.5 in CHCl3).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[C:7]([O:11]C)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1([CH3:13])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1
Reactant: COc1cccc2c1C(C)(C)CO2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)COc2cccc(O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 3,3-dimethyl-4-(methyloxy)-2,3-dihydro-1-benzofuran (Intermediate 5, 4.0 g) in dichloromethane (100 ml, SCRC) was added BBr3 (6.37 ml, 67.3 mmol, SCRC) dropwise under ice-cooling. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature and then water (20 ml) was added. The resulting mixture was extracted with ethyl acetate (3 times 100 ml, SCRC) and the combined organic layers were dried, evaporated and purified by silica gel chromatography with EtOAc/PE as eluents (1/20) to afford the title compound (2.8 g).
Reaction SMILES: [C:1](=[O:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]#[C:24][C:25]([CH3:32])([O:27][Si](C)(C)C)[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:1](=[O:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]#[C:24][C:25]([OH:27])([CH3:32])[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of tert-butyl 2′-fluoro-5′-methoxy-2-(3-methyl-3-((trimethylsilyl)oxy)but-1-yn-1-yl)biphenyl-4-yl carbonate (480 mg) in THF (3 mL) was added a solution (1 M, 2.0 mL) of tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (343 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:16][C:14]2[N:15]=[C:8]3[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:12][CH:11]=[CH:10][N:9]3[N:13]=2)=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: CC(C)(C)c1ccc(Br)cc1
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C(C)(C)C)cc4)nc23)cn1

Procedure:
8-(1-Methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, as described earlier, is coupled with 1-bromo-4-tert-butyl-benzene according to general procedure 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][O:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COCCNc1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (53%). MS (ESI): m/z=503.095 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1)([O-])=O.[N+](C1C=C(C=C([N+]([O-])=O)C=1)N)([O-])=O.NC1C=C([N+]([O-])=O)C=C(N)C=1.[H][H]>>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[CH:5]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: Nc1cc(N)cc([N+](=O)[O-])c1
Agent: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: Nc1cc(N)cc(N)c1

Procedure:
The compounds of the formula (I) can be synthesized e.g. by hydrogenation of 1,3,5-trinitrobenzene, 3,5-dinitroaniline or 1,3-diamino-5-nitrobenzene with hydrogen and an appropriate metal catalyst in an appropriate organic solvent. The thus obtained 1,3,5-triaminobenzene can be isolated or optionally transferred into the corresponding hydrochloride and can be purified in both forms by recrystallization from an appropriate solvent. It is also possible to use the solution of the crude trisamine or the isolated crude trisamine (with or without removal of the water formed in the hydrogenation) for the subsequent acylation reaction. Possible catalysts are e.g. Pd. PtO2, Raney-Nickel etc., preferably the commercially available versions on carbon support. The hydrogenation can be carried out under normal pressure or under pressure at temperatures between 20 and 120° C. (Safety checks are highly recommended before scale up). Appropriate solvents for the hydrogenation are e.g. tetrahydrofuran (THF), THF/methanol, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP). An alternative procedure is reduction with Raney-Nickel and hydrazine as hydrogen source (see e.g. Organikum, chapter 8.1, Reduktion von Nitroverbindungen und Nitresoverbindung, Berlin, 1970) or other known standard reductions. Recrystallization can be carried out e.g. with methanol, ethanol or other alcohols. The free amine (or the amine obtained from the hydrochloride and an appropriate base) can be acylated with a stoichiometric amount or an excess of the corresponding acid chloride, preferably in the presence of an organic or inorganic non-interacting base e.g. triethylamine, tributylamine, pyridine; another method uses a stoichiometric amount or an excess of the anhydride of the carboxylic acid as acylating agent; in this case no base is required. The reaction is carried out in the absence or preferably in the presence of a solvent. The ideal reaction temperature depends on the nature of the acylating agents (e.g. 0°-100° C.). Isolation/purification of the final product is carried out by precipitation/recrystallization/washing with an appropriate mixture of water/organic solvent or organic solvent/organic solvent or with a pure solvent, e.g. DMF/water, NMP/water, ethanol, methanol etc.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.I[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].CCN(CC)CC.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Reactant: CCOC(=O)N1CCN(C(=O)CI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)COc2nsc3nc(C)cc(C)c23)CC1
Yield: 10.8 %

