Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.O.Cl.[NH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>[Cu]Br>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:21]#[C:22][CH:23]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC=O
Reactant: O=C1CCNCC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC(C#C[Si](C)(C)C)N1CCC(=O)CC1
Reaction time: 1 h
Yield: 73 %

Procedure:
A 10 ml schlenk tube was charged with copper (I) bromide (3.6 mg, 0.025 mmol), (R,Rax)-[4-(2-diphenylphosphanyl-naphthalen-1-yl)-phthalazin-1-yl]-(1-phenylethyl)amine (15.7 mg, 0.028 mmol) and 4 Å molecular sieves (powdered, 0.25 g) and then purged with argon for 5 min. Dichloromethane (1 ml) was added and the resulting suspension was stirred for 60 min. To the reaction mixture were added triethylamine (56 mg, 0.55 mmol), 4-piperidone monohydrochloride monohydrate (powder, 154 mg, 1.0 mmol), (trimethylsilyl)acetylene (98 mg, 1.00 mmol) and n-hexanal (50 mg, 0.50 mmol). The flask was rinsed with an additional 1 ml of dichloromethane and then sealed. The reaction mixture was stirred vigorously at 23° C. for 22 hrs. The reaction mixture was directly purified by flash chromatography on silica gel (hexane/EtOAc=9:1) to give 102 mg of the title compound as a colorless oil. (Yield: 73%)
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=O)(=[O:3])[CH3:2].[C:11]1([S:17]([C:20]#[N:21])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(OCCCC)(OCCCC)OCCCC.C(O)CCC>>[C:1]([O:4][C:5]1[C:20]([S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:19])=[O:18])=[N:21][CH:8]=[C:7]([CH3:10])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: CC(=O)OCC=C(C)C=O
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Product: CC(=O)Oc1cc(C)cnc1S(=O)(=O)c1ccccc1
Temperature: 108 °C
Yield: 22.7 %

Procedure:
First, 5.0 g (39.6 mmol) of 4-acetoxy-2-methyl-2-butenal, 7.05 g (39.6 mmol) of benzenesulfonyl cyanide, 0.91 g (4.0 mmol) of tributyl borate and 1-butanol (0.59 g, 7.9 mmol) were introduced to a 3-necked flask (100 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (20 ml) was added as the solvent. Then the mixture was heated under reflux for 22 hours while agitating at an internal temperature of 108° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane =⅓) to give 2.62 g of 3-acetoxy-2-benzenesulfonyl-5-methylpyridine with the following properties as a brown, oily substance (yield of 24% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:30])[N:19]=[C:20]([CH2:21][CH:22]([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:13]2[N:12]=1)[CH2:2][CH3:3].[S:31](Cl)([Cl:34])(=[O:33])=[O:32]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:30])[N:19]=[C:20]([CH2:21][CH:22]([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:13]2[N:12]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCCC)nn12
Product: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 1.4 g (3.41 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f]-[1,2,4]-triazin-4-one (Example 20A). This gives 1.4 g (80.6%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@H:10]1[CH2:15][C@H:14]([NH:16][C:17]([C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12][N:11]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].Br[CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][O:26][C:21]2[CH:20]=[C:19]([C:17]([NH:16][C@@H:14]3[CH2:13][CH2:12][N:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:10]([C:2]4[N:3]([CH2:37][CH2:38][O:39][CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][O:41]5)[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)[CH2:15]3)=[O:18])[CH:28]=[CH:27][C:22]1=2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2[nH]1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOC1CCCCO1
Temperature: 80 °C
Yield: 35.5 %

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(1H-benzo[d]imidazol-2-yl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxylate (200 mg, 0.418 mmol) in DMF (2 mL) was added 2-(2-bromoethoxy)-tetrahydro-2H-pyran (114 mg, 0.543 mmol) and K2CO3 (116 mg, 0.836 mmol), and the reaction mixture was stirred at 80° C. for over night. Water and ethyl acetate were added to the mixture, organic layer was separated and dried over MgSO4 and concentrated. The residue was purified by HPLC with 0.1% HCOOH in water/0.1% HCOOH in ACN from 45-70% to give the named compound as white solid 90 mg (35%). LC-MS: 607.2 (t=2.9 min).
