Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>O>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: NCCc1ccccn1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCCc4ccccn4)nc23)cc1
Temperature: 200 °C

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-pyridin-2-yl-ethyl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and 2-pyridin-2-yl-ethylamine (0.97 mL, 8.1 mmol) combined in a microwave vial and heated to 200° C. for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was dried, filtered, and concentrated. The residue was purified via reverse phase chromatography (Phenomenex Gemini-NX C18 AXIA column acetonitrile in water with trifluoroacetic acid modifier). Fractions containing product were neutralized by combining in saturated sodium bicarbonate and extracting with 3 portions of dichloromethane. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield a light yellow powder (195 mg, 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.70 (d, J=6.7 Hz, 1H), 8.49 (s, 1H), 8.42-8.35 (m, 3H), 8.04 (d, J=7.9 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.31 (m, 1H), 7.04 (t, J=14.6, 7.4 Hz, 1H), 6.93 (m, 1H), 3.51 (m, 2H), 3.28 (s, 3H), 2.93 (t, J=14.1, 7.0 Hz, 2H). MS=394 (MH)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Na].[C:6]1(=[O:13])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[C:6]([N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1=[O:2])([N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])=[O:13]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)Cl
Agent: [Na]
Product: O=C1CCCCCN1C(=O)N1CCCCCC1=O
Yield: 0.6 %

Procedure:
Thus, when phosgene is reacted with the sodium salt of ε-caprolactam according to H. R. Meyer, as described in the summary CA 52: 11781e of 1956, only from 0.6 to 40% of N,N′-carbonylbiscaprolactam is obtained.
Reaction SMILES: N1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)CCCC1.Cl.ClCC[CH2:20][N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21]([CH3:23])[CH2:22][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: CN(C)CCCCl
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: CN(C)CCCOc1ccc(N)cc1
Temperature: 75 °C
Reaction time: 1.3 h

Procedure:
The title compound is prepared as described in Example 1 for 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine but using 1-chloro-3-dimethylamino-propane hydrochloride. After a 1.3 h stirring at 75° C. (oil bath temperature) and usual work-up, purification of the crude material by silica gel (157 g) column chromatography (CH2Cl2/MeOH, 50/50) provides the title compound as a dark brown oil: ES-MS: 195.0 [M+H]+; Rf=0.13 (CH2Cl2/EtOH, 50/50).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:42])=[O:41]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (318 mg) in CH2Cl2 (10 mL) containing Et3N (91 mg) was added methanesulfonyl chloride (70 μL) and the mixture was stirred at room temperature for 1 hour. The solution was washed with water, with brine and dried over Na2SO4, filtered and evaporated. The solid obtained was recrystallized from CH3CN to give the title compound (170 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([N+:17]([O-])=O)[CH:6]=1)=[O:4]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:7]([NH2:17])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccccc2)c(N)c1
Reaction time: 3 h

Procedure:
The product from Example 212b (0.0795 g, 0.309 mmol) was dissolved in ethanol (2 mL) and to this solution was added Pt(IV) oxide (5.2 mg). The reaction mixture was vacuum degassed then exposed to one atmosphere of hydrogen for 3 h at room temperature. The catalyst was removed by filtration through celite and the filtrate concentrated under vacuum to give the title compound in quantitative yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:62]>C1COCC1.O1CCOCC1>[ClH:62].[O:15]([C:22]1[CH:23]=[CH:24][C:25]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidine carboxylate (1.0 g, 5.0 mmol) in anhydrous THF (5 mL) was added 4-phenoxyphenol (1.21 g, 6.5 mmol) in THF (5 mL) and triphenyl phosphine (1.57 g, 6 mmol) in THF (5 mL). The resulting mixture was cooled to 0° C. using ice-water bath and purged with nitrogen. Diisopropyl azodicarboxylate (1.21 g, 6 mmol) was dissolved in 5 mL of THF and added to above solution drop wise over period of 20 min under nitrogen. Reaction then was heated at rt for 3 h and 70° C. for 48 h. THF was removed in vacuo and crude mixture was purified by silica gel flash chromatography (10% EtOAc/Hexane) to obtain the product. To a solution of the product in dioxane (4 mL) was added 4M HCl in dioxane (10 mL) at rt and the resulting mixture was stirred for 3 h at that temperature. The solvent was removed in vacuo and residue was triturated with ether to obtain a white crystalline solid (918 mg, 68%): MS; m/z 270.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.81-1.87 (m, 2H), 2.07-2.12 (m, 2H), 3.02-3.08 (m, 2H), 3.19-3.25 (m, 2H), 3.56 (s, 1H), 4.57-4.61 (m, 1H), 6.92-7.10 (m, 7H), 7.33-7.37 (m, 2H), 8.91 (s, 2H); HPLC (UV); 96%. Elemental analysis. Calc C 66.77 H 6.59 N 4.58. Found C 65.82 H 6.70 N 4.77.
Reaction SMILES: [CH2:1]([C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.[CH2:31]=[O:32].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:24]1([CH3:23])[C:29]([CH:31]=[O:32])=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1
Reactant: C=O
Reactant: Cc1ccc(C)cc1
Agent: CCCCCCCCCCCCc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc(C)c(C=O)c1