Procedure:
Pyridinothiazolone 4 (300 mg, 1.66 mmol) was treated with ethyl 4-(2-iodoacetyl)piperazine-1-carboxylate (541 mg, 1.66 mmol), Et3N (840 mg, 8.30 mmol) and Cs2CO3 (500 mg, 1.54 mmol) in anhydrous CH2Cl2 (25 mL) at room temperature for 24 h, and then washed with H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (EtOAc/hexane (1:1)) to give the title compound (68 mg, 11% yield) in addition to the main N-alkylation product 21 (YMU1, 60%). The purity of product 28 was 99.5% as shown by HPLC on an HC-C18 column (Agilent, 4.6×250 mm, 5 μM), tR=4.9 min (gradients of 40-90% aqueous CH3CN in 15 min).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([C:14]2[C:18]([C:19]3[N:20]=[CH:21][N:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=3)=[C:17]([CH3:33])[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1>>[CH:1]1([NH:6][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([N:22]3[CH:23]=[C:19]([C:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=5)=[N:15][O:16][C:17]=4[CH3:33])[N:20]=[CH:21]3)[CH:25]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CCCC3)c2)cn1
Yield: 59 %

Procedure:
As described for Example 71c, cyclopentylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (70 mg, 59%) which was obtained as an off-white solid. MS: m/e=431.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 82%).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:19]O>>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccccc1
Yield: 100 %

Procedure:
To a 1.0 L round bottom flask was added 89 g (0.5 mol) of 3-benzoylpropionic acid and 200 mL of methanol. The solution was stirred until all of the acid had dissolved. To this solution was added approximately 2.0 mL of conc. H2SO4 and the reaction refluxed for 2.5 hours. After the reaction was determined to be complete, the methanol was removed on the rotoevaporator and to the residual oil was added ethyl acetate (˜500 mL). To the ethyl acetate layer was then added 150 mL of a saturated sodium carbonate solution. The layers were extracted and allowed to separate. The organic layer was then dried (MgSO4), filtered, and concentrated to yield methyl 3-benzoylpropionate (1) as a light yellow oil. Yield 96 g; yield 100%; >97% cp. Lit bp 172–174° C. at 10 mm Hg.; 1H NMR ppm (δ), CDCl3 7.98 (dd, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 3.70 (s, 3H, OCH3), 3.32 (t, 2H), 2.76 (t, 2H). 13C NMR ppm (δ), CDCl3 198.0 (C═O), 173.3 (CO2), 136.5 (q), 133.2, 128.6, 128.0, 51.7 (OCH3), 33.3, 28.0. IR oil cm−1 2952, 1737, 1687, 1596, 1449, 1358, 1221, 1168 1001, 750, 691.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:2][C:1]1([C:4]2([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=3)[CH2:6][CH2:5]2)[O:18][CH2:17][CH2:16][O:3]1
Reactant: OCCO
Reactant: CC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(C2(c3ccc([N+](=O)[O-])cc3)CC2)OCCO1

