Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[N:10]([O-])=[O:11].[Na+].CC(O)=O>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:10]=[O:11])=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(N)n1

Procedure:
The process according to claim 1 wherein 2,4,6-triaminopyrimidine is reacted with an equimolar amount of sodium nitrite in the presence of about 1.5 molar amount of HOAc in the presence of water to produce the intermediate 2,4,6-triamino-5-nitrosopyrimidine in the form of a stirrable slurry.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[C:19](/[CH:24]=[C:25]1\[CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](O\1)=[O:30])([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:19]([CH:24]=[C:25]1[N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([O:3][CH3:4])=[O:2])=[CH:18][CH:17]=2)[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C=C1\CC(C)(C)CC(=O)O1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)(C)CC(=O)N1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Compound (i) of Example 9 (1.2 g, 0.005 mole) and compound (b) of Example 2 (1.1 g, 0.005 mole) are combined in toluene (50 mL) and refluxed for 5 hours. The toluene is removed in vacuo and the residue is chromatographed on silica gel using hexane/ethyl acetate as the mobile phase. The title compound is isolated as a colorless oil (1.2 g, 52%). Mass Spec. (DCI) m/z 436 (M+H). Analysis--calc'd for C26H29NO5 : C, 70.96; H, 6.76; N, 3.18; found: C, 70.76; H, 7.11; N, 2.77.
Reaction SMILES: [Mg].BrC.Cl[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CN(C)[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[O:8]1[CH2:9][CH2:10][CH:5]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:7]1
Reactant: ClC1CCOCC1
Reactant: CCOC(=O)C=CN(C)C
Agent: CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCOCC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
9.6 g (400 mmol) of magnesium turnings are covered with tetrahydrofuran, about 2 ml of bromomethane are added, and the mixture is warmed to reflux. 38.45 g (300 mmol) of 4-chlorotetrahydropyran, dissolved in 100 ml of tetrahydrofuran, are added dropwise. The mixture is subsequently stirred for a further 30 minutes and cooled to 10° C., 42.9 g (300 mmol) of ethyl 1-(dimethylamino)eth-1-ene-2-carboxylate are added dropwise, and the mixture is stirred for a further 12 hours. Customary work-up gives 31.4 g (60%) of ethyl 1-(4-tetrahydropyranyl)eth-1-ene-2-carboxylate of boiling point 120° to 140° C./10 mmHg.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[N:10]=[C:11]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:16][C:15]=2[Cl:30])[CH:13]=1)=O)([CH3:5])[CH3:4].C1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:46]>CCOC(C)=O>[Cl:30][C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=2)[CH:18]=[CH:19][C:14]=1[N:12]1[CH:13]=[C:9]([C:7]2[S:46][CH2:2][C:3]([CH3:5])([CH3:4])[N:6]=2)[N:10]=[C:11]1[C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38]
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CSC(c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3c(Cl)cccc3Cl)n2)=N1
Yield: 17.2 %

Procedure:
To a N2 purged 50 mL round bottom flask attached with condenser was added 1-(3-Chloro-3′-methanesulfonyl-biphenyl-4-yl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (140 mg, 236 μmol), anhydrous benzene (14 mL) and P2S5 (500 mg, 2.25 mmol). The reaction solution was stirred at reflux for 1 hr. The reaction solution was diluted with EtOAc (100 mL) and filtered through a Buchner funnel to remove excess P2S5. The filtrate was washed with aq. 0.1 N NaOH. The organic phase was partitioned, dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 25 g SiO2 column using a gradient of 100% Hexane to 80% EtOAc to afford 24 mg (17% yield) of title compound. MS (ESI) 590.0, 592.0, 594.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (t, J=2 Hz, 1H), 8.21 (t, J=2 Hz, 1H), 8.17 (d, J=2 Hz, 1H), 8.14 (d, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.78-7.85 (m, 2H), 7.74 (t, J=8 Hz, 1H), 7.49-7.61 (m, 3H), 7.43 (d, J=8 Hz, 1H), 3.36 (br s, 2H), 3.26 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=[C:18](Cl)[N:19]=1)([CH3:4])([CH3:3])[CH3:2].C1(NC2C3SCCC=3N=C([N:38]3[CH2:43][CH2:42][N:41]([C:44]4[CH:54]=[CH:53][C:47](C(OCC)=O)=[CH:46][CH:45]=4)[CH2:40][CH2:39]3)N=2)CCCCC1>O1CCOCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=[C:18]([N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:54]=[CH:53][CH:47]=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)[N:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(Cl)nc2c1SCC2
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Temperature: 160 °C

