Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([N+:59]([O-])=O)[CH:53]=3)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:45]=[CH:46][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([NH2:59])[CH:53]=3)=[O:51])=[CH:48][CH:49]=2)=[CH:42][CH:43]=1
Reactant: Nc1ccc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)cc1N

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 1-(4-bromophenyl)-4-(4-amino-3-nitrophenylsulfinyl)-benzene, the title compound is obtained; M.P.=161°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2[O:19][CH2:18][CH2:17][O:14]2)=[C:8]([CH3:15])[CH:7]=1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCc1cc(C)c(C2OCCO2)c(C)c1

Procedure:
To a stirred solution of 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester, (2.2 g, 10 mmol) and ethane-1,2-diol (1.86 g, 30 mmol) in toluene (50 mL) was added p-TsOH.H2O (38 mg, 0.2 mmol) and the solution was refluxed using a Dean-Stark apparatus overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) as eluent to give 3-(4-[1,3]dioxolan-2-yl-3,5-dimethylphenyl)-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[N:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:14]3[N:13]([C:4]4[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=3)[CH2:37][CH2:36]2)=[CH:33][CH:34]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cc(C(F)(F)F)ccc1OC
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 565 mg (1.50 mmol) of the carbodiimide from Example 18A and 297 mg (1.65 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:48]1([NH:53][C:30](=[O:32])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:36][CH3:37])[CH2:1][CH3:2])[N:9]=3)[CH:28]=2)[CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC3CCCC3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and cyclopentanamine (8.91 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6.0 mg, 17%). LC-MS m/z 575 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[C:34]1[CH:33]=[C:32]([CH2:31][O:30][CH3:29])[CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: COCc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2cccc(COC)c2)c(OC)c1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a solution of Ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) (2 g, 5.8 mmol) in DME (36 mL) and water (9 mL) was added potassium carbonate (1.61 g, 11.6 mmol) and 3-(methoxymethyl)phenylboronic acid (962 mg, 5.8 mmol) and the mixture was degassed using argon stream for 30 minutes. Pd[PPh3]4 (330 mg, 0.29 mmol) was added and the mixture was heated at 80° C. under argon overnight. The solvents were removed under reduced pressure and the residue extracted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% EtOH/hexanes) to yield 1.38 g (76%) of ethyl 2-(2-methoxy-5′-(methoxymethyl)biphenyl-4-yl)acetate. 1H NMR(400 MHz, dMSO): δ 1.16-1.20 (t, 3H), 3.27 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 4.06-4.11 (q, 2H) 4.41 (s, 2H) 6.89 (d, 1H), 7.00 (s, 1H) 7.19-7.24 (m, 2H), 7.34-7.36 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[SH2:28]>N1C=CC=CC=1>[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11]
Reactant: S
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21

Procedure:
Triethylamine (98.4 cc) is added to a solution of 10-[(1RS)-2-hydroxy-1-methylethyl]-2-phenothiazine-carbonitrile (197.7 g) in anhydrous pyridine (750 cc), and hydrogen sulphide is bubbled through for 6 hours 30 minutes at 25° C. while the mixture is kept stirred. The mixture is stirred for 16 hours at 25° C., then purged with a stream of nitrogen for 2 hours and poured into distilled water (3000 cc). The oil which forms is separated after settling has taken place, washed with distilled water (3×1000 cc) and dissolved in ethyl acetate (3000 cc). The solution obtained is washed with distilled water (7×1 liter), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a yellow crystalline mass (225 g). This product is recrystallized in ethanol (1350 cc) to give 10-[(1RS)-2-hydroxy-1 -methylethyl]-2-phenothiazinecarbothioamide (158.4 g) in the form of yellow crystals, m.p. 152° C.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[Na+].O.Cl>C(O)C>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
Ethyl (RS)-2-{3-[1-(acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetate (1.6 g) was dissolved in ethanol (10 ml) and 2N-aqueous sodium hydroxide solution (10 ml) was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, thereto was added to 1N-hydrochloric acid for neutralization, and the mixture was extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained solid was washed with ethyl acetate to give the title compound (1.3 g) as pale-yellow crystals.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=O>O1CCOCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[N:12]=[C:27]([C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)[O:1][N:2]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)Oc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(Oc2noc(-c3ccco3)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To the mixture of 4-chlorophenyl hydroxycarbamimidate (0.5 mmol. 1 eq) and DIEA (1.25 mmol, 2.5 eq) in dioxane was added dropwise furan-2-carbonyl chloride (0.53 mmol, 1.05 eq) at 0-5° C. The mixture was allowed to warm to room temperature and then stirred for 0.5-1 h or until complete as determined by LC-MS analysis of the reaction mixture. The cyclodehydration reaction was run at reflux (115-120° C.) overnight. The mixture was cooled down and solvent was removed in vacuo. The resulting residue was purified by HPLC purification to provide desired 3-(4-Chloro-phenoxy)-5-furan-2-yl-[1,2,4]oxadiazole in a yield of 50% and purity of 99.9%. LC-MS [M+H] 263.3 (C12H7C1N2O3+H, requires 263.65). 1H NMR (DMSO-d6) δ 8.17 (d, 1H, J=1.75), 7.63 (d, 1H, J=3.5), 7.55 (d, 2H, J=8.8), 7.46 (d, 2H, J=8.8), 6.87 (m, 1H).
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][NH:13][CH3:14]>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:13]([CH3:14])[CH3:12])[N:11]=[C:5]2[CH:6]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: CNC
Product: CN(C)c1nc2cc(Br)ccn2n1
Yield: 72.3 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (2.16 g, 7.8 mmol) in dimethylamine (30% in EtOH, 60 ml, 355 mmol) is heated in 4 portions a ca. 540 mg/15 ml of dimethylamine in a high pressure vessel to 100° C. for 3 hours each. The batches are combined and the solvent evaporated. The light brown crude material (4.77 g) is loaded on silicagel and purified by chromatography on a 70 g silica column using heptane/ethyl acetate 10-40% as eluent affording 7-bromo-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.36 g, 72.3%) as a light yellow solid. Mp.: 133-4° C. MS: m/z=243.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][Mg]Br.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([Cl:14])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Br)cc1Cl

