Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[CH3:20][O:21][C:22]([C:24]#[C:25][C:26]([O:28]C)=O)=[O:23].C1(C)C=CC(S(O)(=O)=[O:37])=CC=1>C(Cl)(Cl)Cl>[CH2:11]([O:10][C:9]([NH:8][C:7]1[C:2]2=[N:1][C:24]([C:22]([O:21][CH3:20])=[O:23])=[C:25]([OH:37])[C:26](=[O:28])[N:3]2[CH:4]=[CH:5][CH:6]=1)=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(NC(=O)OCc2ccccc2)ccc[n+]1[O-]
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc2c(NC(=O)OCc3ccccc3)cccn2c(=O)c1O
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of benzyl (2-amino-1-oxidopyridin-3-yl)carbamate in chloroform (filtered over alumina) was added DMAD and p-toluenesulfonic acid. The suspension was stirred at 70° C. for 12 hours. The solvent was then removed under reduced pressure and to the residue was added MeOH. The solid was filtered, washed with MeOH and dried under vacuum.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.[CH2:50]1[C:55]2([CH2:60][CH2:59][N:58]([C:61](=[O:71])[CH2:62][NH:63][C:64]([NH:66][CH2:67][CH:68]([CH3:70])[CH3:69])=[O:65])[CH2:57][CH2:56]2)[CH2:54][NH:53][CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C.C[O-].[Na+]>CO.C(#N)C>[CH2:67]([NH:66][C:64]([NH:63][CH2:62][C:61]([N:58]1[CH2:59][CH2:60][C:55]2([CH2:50][CH2:51][CH2:52][N:53]([CH2:44][CH2:43][CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:35]([CH2:34][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])[N:24]([C@H:8]5[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]5)[CH:25]=4)=[CH:36][CH:37]=3)[CH2:54]2)[CH2:56][CH2:57]1)=[O:71])=[O:65])[CH:68]([CH3:69])[CH3:70]
Reactant: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCNC2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCOS(C)(=O)=O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c1c(Cc1ccc(OCCCN3CCCC4(CCN(C(=O)CNC(=O)NCC(C)C)CC4)C3)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 80 °C

Procedure:
To a 0.25 L round bottom flask add [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[4-methyl-3-[[4-(3-methylsulfonyloxypropoxy)phenyl]methyl]indol-1-yl]tetrahydropyran-2-yl]methyl acetate (7.2 g, crude), 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (12.28 mmol), acetonitrile (100 mL), and diisopropylethylamine (40.92 mmol). Heat at 80° C. for 16 hours then concentrate under reduced pressure. Add methanol (50 mL) and sodium methoxide (20.46 mmol, 30% solution in MeOH) and stir at room temperature for 1 hour. Quench by adding a small piece of dry ice. Concentrate under reduced pressure. Purify by reverse phase flash chromatography (400 g C18 cartridge) eluting with 5-80% water (0.1% formic acid) in acetonitrile (0.1 % formic acid) in three portions. Concentrate under reduced pressure to yield the title compound as a formic acid salt containing small impurities. Dissolve the salt in 7N ammonia in methanol (20 mL) then concentrate to form the free base. Purify the free base by flash chromatography (330 g silica gel cartridge) eluting with 5% 7N ammonia in methanol/dichloromethane. Concentrate the product fractions under reduced pressure to yield the title compound (1.75 g, 22.81%): MS (m/z): 746.6 (M+H). H1 NMR (400.31 MHz, CD3OD): δ 7.28 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.97 (t, J=8.8 Hz, 1H), 6.69 (d, J=7.2 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 4.15 (s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.91 (d, J=1.6 Hz, 2H), 3.87-3.80 (m, 2H), 3.65 (dd, J=11.6, 5.6 Hz, 1H), 3.57-3.38 (m, 5H), 3.31 (bm, 2H), 2.90 (d, J=6.8 Hz, 2H), 2.46-2.13 (m, 8H), 1.88 (pentet, J=6.8 Hz, 2H), 1.68 (septet, J=6.8 Hz, 1H), 1.61-1.28 (m, 8H), 0.86 (d, J=6.8, 6H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10].[NH2:21][OH:22].[OH-].[K+].CO>C1COCC1>[OH:22][NH:21][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)CCCCCS(=O)c1ccc(N(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(S(=O)CCCCCC(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the 6-(4-dimethylamino-benzenesulfinyl)-hexanoic acid methyl ester (1.2 g, 4.0 mmol) in distilled THF (30 mL) containing 50% aqueous hydroxylamine (2.65 mL, 40 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (6.8 mL, 1M, 6.8 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (30 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine (100 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The solid residue was recrystallised from acetone to give the title compound (728 mg, 61%) as a white powder, mp 95-97° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[I:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=O)[CH2:22][C:21]1=[O:27]>>[F:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]2[C:22]3[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]=3[NH:1][C:2]3[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]2=3)=[CH:11][C:10]=1[I:9]
Reactant: O=Cc1ccc(F)c(I)c1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)C(C)(C)CC1)C2c1ccc(F)c(I)c1
Yield: 64.2 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.06 g, 0.5 mmol), 3-iodo-4-fluorobenzaldehyde (0.125 g, 0.5 mmol), and 4,4-dimethyl-1,3-cyclohexanedione (0.07 g, 0.5 mmol) were processed as described in Example 22 to provide 0.15 g (66%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3H), 0.98 (s, 3H), 1.78 (t, 2H), 2.63 (m, 2H), 3.42 (s, 3H), 4.81 (s, 1H), 7.05 (t, 1H), 7.1 (m, 1H), 7.5 (dd, 1H), 9.5 (s, 1H), 9.61 (s, 1H); MS (ESI−) m/z 466 (M−H)−; Anal. calcd for C19H19N3FIO2: C, 48.82; H, 4.07; N, 9.00.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[CH:16]([OH:19])([CH3:18])[CH3:17]>CN(C=O)C>[CH:16]([O:19][C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)([CH3:18])[CH3:17]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OC(C)C)nn2c(N)nnc2c1C