Procedure:
1.08 g (2.9 mmol) of tert-butyl[(1S,2S)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)cyclopentyl]carbamate (V) (chiral) and is 9.9 mmol of 1-phenylpiperazine (VI) are placed in 14 mL of dioxane, then heated to 160° C. for 2.3 hours. The reaction mixture is concentrated by evaporation, the residue is then purified by HPLC through an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroacetic acid (B)).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH:12]1[C:20]([OH:22])=[O:21]>[OH-].[Na+]>[C:1]1([S:7]([N:11]2[CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13][CH:12]2[C:20]([OH:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CC2CCCCC2N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CC2CCCCC2N1S(=O)(=O)c1ccccc1
Reaction time: 24 h

Procedure:
29.8 mmol (3.8 ml) of benzenesulphonyl chloride and 7.4 ml of 4M sodium hydroxide solution are added in succession to a solution, cooled to 0° C., of 29.6 mmol (5 g) of 2-perhydroindolecarboxylic acid in 7.4 ml of 4M NaOH. The reaction mixture is left at room temperature, with stirring, for 24 hours. The mixture is then rendered acidic to pH 2-3 and filtered. The resulting solid is washed with ether to yield the expected product.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[OH-].[K+].I[CH3:14]>CO.O>[CH3:14][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2]1=[O:1]
Reactant: CI
Reactant: O=C(O)c1ccc[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cccc(C(=O)O)c1=O

Procedure:
To 2-oxo-1H-pyridine-3-carboxylic acid (2.00 g, 14.4 mmol) in methanol (20 mL) was added a solution of KOH (1.60 g, 28.5 mmol) in water (3 mL) and the mixture was vigorously stirred until a thick suspension formed. Iodomethane (10 μL, 0.16 mmol) was added and the mixture was heated at reflux for 1.5 h. The mixture was concentrated to ⅓ volume and was acidified to pH 1 with 6N HCl. The solids were filtered off and were washed with water (3×2 mL) and acetonitrile (2×2 mL), and then dried in vacuo to give 1-methyl-2-oxo-pyridine-3-carboxylic acid as a white solid. ESI-MS m/z calc 153.0, found 154.1 (M−1)−. Retention time: 0.65 minutes (3 min run).
Reaction SMILES: N[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)/[C:5](=[CH:13]\[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)/[C:4]=1[CH3:22].Cl[O:24]C(C)(C)C.CC(C)([O-])C.[K+].Cl>CCOCC.C(O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)/[C:5](=[CH:13]\[C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=1)/[C:4]([CH3:22])=[C:3]2[CH:2]=[O:24]
Reactant: CSc1ccc(/C=C2/C(C)=C(CN)c3cc(F)ccc32)cc1
Reactant: CC(C)(C)OCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CSc1ccc(/C=C2/C(C)=C(C=O)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of freshly liberated amine from Step 1 (11.5 g, 37 mmol) in ether (220 mL) at 0° C. there was added a solution of t-butyl hypochlorite (4.0 g) in ether (10 mL); the mixture was stirred at 0° C. for 5 minutes as a yellow solid formed. The mixture was then allowed to warm up to room temperature and there was slowly added a solution of potassium tert-butoxide (15 g, 133 mmol) in ethanol (200 mL). The mixture was boiled on a steam bath for 10 minutes and then cooled down. There was added 1N aqueous HCl (200 mL) and after stirring for 20 minutes, the mixture was extracted with ether to afford the crude aldehyde which was purified by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate:hexane. The pure title compound was obtained as an oil.
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])#[N:2].I([O-])(=O)(=O)=[O:20].[Na+].[K+].[Br-]>O1CCOCC1.O>[C:1]([CH2:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:20])#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)CC#N
Temperature: 40 °C