Reaction SMILES: [OH:1][C:2]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C>[Si:23]([O:1][C:2]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CCCc1cc(C(=O)OCC)cc([N+](=O)[O-])c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)cc([N+](=O)[O-])c1O[Si](C)(C)C(C)(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of ethyl 4-hydroxy-3-nitro-5-propylbenzoate (1.5 g, 5.9 mmol), TBSCl (1.3 g, 8.9 mmol) and imidazole (800 mg, 11.8 mmol) in DMF (20 mL) was stirred at 30° C. overnight. A standard aqueous/EtOAc workup was followed by a purification by column chromatography (PE:EtOAc=15:1) to give product as a yellow oil (1.9 g, yield 86%).
Reaction SMILES: C1C=C(OC(OC2N=CC=CC=2)=S)N=CC=1.NC1C=CN=CN=1.[NH:24]([C:26](=[O:47])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)=[O:28])[NH2:25].CC[N:50]=[C:51]=[N:52][CH2:53][CH2:54][CH2:55][N:56]([CH3:58])C>C(Cl)Cl.CO.CN(C=O)C>[N:52]1[CH:53]=[CH:54][C:55]([NH:56][C:58]2[O:47][C:26]([C:27]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C@H:36]4[CH2:37][CH2:38][C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[O:28])=[N:24][N:25]=2)=[N:50][CH:51]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: Nc1ccncn1
Agent: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccncn4)o3)cc2)CC1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Di-2-pyridyl thionocarbonate (367 mg, 1.58 mmol) was added in one portion to a stirred solution of 4-aminopyrimidine (150 mg, 1.58 mmol) in DCM (3 mL) and the reaction mixture was heated at 100° C. for 20 minutes in the microwave and then cooled to room temperature. This solution was added to a suspension of methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenyl)cyclohexyl]acetate (Intermediate 43, 421 mg, 1.26 mmol) in DCM (5 mL) and the mixture stirred at room temperature for 5 minutes. DMF (8 mL) was added and the DCM was removed under reduced pressure. The solution was heated at 85° C. for 40 minutes in the microwave and then cooled to room temperature. EDCI (303 mg, 1.58 mmol) was added in one portion and the reaction mixture was heated at 85° C. for 60 minutes in the microwave. The reaction was quenched by the addition of H2O (200 mL) and EtOAc (250 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layer was washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to leave a dark brown gummy solid. MeOH (40 mL) was added and the mixture was heated to reflux for 2 minutes and then cooled to room temperature to leave a white suspension. The solid was filtered to give the title compound (110 mg, 20%) as a solid; 1H NMR δ 1.10-1.17 (2H, m), 1.43-1.47 (2H, m), 1.75-1.81 (5H, m), 2.24-2.26 (2H, d), 2.44 (1H, t), 3.61 (3H, s), 7.24 (2H, d), 7.69-7.73 (2H, m), 7.92 (1H, d), 8.69 (1H, d), 8.87 (1H, s), 11.02 (1H, s); MS m/e MH+ 437.
Reaction SMILES: C(OC([C@@H:11]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:12]([C@H:21]1[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH2:23][N:22]1C(OC(C)(C)C)=O)[O:13][Si](C(C)(C)C)(C)C)=O)C1C=CC=CC=1.[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@H](OC3C=CC=CN=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47].OOS([O-])=O.[K+]>CO.O>[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H:11]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:12]([OH:13])[C@H:21]2[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH2:23][NH:22]2)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@](NC(C)=O)([C@H](C)CC)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Step 22 (D): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. A solution of 130 mg (0.2 mmol) of the compound of step 22 (C) dissolved in 2 mL of methanol was treated with a solution of 240 mg (0.4 mmol) of oxone dissolved in 0.4 mL of water. After stirring at rt for 30 min, the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a gradient of 20 to 80% ethyl acetate in hexanes to provide 86 mg (64%) of the desired sulfone and 37 mg (28%) of the sulfoxide intermediate as a lower-eluting compound. 1H NMR (500 MHz, CDCl3) δ 0.06 (s, 3 H) 0.11 (s, 3 H) 0.96 (s, 9 H) 1.07 (t, J=7.32 Hz, 3 H) 1.47 (s, 9 H) 1.87 (dd, J=13.43, 6.71 Hz, 3 H) 2.03 (s, 1 H) 2.26 (t, J=12.21 Hz, 1 H) 2.38 (s, 1 H) 2.68 (s, 1 H) 2.90 (s, 2 H) 3.46 (m, 2 H) 3.75 (s, 1 H) 4.09 (m, 2 H) 4.26 (d, J=7.02 Hz, 1 H) 4.77 (m, 1 H) 4.95 (m, 1 H) 7.18 (m, 10 H) MS (ESI) (M+H−Boc)+=575.25