Procedure:
Isopropanol (27 ml) was deprotonated analogously to W1.056 with sodium hydride (1.3 g) and reacted with 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 1 g), dissolved in isopropanol (10 ml) and DMF (10 ml), and worked up. 847 mg of the title compound were isolated in sufficient purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(N(CC)CC)C.[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21]>C(#N)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:22][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1cc(Br)cs1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(C#CCCO)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A 50 mL round bottom flask, equipped with a magnetic stirrer and gas inlet, was charged with 0.8 mg (0.005 eq) of palladium chloride, 2.3 mg (0.01 eq) of triphenylphosphine, 1.6 mg of copper (1) iodide, 0.19 g of methyl 4-bromothien-2-ylcarboxylate (obtained by oxidation of 4-bromothien-2-ylaldehyde followed by esterification), 0.43 g of triethylamine, and 0.06 g of 3-but-yn-1-ol in 20 mL of acetonitrile under a nitrogen atmosphere. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 18 hours. After cooling to room temperature, volatiles were removed under reduced pressure and the residue was partitioned between chloroform and water. The organic extract was washed with water (2×), brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 2:1 hexane/ethyl acetate. Fractions homogeneous by thin layer chromatography for the major component were combined and concentrated under reduced pressure to give 0.12 g (66.7%) of methyl 4-(4-hydroxybut-yn-1-yl)thien-2-ylcarboxylate as a yellow oil; IR (KBr, cm-1): 3025 3021, 3015, 1713, 1446, 1293, 1261, 1231, 1228, 1225, 1222, 1214, 1192, 1080, 1053; UV (Ethanol):λmax =294 nm (epsilon=3680), 228 nm (epsilon=26,900); 1H NMR (CDCl3, 300 MHz) delta 7.72 (s, 1H), 7.53 (s, 1H), 3.87 (s, 3H), 3.79 (t, J=6.2 Hz, 2H), 2.65 (t, J=6.3 Hz, 2H), 1.87 (bs, 1H); MASS: M+ =210 (EICEC).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c2ccc(-c3cc(C4CCCNC4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c2ccc(-c3cc(C4CCCN(C(=O)CN(C)C)C4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
A mixture of 5-(2-benzyl-3-methyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (28 mg, 0.27 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.69 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (16%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, 1 H), 7.76 (d, 1 H), 7.53 (s, 1 H), 7.25-7.38 (m, 3 H), 7.21 (d, 2 H), 7.08 (d, 1 H), 6.63-6.68 (m, 1 H), 5.63 (s, 2 H), 3.96-4.95 (m, 2 H), 2.83-3.34 (m, 5 H), 2.57-2.77 (m, 4 H), 2.06-2.23 (m, 6 H), 1.69-1.92 (m, 2 H), 1.39-1.64 (m, 1 H); ES-MS m/z 523.41 [M+H]+, HPLC RT (min) 2.20.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH:24]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:8].[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][N:13]1[CH2:12][CH:11]([OH:23])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:24]=[C:2]([NH:1][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH:3]=[CH:4][C:5]=1[F:25]
Reactant: Nc1ccc(F)c(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cc(NC2CCOCC2)ccc1F
Temperature: 17 °C
Reaction time: 4 h
Yield: 26.3 %

Procedure:
A solution of 5-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluorobenzamide (372 mg, 1.08 mmol), dihydro-2H-pyran-4(3H)-one (108 mg, 1.08 mmol) and AcOH (0.05 mL) in MeOH (20 mL) was stirred at 17° C. for 2 h. Then NaBH3CN (109 mg, 1.63 mmol) was added and the resulting solution was stirred at 17° C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to afford the title product (121.5 mg, Yield 17.5%). 1H NMR (CD3OD, 400 MHz): δ 7.16-7.07 (m, 3H), 7.03 (dd, J=2.9, 5.9 Hz, 2H), 6.95 (dd, J=8.9, 10.7 Hz, 1H), 6.79 (td, J=3.6, 8.8 Hz, 1H), 4.11 (quin, J=6.0 Hz, 1H), 3.98 (d, J=11.5 Hz, 2H), 3.80-3.69 (m, 2H), 3.64-3.40 (m, 5H), 2.98-2.81 (m, 4H), 2.72-2.60 (m, 2H), 1.99 (d, J=12.8 Hz, 2H), 1.56-1.39 (m, 2H). LCMS (m/z): 428.2 (M+1).
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][OH:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:42]([CH3:51])([CH3:50])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C)C=O.C(OCC)(=O)C.O>[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([CH3:51])[CH3:50])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 0.05 h