Procedure:
A solution of N-(2-cyanomethylsulfanyl-5-trifluoromethylphenyl)acetamide(0.42 g) in dioxane (2.50 ml) was added dropwise to a stirred solution of sodium periodate (0.69 g) in a mixture of water (6 ml) and dioxane (1.50 ml) at ambient temperature. An additional amount of dioxane (2.50 ml) was added. The mixture was stirred at 40° C. for 6½ h, then at room temperature overnight. A precipitate was removed by filtration and washed on the filter with dichlorometane (20 ml). The two phases of the filtrate were shaken and separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The more polar component of the residue was isolated by flash chromatography on silica gel eluted with 1) ether and 2) ethyl acetate to give a slowly crystallizing oil. Trituration with petroleum ether and subsequent drying gave white crystals. Yield 0.16 g (38%); mp 149-151° C.; 1H-NMR(CDCl3) δ (ppm): 9.9 (br, 1H), 8.70 (d, J=2 Hz, 1H), 7.68-7.46 (d+dd, J=8Hz and 8 Hz/2 Hz, 1H+1H), ABX-system at 4.13 (d, J=16 Hz, 1H) and 3.98 (d, J=16 Hz, 1H), 2.25 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 170.1, 141.3, 135.8, 132.7 (q, J=32 Hz), 127.0, 123.5 (CF3, J=273 Hz), 123.1 (J=3.6 Hz), 122.0 (J=3.6 Hz), 113.3 (C≡N), 42.6 (CH2), 23.2 (CH3); IR (KBr) ν (cm−1): 3220 (NH), 2252 (C≡N), 1691 (C═O), 1532, 1476, 1337, 1273, 1176, 1128, 1033, 888, 675.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C@H:7]2[N:9]([CH3:10])[CH:3]1[CH2:4][C:5](=[O:11])[CH2:6]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:10][N:9]1[CH:3]2[CH:2]([O:1][C:19](=[O:21])[CH3:20])[CH2:8][C@@H:7]1[CH2:6][C:5](=[O:11])[CH2:4]2
Reactant: CN1C2CC(=O)C[C@H]1CC2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1C[C@@H]2CC(=O)CC1N2C
Reaction time: 12 h

Procedure:
To an ice bath cooled, stirred solution of (R)-6-hydroxy-8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (4.08 mmol, 0.634 g), triethylamine (20.4 mmol, 2.86 mL), and DMAP (0.245 mmol, 0.03 g) in dry DCM (3.5 mL) was added acetic anhydride (6.12 mmol, 0.58 mL). The reaction mixture was allowed to come to room temperature and was stirred for 12 hours. The reaction was evaporated and the resulting residue was purified on a 12 g SiO2 cartridge using 0-3% (2N NH3 in MeOH) in DCM to give acetic acid (R)-8-methyl-3-oxo-8-aza-bicyclo[3.2.1]oct-6-yl ester.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C@H:20]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)cc3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl) propane-1,3-diol, 1.4 g (0.01 mol) of 4-fluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was continuously removed from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.1 g (0.004 mol) of trans-2-(4'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR25## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: C(OP([CH:9]1[S:14][CH2:13][CH2:12][CH2:11][S:10]1)(OCC)=O)C.CCCCCC.C([Li])CCC.[CH:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=O)=[CH:28][CH:27]=1.[Cl-].[Na+]>O1CCCC1>[O:36]([C:35]1[CH:27]=[CH:28][C:29]([C:30](=[C:9]2[S:10][CH2:11][CH2:12][CH2:13][S:14]2)[CH2:31][CH3:26])=[CH:32][CH:34]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
2-Diethoxyphosphoryl-1,3-dithiane, 4.18 g, was dissolved in 40 ml of tetrahydrofuran and 10.5 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -65° C. The mixture was stirred at the same temperature for an hour. Then, a solution of 36.2 g of 4-phenoxypropiophenone in 15 ml of tetrahydrofuran was dropwise added to the mixture at the same temperature. The reaction mixture was gradually warmed to room temperature overnight. This suspension was poured onto saturated sodium chloride aqueous solution followed by extraction with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 4.15 g of the product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:31]([O-:33])=[O:32])=[CH:4][C:5]([Cl:30])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.N1CCCCC1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:30][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[C:3]([N+:31]([O-:33])=[O:32])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCNCC1
Product: COc1ccc(C(=O)Nc2cc(N3CCN(C(=O)c4c(-c5ccccc5OC)noc4C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A mixture of (4-(5-amino-2-chloro-4-nitrophenyl)piperazin-1-yl)(3-(2-methoxyphenyl)-5-methylisoxazol-4-yl)methanone (16 mg, 0.034 mmol, Preparation L), 4-methoxybenzoyl chloride (12 mg, 0.068 mmol), DMAP (6 mg, 0.034 mmol), and BEMP (19 mg, 0.068 mmol) in DCE (1 mL) was heated at 80° C. for 3 h. Cooled down to RT, the mixture was treated with piperidine (0.3 ml) for 1 h and concentrated in vacuo. HPLC purification gave the title compound (15.7 mg, 0.025 mmol, 74.9% yield).
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH2:29]([C:32]1[CH:36]=[C:35]([CH2:37][O:38][NH2:39])[O:34][N:33]=1)[CH2:30][CH3:31]>>[CH2:29]([C:32]1[CH:36]=[C:35]([CH2:37][O:38][NH:39][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:34][N:33]=1)[CH2:30][CH3:31]
Reactant: CCCc1cc(CON)on1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Product: CCCc1cc(CONC(=O)c2ccccc2NCc2ccncc2)on1