Procedure:
To a stirring solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (890 mg, 3195 μmol) in THF (10 mL) at −5° C. under nitrogen was slowly added methylmagnesium bromide 3.0 m in diethyl ether (1278 μl, 3834 μmol). After 30 min another 1.3 mL (3.8 mmol; 1.2 eq) of MeMgBr added at 23° C. After an additional hour, LCMS suggests 95% conversion. Reaction quenched with sat NH4Cl (10 mL) and resulting white cake washed repeatedly with diethyl ether. Combined organics washed with water and sat NaCl then pushed through a plug of silica (10 g). 1-(4-bromo-2-chlorophenyl)ethanone isolated as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>[OH-].[Na+]>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)NCCCCCCCC(=O)O)cc1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-methoxybenzenesulphonylchloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous 2-propanol, had a melting point of 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([C@H:33]2[CH2:37][C:36]([F:39])([F:38])[CH2:35][N:34]2C(OC(C)(C)C)=O)=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([C@H:33]2[CH2:37][C:36]([F:38])([F:39])[CH2:35][NH:34]2)=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)[C@H]1CC(F)(F)CN1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
(R)-tert-butyl 2-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate (33.9 mg, 0.05 mmol) was dissolved in a solution of TFA/CH2Cl2 (2 mL/2 mL) and the reaction mixture was stirred overnight. The solvent was removed and the residue dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 100A, C18; mobile phase: MeCN/H2O/TFA) to yield (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4-difluoropyrrolidine-2-carboxamide as a white solid (22.4 mg, 78% yield). LC/MS RT=3.876 min; [M+H]=576.2 (LCMS Method 3). NMR: 500 MHz 1H (CDCl3); 8.35 ppm, 1H, d, J=5 Hz;, 7.79 ppm, 1H, m; 7.38 ppm, 1H, d, J=10 Hz; 7.17 ppm, 1H, m; 7.04 ppm, 4H, m; 6.89 ppm, 1H, m; 6.51 ppm, 1H, d, J=5 Hz; 6.21 ppm, 1H; m; 4.56 ppm, 1H′ t, J=9 Hz; 4.19 ppm, 1H, d, J=13 Hz; 3.84 ppm, 1H, d, J=13 Hz; 3.60 ppm, 2H′ t, J=12 Hz; 2.68 ppm, 1H, m; 2.22 ppm, 1H, m.
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([NH:17][CH2:18][CH:19]=[O:20])[CH3:16]>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]=[O:20])[C:13]([NH:12][C:10]1[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][N:9]=1)=[O:14])[CH3:16]
Reactant: CCNCC=O
Reactant: CCCCCCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCCCCc1nnc(NC(=O)N(CC)CC=O)s1