Procedure:
A solution of 4-(1-acetylcyclopropan-1-yl)nitrobenzene (2.40 g), ethylene glycol (6.5 mL), and pyridinium p-toluenesulfonate (1.47 g) in benzene (120 mL) was heated under reflux with Dean-Stark apparatus for 15 hours. After cooling, dilution with saturated sodium hydrogencarbonate solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=4:1) of the residue gave 4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)nitrobenzene (2.83 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[S:5][CH:6]=1.C[Al](C)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C)[N:18]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26]([NH:10][S:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[N:3]=2)(=[O:9])=[O:8])=[O:27])[N:20]=1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Reactant: NS(=O)(=O)c1nc(Cl)cs1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2nc(Cl)cs2)n1
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a suspension of 1.6 g of 4-chloro-2-thiazolesulfonamide in 100 ml methylene chloride under a nitrogen atmosphere, 4.4 ml of a 2.0M solution of trimethylaluminum in toluene was added slowly via a syringe. The reaction mixture was stirred 10 minutes; 1.9 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled to 0°, and 55 ml of 5% hydrochloric acid was added dropwise giving a flocculant solid. The reaction mixture was extracted with 100 ml of ethyl acetate. The organic solution was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated. The resulting tan solid was slurried in 1-chlorobutane, collected, washed with hexane and dried giving 1.25 g of the title compound as a white solid, m.p. 182°-183°(d). IR: 2.98 and 3.25μ(NH), 5.80μ (C=O).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)C1)[CH2:42]2>>[Cl:17][C:18]1[C:19]([O:46][CH:45]2[CH2:40][CH:39]3[CH2:44][CH:35]2[CH:42]2[CH:38]3[CH2:37][CH2:43][CH2:41]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2CC3CC2C2CCCC32)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-tricyclo[5.2.1.0 {2,6}]decan-8-ol, the title compound was obtained as a colorless solid (0.03 g, 7%): 1H NMR (300 MHz, CDCl3) δ 8.70-8.58 (m, 1H), 8.10-8.03 (m, 1H), 6.70-6.58 (m, 1H), 4.27-4.09 (m, 1H), 3.03 (s, 6H), 2.28 (s, 1H), 2.17-2.10 (m, 1H), 2.02-1.65 (m, 6H), 1.65-1.56 (m, 1H), 1.54-1.39 (m, 2H), 1.36-1.17 (m, 1H), 1.13-0.90 (m, 2H); MS (ES+) m/z 431.1 (M+1), 433.1 (M+1);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([C:29]2[C:30](=[O:43])[N:31]([CH3:42])[C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][CH:34]=2)[CH:25]=[CH:26][C:27]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:21][C:22]1[CH:23]=[C:24]([C:29]2[C:30](=[O:43])[N:31]([CH3:42])[C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][CH:34]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To a 10 mL round bottom flask was added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (18.7 mg, 0.065 mmol; prepared according to the procedure of Example 43, Step E), 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (13.5 mg, 0.043 mmol) and the solids were dissolved in DMF (0.5 mL). Potassium carbonate (9.0 mg, 0.065 mmol) was added followed by a 1M solution of potassium t-butoxide in THF (0.065 mL, 0.065 mmol), and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was cooled to room temperature and then partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer washed with water, brine, dried over Na2SO3 and concentrated to afford 24.3 mg of crude oil. The crude product was triturated with ether to afford the desired product (16 mg, 65%) as a tan solid. LRMS (APCI pos) m/e 563.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:27][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([C:11]3[N:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=2)=[O:10])([CH3:25])[CH3:26])=[CH:22][CH:23]=1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Reactant: CC(C)(N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (110 mg, 0.5 mmol), 2-(4-bromophenyl)propan-2-amine, 36-b, (70 mg, 0.32 mmol), HATU (290 mg, 0.76 mmol) and DIEA (82 mg, 0.64 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was washed with aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL). The organic layers were dried and concentrated in vacuo. The residue was washed with hexane to afford compound 36-c (80 mg, 57%). 1H NMR (300 MHz, CDCl3) δ11.62 (s, 1H), 9.55 (s, 1H), 9.41 (dd, J=1.5, 4.8 Hz, 1H), 9.00 (d, J=4.2 Hz, 1H), 8.63 (dd, J=1.5, 8.1 Hz, 1H), 7.78 (dd, J=5.1, 8.4 Hz, 1H)), 7.43 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 1.78 (s, 6H). LC-MS: (M+H)+ 414.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17].Cl>[Cu](I)I.O1CCCC1>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: ClC[C@@H]1CO1
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O[C@H](CCl)Cc1cc(F)c(F)cc1F
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
84.4 g of 1-bromo-2,4,5-trifluorobenzene and 42.1 mL of tetrahydrofuran were added to 250 mL flask, and the resulting reaction solution was cooled to −15-20° C. Under nitrogen atmosphere, 20 mL of isopropylmagnesium chloride [2.0 M tetrahydrofuran solution] was dropped to the reaction solution, and stirred at 0-5° C. for 2 hours to produce Grinard reagent. 31.6 mL of (S)-epichlorohydrin and 42.1 mL of tetrahydrofuran were added to another 250 mL flask; the resulting reaction solution was cooled to −15-−20° C.; and then 7.6 g of copper iodide was added thereto. 42.1 mL of the Grinard reagent produced under nitrogen atmosphere was dropped, and stirred for 3 hours while the reaction temperature was maintained at −15-−20° C. 297 mL of 2 N hydrochloric acid aqueous solution that was cooled at 0-5° C. was dropped to the reaction solution, and then extracted with 297 mL of isopropylether. An organic layer was dehydrated with sodium sulfate, and then concentrated under reduced pressure to obtain 89.8 g of a title compound.