Procedure:
To a mixture of 30.6 parts of 5-dodecylsalicylic acid, 21.2 parts of p-xylene, 3.8 parts of 87% paraformaldehyde and 30 parts of acetic acid was added 2.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 6 hours, the reaction mixture was washed with water, and unreacted p-xylene and water were removed by vacuum distillation to give 43 parts of 5-dodecylsalicylic acid-p-xylene-formaldehyde co-condensation product. 10 parts of the co-condensation product was added to 32 parts of aqueous 10% potassium hydroxide solution and dissolved at 80° C. The solution was cooled to 40° C., and 28 parts of aqueous 10% solution of nickel chloride hexahydrate was added thereto. After the reaction had been allowed to proceed at 40° C. for 30 minutes, precipitates formed were collected by filtration, washed with water and dried to give 11 parts of nickel salt of 5-dodecylsalicylic acid-p-xylene-formaldehyde co-condensation product.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[CH:31][C:32](O)=[N:33][C:34]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[CH:31][C:32]([O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:33][C:34]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of, ethyl 2-(3-(((methylsulfonyl)oxy)methyl)phenoxy)acetate (100 mg) and 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (100 mg) in DMF (3.0 mL) was added potassium carbonate (72 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium 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 (77 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:25]([NH2:26])=[N:24][C:23]2[N:13]([C@@H:14]3[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](C)(C)[CH3:29].Cl>C/C(/O)=C/C(C)=O.[Ag].CN(C)C=O>[CH2:1]([N:8]1[C:25]([NH2:26])=[N:24][C:23]2[N:13]([C@@H:14]3[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]3[O:16][CH3:29])[CH:12]=[N:11][C:10]=2[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[SiH](C)C
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1Cc1ccccc1
Agent: [Ag]
Agent: CC(=O)/C=C(/C)O
Agent: Cl
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)n(Cc3ccccc3)c(N)nc21
Temperature: 70 °C

Procedure:
A 1 L pear shaped recovery flask with stir bar was charged with a mixture of 16 (50 g, 134 mmol), silver acetylacetonate (41 g 200 mmol), TMSH (200 ml of 1N solution in methanol) and dimethylformamide (400 ml). The flask was heated to 70° C. for two hours. The solution was cooled to ambient temperature, neutralized to pH 7 with 1M HCl, and dried to a solid tar. The tar was dissolved in water (500 ml) and filtered through a sintered glass funnel to remove silver salts. The product was evaporated to dryness to remove water and residual solvents and 10 grams (26 mmols) was redissolved in 50 ml of water prior to purification on a Waters Delta-Pak ODS 50 mm×300 mm HPLC column. The N1-Bz-2′-OMe guanosine isomer eluted first and was recovered using a rotary evaporator. The product (7 g, 18 mm, 70%) was identical to an authentic sample by HPLC, UV-, 1H-NMR-spectroscopy. 1H NMR (dmso-d6): 8.02 (s, 1H, H8), 7.26 (m, 5H, ph), 7.02 (bs, 2H, 2NH2), 5.82 (d, J1′,2′=6.4, 1H, H1′), 5.23 (s, 2H, CH2-Bz), 5.18 (d, JOH,3′=4.8, 1H, 3′-OH), 5.04 (t, JOH,5′=5.2, JOH,5″=5.6, 1H, 5′-OH), 4.28 (m, J3′,2′=4.8, J3′,4′=3.2, 1H, H3′), 4.20 (t, J2′,1′=6.4, J2′,3′=4.8, 1H, H2′), 3.90 (m, J4′,3′=3.6, J4′,5′=4.0, 1H, H4′), 3.65-3.53 (m, 2H, H5′, H5″ JOH,5′=5.2, J5′,5″=11.6), 3.33 (s, 3H, OCH3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([CH2:13]Br)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>>[C:15]([O:18][CH2:2][C:3]1[CH:12]=[C:11]([CH2:13][O:7][C:5](=[O:6])[CH3:4])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(CBr)cc1CBr
Agent: [Na+]
Product: COC(=O)c1ccc(COC(C)=O)cc1COC(C)=O
Yield: 109.7 %