Procedure:
Prepared by the same method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-Propyl-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 63).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[CH:31](O)=[O:32]>>[CH:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)=[O:32]
Reactant: O=CO
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Product: O=CN1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
A solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml formic acid was heated to 100° C. for 5 h. After removal of the solvent under reduced pressure the residue directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid. Yield: 14 mg MS (ES+): m/e=469, chloro pattern.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.[I:10]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([N:4]2[C:8]([NH2:9])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: Nc1ccnn1C1CC1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(I)cnn1C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A 100-mL round-bottom flask was charged with 1-cyclopropyl-1H-pyrazol-5-amine (0.410 g, 3.33 mmol) and N,N-dimethylformamide (10 mL). N-Iodosuccinimide (0.820 g, 3.64 mmol) was added, and the resulting solution stirred for 18 h at room temperature. The reaction mixture was poured into saturated aqueous sodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether) to afford 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.440 g, 48%) as light yellow oil. MS (ESI, pos. ion) m/z 250 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:22]1([CH2:28][N:29]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)CCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: NCC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Yield: 92.4 %

Procedure:
To a solution of 5a (6.4 g, 22.2 mmol) in toluene (100 mL) was added cyclohexylmethanamine (2.8 g, 24.4 mmol) and TsOH (0.3 g). This mixture was refluxed for 20 h, cooled, concentrated and purified by CC to afford compound 5b (7.5 g, 93%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[I:33]I.O>CC#N>[F:1][C:2]1[CH:9]=[C:8]([I:33])[C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: II
Reactant: COc1ccc(F)c(C=O)c1
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COc1cc(C=O)c(F)cc1I
Temperature: 80 °C
Yield: 82 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (Oakwood, 6.000 g, 38.9 mmol) and Selectfluor (13.79 g, 38.9 mmol) in 40 mL MeCN was treated with iodine (10.87 g, 42.8 mmol) and was heated to 80° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organic were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-20% EtOAc/heptane) gave 2-fluoro-4-iodo-5-methoxybenzaldehyde (8.92 g, 31.9 mmol, 82% yield) as a 3:1 mixture with starting material. (M+H)+=281.0.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([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)[CH2:9][NH:8]1.Cl[C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=1.C(N(C(C)C)C(C)C)C>[Cu]I>[CH2:45]([C:42]1[CH:41]=[N:40][C:39]([N:8]2[CH2:9][C@H:10]([S:12][C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:11][C@H:7]2[CH2:6][O:5][CH2:4][C:3]2[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:2]=2[F:1])=[N:44][CH:43]=1)[CH2:46][CH3:47]
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: CCCc1cnc(Cl)nc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Yield: 81.2 %

Procedure:
A mixture of 2 g (3.85 mmol)(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 1.2 g (7.7 mmol) 2-chloro5-n-propylpyrimidine, 1.98 ml (11.55 mmol) N-ethyldiisopropylamine and a catalytic amount of copper(I) iodide was heated for 10 h at 80° C. The reaction was cooled and partitioned between H2O/Et2O (3×300). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (toluene/Et2O 99:1) gave 2 g (81%) (2S,4R)-5-Propyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 640 (MH+).