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=[N:22][N:21]=1)[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[N:22]1[N:21]=[C:20]([CH:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nnc3ccccn23)cc2cn[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(N)c2nnc3ccccn23)cc2cn[nH]c12
Reaction time: 1 h

Procedure:
tert-Butyl-1-([1,2,4]triazolo[4,3-a]pyridine-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethylcarbamate (43.2 mg, 0.11 mmol) was dissolved in a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) and stirred under nitrogen for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cationic exchange column. After washing the column with several volumes of methanol, the desired amine was obtained by washing the column with 2M ammonia in methanol. Concentration afforded 33 mg (93%) of the crude product which was used without purification. 1H-NMR (CD3OD, 300 MHz) δ 2.41 (s, 3H), 3.50-3.66 (m, 2H), 5.50 (bs, 2H), 6.63 (dd, J=6.6, 6.2, 1H), 6.95 (s, 1H), 7.11-7.20 (s, 1H), 7.38 (s, 1H), 7.71 (d, J=9.2, 1H), 7.88 (d, J=7.0, 1H), 7.91 (s, 1H). Mass spec.: 293.02 (MH)+.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:41][C:40]3[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (230 mg, 0.494 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (75.6 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (34.5 mg, mp =105° C.). 1H NMR (360 MHz, CDCl3) δ 1.36 (3H, t, J=7.3 Hz), 1.53-1.91 (8H, m), 2.87 (3H, s), 3.41 (1H, m), 4.10 (2H, q, J=7.3 Hz), 5.45 (2H, s), 7.23-7.36 (2H, m), 7.58-7.75 (2H, m), 7.88 (1H, s); MS (ES+) m/e 422 [MH]+. Anal. Found C, 62.56; H, 5.67; N, 23.18%. C22H24FN7O requires C, 62.69; H, 5.74; N, 23.26%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:15]([Li])CCC.[C:20](=[O:22])=[O:21]>C1COCC1.CCCCCC.O>[O:8]([C:7]1[C:2]([CH2:1][C:20]([O:22][CH3:15])=[O:21])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=O
Reactant: Cc1ncccc1Oc1ccccc1
Reactant: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ncccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-methyl-3-phenoxypyridine (3.2 g, 0.017 mol) in THF (25 ml) at -60° C. was added n-butyllithium (7 ml of a 2.5M solution in hexane) via syringe over 15 minutes. A deep red colour formed immediately and there was a slight exotherm. After stirring for a further 20 minutes, carbon dioxide gas was passed over the reaction mixture. A mildly exothermic reaction took place and a cream precipitate formed. The reaction mixture was allowed to warm to room temperature over 2 hours, diluted with water (100 ml), and then extracted with dichloromethane (×2) and ether (×1). The aqueous phase was evaporated in vacuo at 50° C., and the resulting cream-coloured residue redissolved in methanolic hydrogen chloride [formed from acetyl chloride (10 ml) and methanol (100 ml)] and left overnight at room temperature. The solvent was removed in vacuo and the residue redissolved in dichloromethane and washed with dilute sodium hydrogen carbonate. The organic phase was dried and evaporated to give an oily residue. Chromatography (eluent dichloromethane-ether) afforded methyl (3-phenoxypyrid-2-yl)acetate (1.5 g) as a brown oil; infrared max (film)1735, 1400, 1250 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C)C=O.CS(C)=O>[N+:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([O-:21])=[O:20]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(F)ccc1Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 336 h
Yield: 42.7 %

Procedure:
3.0 g (19.3 mmol) of 2-amino-5-fluorobenzoic acid and 5.88 g (29.0 mmol) of 1-chloro-2,6-dinitrobenzene were dissolved in a mixture of 30 ml of dimethylformamide with 30 ml of dimethyl sulfoxide. After adding 6.74 ml of triethylamine, the reaction mixture was stirred in a nitrogen atmosphere at room temperature for 14 days and concentrated followed by the addition of 1N hydrochloric acid thereto. Then it was extracted with ethyl acetate, washed with 1N hydrochloric acid and dried over magnesium sulfate. After concentrating, chloroform was added thereto. The crystals thus precipitated were collected. Thus 2.65 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([OH:19])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1.[CH3:36]I.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([O:19][CH3:36])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:26])[F:27])[O:11][N:10]=1