Procedure:
According to a similar procedure to that described in Example 1-(5), methyl 2,4-bis(bromomethyl)benzoate (described in Chem. Ber., 127, 2081 (1994); 13.3 g, 41.3 mmol) and sodium acetate (16.4 g, 200 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction, the title compound as a crude product. The crude product was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=3:17˜3:5) to afford the title compound (6.35 g, 55% yield) as an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26]>ClCCl>[CH:1](=[N:16]/[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
To a stirred mixture of benzaldehyde (1.91 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (100 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (3.38 g, yield 95%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.41 (s, 2H), 7.36-7.37 (d, J=7.6 Hz, 1H), 7.49-7.59 (m, 4H), 7.77-7.78 (d, J=7.6 Hz, 1H), 7.92-7.94 (d, J=8.0 Hz, 2H), 8.55 (s, 1H), LC-MS (ESI) m/z: 238 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3cccnc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Quinoline-8-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=488.3.
Reaction SMILES: ClCCCl.C[Si](Cl)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1>C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:40][CH:41]=1)([O-:47])=[O:46]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 0.07 h

Procedure:
DCE (0.146 mL, 1.69 mmol) was added to a vigorously stirred suspension of zinc dust (0.901 g, 13.8 mmol) in THF (3.5 mL) under nitrogen. The resulting suspension was heated at 80° C. for 10 minutes then cooled to room temperature. Trimethylsilyl chloride (0.202 mL, 1.59 mmol) in THF (1.75 mL) was added and the mixture was stirred at room temperature for 4 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (3.00 g, 10.6 mmol) in THF (3.5 mL) was added dropwise over 15 minutes and the resulting mixture stirred at room temperature for 2 hours. Pd2(dba)3 (0.155 g, 0.170 mmol) and tri-2-furylphosphine (0.143 g, 0.615 mmol) were added followed by 1-iodo-4-nitrobenzene (2.90 g, 11.7 mmol) in THF (18 mL). The resulting mixture was then heated at 55° C. for 3 hours then quenched with an aqueous saturated sodium chloride solution (15 mL). After filtration through a pad of Celite, the layers were separated and the aqueous phase extracted with DCM (2×15 mL). The combined organic fractions were dried (MgSO4), filtered and evaporated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 10-40% EtOAc in cyclohexane) to give the title compound A76 as an orange oil (2.14 g, 72%); 1H NMR (300 MHz, CDCl3) δ 8.24 (dd, J=6.8, 1.9 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 4.41 (t, J=8.7 Hz, 2H), 3.98 (dd, J=8.5, 5.7 Hz, 2H), 3.89-3.81 (s, 1H), 1.49 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ncc2c(n1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2nc(Br)ncc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-bromo-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.1 g, 0.47 mmol) and triethylamine (0.2 mL) in 2 mL of DCM, at 0° C., was added MsCl (0.1 mL). The mixture was stirred at room temperature for 1 h then diluted with 20 mL of DCM and washed with a mixture of saturated NaHCO3 (15 mL) and water (15 mL). The DCM was evaporated to afford the crude 59a.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[N+:19]([O-])=O)[CH3:2].O>C(O)C.Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cc(C=O)ccc1N
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(5-formyl-2-nitro-phenoxy)-hexanoic acid ethyl ester (1.0 g, 3.23 mmol) in ethanol (20 ml) and concentrated HCl (5 ml) was added stannous chloride (2.17 g, 11.63 mmol). The mixture was stirred at 70° C. for 90 minutes while being monitored by thin layer chromatography. After cooling to room temperature, the mixture was poured into water (100 ml) and neutralized with a saturated solution of sodium bicarbonate resulting in the precipitation of tin salts and a dark brown oil. The salts were washed with ethyl acetate and the washings were combined with the original filtrate, the aqueous phase was separated and the remaining ethyl acetate phase was dried with magnesium sulfate, filtered and concentrated by rotary evaporation to a brown oil which was purified by column chromatography (45% CH2Cl2, 45% hexane, 10% Et3N). The product, 6-(2-amino-5-formyl-phenoxy)-hexanoic acid ethyl ester, was obtained as a red oil (0.33 g, 35%). An additional 0.32 g of red oil was obtained from the column but found to be a mixture of unidentified byproducts. 1H NMR (400 MHz, CDCl3) δ: 9.72 (s, 1H), 7.30 (m, 2H), 6.73 (d, 1H, J=8.4 Hz), 4.50 (s, 2H), 4.15 (q, 2H, J=7.2 Hz), 4.08 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=8.8 Hz), 1.88 (m, 2H), 1.74 (m, 2H), 1.55 (m, 2H) 1.30 (t, 3H, J=6.8 Hz). 13C NMR (400 MHz, CDCl3) δ: 109.59, 173.60, 146.08, 143.31, 127.78, 127.55, 112.72, 109.11, 68.18, 60.35, 34.20, 28.83, 25.69, 24.61, 14.18. IR (neat): 3481, 3362, 2936, 2868, 2722, 2360, 2341, 2229, 2156, 1964, 1727, 1671, 1612, 1587, 1572, 1517, 1444, 1394, 1368, 1313, 1243, 1164, 1140, 1095, 1029, 864, 817, 789, 748.
Reaction SMILES: [Cl:1][C:2]([O:4]C(Cl)(Cl)Cl)=O.[CH3:9][N:10]([CH3:22])[S:11]([C:14]1[S:18][C:17]([NH:19][CH3:20])=[N:16][C:15]=1[CH3:21])(=[O:13])=[O:12]>O1CCOCC1>[CH3:9][N:10]([CH3:22])[S:11]([C:14]1[S:18][C:17]([N:19]([CH3:20])[C:2]([Cl:1])=[O:4])=[N:16][C:15]=1[CH3:21])(=[O:12])=[O:13]
Reactant: CNc1nc(C)c(S(=O)(=O)N(C)C)s1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nc(N(C)C(=O)Cl)sc1S(=O)(=O)N(C)C
Yield: 124.9 %