Procedure:
A mixture of 5-hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-hexyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3]1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:29](Cl)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=2)=[O:27])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:29]([NH:1][CH:2]3[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3]3)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NC2CCS(=O)(=O)C2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
To a suspension of 3-amino-1,1-dioxotetrahydrothiophene (345 mg, 2.01 mmol) in methanol (5 mL) was added DIPEA (350 μL) followed by 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (200 mg, 0.67 mmol). The mixture was allowed to stir for 16 h. The resulting mixture was poured into ice-water and the resulting solids were collected by filtration. The solids were washed with ethyl acetate and hexanes and were dried. This afforded 147 mg (0.37 mmol, 55% yield) of the titled product as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.78 (d, 1H), 8.65 (s, 1H), 7.65 (m, 2H), 7.18 (m, 2H), 4.87 (m, 1H), 3.52 (m, 1H), 3.35–3.04 (m, 3H), 2.50, M, 1H), 2.22 (m, 1H); MS (EI) m/z 395.05 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[O:28][C:27]([F:26])([F:37])[F:38])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NCc1ccccc1OC(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
The 4-[(2-chloro-5-nitro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.27 mmol) was dissolved in DMA (5.0 mL). 2-Trifluoromethoxybenzyl amine (153 mg, 0.80 mmol) was added followed by diisopropylethylamine (0. 14 mL, 0.80 mmol). The reaction was heated to 100° C. and stirred for 18 h, then cooled to 25° C. The volatiles were removed in vacuo and the crude product was purified by flash column chromatography (SiO2, 15-50% EtOAc-hexanes) to afford 4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyridin-4-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (91 mg, 64%).
Reaction SMILES: [C:1]([C:3]1(O)[CH2:12][CH2:11][CH2:10][CH2:9][C:4]21[CH2:8][CH2:7][CH2:6][CH2:5]2)#[CH:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[C:4]2([CH2:9][CH2:10][CH2:11][CH:12]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2)#[CH:2]
Reactant: C#CC1(O)CCCCC12CCCC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C#CC1=CCCCC12CCCC2
Temperature: 87.5 °C
Yield: 76.7 %

Procedure:
At 20-27° C., a solution of 6-ethynylspiro[4.5]decan-6-ol (180 g, 1 mol) in pyridine (1 l) was treated dropwise with POCl3 (207 g, 2 mol). The resulting mixture was heated for 5.5 h heating at 85-90° C., poured into ice and extracted twice with pentane (800 and 300 ml). The combined organic phases were washed twice with water (500 ml), with a saturated aqueous solution of NaCl (300 ml), dried (MgSO4), and concentrated. Short-path Vigreux-distillation (8 mbar, head temperature: 85° C.) of the crude product (146 g) gave 6-ethynylspiro[4.5]dec-6-ene (122.9 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.Cl[S:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:33])=[O:32])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CCOC(=O)CCS(=O)(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 200 mg (0.512 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 309 mg (1.54 mmol) ethyl 3-(chlorosulfonyl)propanoate and 0.21 ml (1.54 mmol) triethylamine. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 41 mg (14% of th.) of the title compound.
Reaction SMILES: [C:1](OC1C=CC(C#CC(C2CCCC2)(O)CC2OC(C)(C)OC(=O)C=2)=CC=1COC(=O)C)(=O)C.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1.[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][OH:89])[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1>>[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][O:89][CH3:1])[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CO)c2)(C2CCCC2)C1
Reactant: CC(=O)OCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1OC(C)=O
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to step 4 from Example A(97) where Acetic acid 2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl) -3-hydroxy-but-1-ynyl]-benzyl ester (from step 2 below) was substituted in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. The product was obtained together with Example A(195) 6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl -phenyl)-ethyl]-dihydro-pyran-2,4-dione below. 1H NMR (400 MHz, CDCl3): δ 1.48–1.82 (m, 8H), 1.87–2.09 (m, 3H), 2.22–2.28 (m, 1H), 2.55–2.61 (m, 2H), 2.76 (s, 2H), 3.41 (s, 2H), 3.45 (2, 3H), 4.62 (2, 2H), 6.78–6.82 (m, 1H), 6.96–6.99 (m, 1H), 7.38 (s, 1H). ESIMS (MH−): 345.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH:7]([CH3:32])[CH:8](N)[O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:2]1.[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40][CH2:32][CH:7]([O:6][C:3]1[CH:4]=[CH:5][O:1][N:2]=1)[CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OC(N)C(C)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1

Procedure:
2-(3-Isoxazolyloxy)-1-octadecylcarbamoyloxypropylamine IVj2 is allowed to react and worked up by the same procedure as described in (4). m.p. 63.5°-65° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.