Reactant: Oc1csc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3cccc(F)c3)c2C(F)(F)F)n1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1csc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3cccc(F)c3)c2C(F)(F)F)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 52 mg (0.1 mmol) hydroxyl thiazole (example 9) in 5 ml dioxane were added alternately in small portions 0.140 g (1.0 mmol) of CH3I and a solution of 40 mg (1.0 mmol) NaOH in 1 mL water. The pH has to be kept at 8-9 and the temperature at 40-50° C. Then the reaction mixture was stirred for 1 hour at 40-50° C., diluted with 15 mL water, neutralized with HCl to pH 6-7. Thick oil was extracted with CCl4, dried with MgSO4 and purified by column chromatography on silica gel, using CCl4, then CHCl3/CCl4 (1:1, v/v) as eluents. Yield of glassy substance of example 10 is 20 mg (37%). Result of LC/MS MH+: 539.03; 1H NMR (DMSO-d6; CCl4): 3.73 (3H, s, CH3), 6.59 (1H, s, CH-thiazole), 7.52-7.78 (7H, m, CH-arom.), 8.62 (1H, s, CH-pyraz.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH:33]([N:11]([C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:35])[CH3:34]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(c3cc(C)c(C)nc3OC)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.0 mg, 0.25 mmol) was added, followed by stirring at room temperature for 15 min, and then 2-iodopropane(42 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[CH:12](OC)(OC)[O:13]C.[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1>CO>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:13][CH3:12])([O:4][CH3:19])[CH2:2][Br:1])[CH:6]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(CBr)(OC)c1cccc(Br)c1
Temperature: 75 °C
Yield: 100 %

Procedure:
A solution of 2-bromo-1-(3-bromophenyl)ethanone (48.23 g, 174 mmol) in MeOH (200 ml) was treated with trimethyl orthoformate (57.5 mL) and pTsOH (1.650 g, 8.68 mmol) and heated at reflux (75° C. oil bath) under nitrogen for 2.5 hrs. The mixture was cooled, concentrated to a viscous oil, diluted with Et2O (250 mL), and washed with 2.0 M aq. K2CO3 (100 mL), then brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure, affording the product (56.43 g, 174 mmol, 100% yield) as a mobile yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.69 (t, J=1.8 Hz, 1H), 7.48 (ddd, J=7.9, 2.0, 1.0 Hz, 1H), 7.43 (dq, J=7.8, 0.9 Hz, 1H), 7.29-7.24 (m, 2H), 3.60 (s, 2H), 3.24 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 141.0, 131.5, 130.6, 129.6, 125.9, 122.3, 100.8, 49.5, 35.0. LCMS (M+H-MeOH)=291.97.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][O:35]C(=O)C)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=O)[CH2:4][CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:51]([NH2:55])[CH2:52][CH2:53][CH3:54].O>CN(C)C=O>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([NH:55][CH2:51][CH2:52][CH2:53][CH3:54])=[O:13])[CH2:4][CH2:3]1
Reactant: CC(=O)OCCOc1ccccc1C1(O)CCN(CCC(C(=O)O)(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)C(CCN1CCC(O)(c2ccccc2OCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
In 5 mL of anhydrous dimethylformamide was dissolved 81 mg (0.17 mmol) of 4-(4-hydroxy-4-(2-(2-acetoxyethoxy)phenyl)piperidino)-2,2-diphenylbutyric acid. The resulting solution was stirred at room temperature for 1 hour. To the reaction mixture were added 36 mg (0.22 mmol) of carbodiimidazole, and after one hour 16 mg (0.22 mmol) of n-butylamine. After stirring at 70° C. for 24 hours, stirring was conducted for further 3 hours at 130° C., whereby the reaction was completed. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with water and drying. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on an alumina column and then chromatography on a silica gel column, whereby 35 mg (yield: 38.9%) of 4-(4-hydroxy-4-(2-(2-hydroxyethoxy)phenyl)piperidino)-N-butyl-2,2-diphenylbutaneamide (Compound No. 73) was obtained.