Procedure:
15.4 g (78 mmol) of trichloromethyl chloroformate (“diphosgene”) were added at room temperature to a solution of 22.9 g (97 mmol) of N,N,4-trimethyl-2-(methyl-amino)-1,3-thiazole-5-sulphonamide in 360 ml of dioxane, and the mixture was heated to reflux until a homogeneous solution was obtained, and TLC showed that no starting material remained. After removal of the solvent in vacuo, 29.0 g of the product were obtained in the form of an oil. (Yield 100%, NMR (CDCl3): 3.89 (3H), 2.81 (6H), 2.62 (3H) ppm).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([Cl:19])[CH:13]=2)[N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([Cl:19])[CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cc(Cl)nc(Cl)c2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cc(Cl)nc(Cl)c3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine (52 mg, 0.159 mmol) and 2-chloro-5-methoxyaniline (40 mg, 0.255 mmol) similar to Example 160 and was isolated as a yellow crystalline solid (13 mg, 0.029 mmol, 18%). 1H NMR (CDCl3): 8.27 (s, 2H), 7.76 (s, br, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.02 (s, 1H), 6.77 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[C:5](\C)/[CH:6]=[CH:7][C:8]1[N:9]([CH:24]([CH3:26])[CH3:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-:29].[NH4+].[Cl-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5](=[O:29])/[CH:6]=[CH:7]/[C:8]1[N:9]([CH:24]([CH3:26])[CH3:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: COC(=O)/C=C(\C)C=Cc1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.63 g (1.49 mmol) of (E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylpenta-2,4-dienoic acid methyl ester in 20 ml of THF are introduced into a 50 ml round-bottomed flask equipped with a magnetic stirrer and nitrogen delivery line, 4 ml of 1N ammonium hydroxide solution are added, and the mixture is stirred for 6 hours at room temperature. The reaction mixture is poured into 200 ml of saturated sodium chloride solution and extracted twice with 100 ml of ethyl acetate, and the organic phase is washed three times with 50 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product is purified by means of flash chromatography (hexane/ethyl acetate=9:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.