Procedure:
A mixture of 9.88 g of the hydrochloride of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetate and 8.28 g of potassium carbonate in 25 ml of dry dimethylformamide was cooled in a bath at -10° C. for 10 minutes and 19 ml of raw tert.-butyl 2-bromo-2-methyl-propionate were added thereto over 3 minutes. The mixture was stirred for 16 hours during which it solidified into a mass which was poured into a mixture of 400 ml of distilled water and 200 ml of ethyl acetate. The mixture was stirred and decanted and the organic phase was washed with water. The aqueous phase was extracted twice with 100 ml of ethyl acetate and the combined organic phases were dried and vacuum filtered. The filtrate was evaporated to dryness to obtain an oil residue which was added to 240 ml of petroleum ether. The mixture was cooled and crystallization was effected. The mixture was vacuum filtered after 30 minutes to obtain 10.8 g of the syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(1-tert.-butoxycarbonyl-1-methylethyl oxyimino)-acetate melting at 134° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1CCCC1)OCc1ccccc1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A mixture of cyclopentylacetic acid (10.02 g, 78.2 mmol), benzyl alcohol (8.45 g, 78.2 mmol) and p-toluenesulfonic acid monohydrate (1.48 g, 7.82 mmol) in benzene (60 mL) was refluxed using a Dean-Stark water separator for 2h. After cooling, benzene was removed and the mixture was diluted with ether (50 mL) and washed successively with saturated NaHCO3 solution, saturated brine solution, dried and evaporated to give the compound (15.40 g) as an oil; 1H NMR (300 MHz, CDCl3)δ: 7.35(m, 5H), 5.10(s, 2H), 2.40(d, j=8 Hz, 2H), 2.26(m, 1H), 1.81 (m, 2H), 1.6 (m, 4H), 1.18(m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=O)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)(=[O:26])=[O:27])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:21])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(NC(C)=O)cc2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
87 mg (0.16 mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 1 ml of dimethylformamide and 79 mg (0.8 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 57 mg. MS (ES+): m/e=615.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:19][C:20]1([CH3:28])[CH2:25][C:24](=[O:26])[CH2:23][C:22](=O)[CH2:21]1>C1C=CC=CC=1>[CH3:19][C:20]1([CH3:28])[CH2:25][C:24](=[O:26])[CH:23]=[C:22]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC(=O)C=C(N2CCCCC2)C1
Temperature: 25 °C

Procedure:
Piperdine (7.0 mL; 0.0713 mol) and a catalytic quantity of p-toluenesulfonic acid monohydrate was added to a solution of 5,5-dimethylcyclohexane-1,3-dione (10.0 g; 0.0713 mol) in benzene (100 mL) and the resultant solution was heated at reflux. After 3 hours further piperidine (0.71 mL; 7.13 mmol) was added and the solution was allowed to reflux for a further 16 hours. The reaction mixture was cooled to room temperature and washed with 10% NaCHO3 solution (20 mL), dried over anhydrous sodium sulfate and the solvent evaporated (in vacuo) to leave an orange crystalline solid. (14.23 g, 96%). 1H-nmr (CDCl3) d: 5.3, (s 1H, H-2), 3.4-3.2 (m, 4H, H-2′, H-6′), 2.2 (s, 2H, H-6), 2.1 (s, 2H, H-4), 1.75-1.4 (m, 6H, H-3′, H-4′, H-5′), 1.00 (s, 6H, 2×CH3).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:21]1([C:27]2[NH:31][N:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:68])[C:59]2[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=2[Br:67])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[Br:67][C:60]1[CH:61]=[CH:62][C:63]([O:65][CH3:66])=[CH:64][C:59]=1[C:58]([N:55]1[CH2:54][CH2:53][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:32]([C:29]2[CH:28]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:31][N:30]=2)=[O:34])[CH2:57][CH2:56]1)=[O:68]
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2)c1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
HOBt (22 mg, 0.16 mmol) and DIPEA (66 mg, 0.51 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid hydrochloride (29 mg, 0.13 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (30.5 mg, 0.16 mmol) followed by 2-amino-1-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.13 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration. The crude product was washed with hexane and diethyl ether to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 59% yield. LC-MS purity: 89.83%, 1H-NMR (DMSO): δ 8.62 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.58 (m, 1H), 7.5 (m, 2H), 7.4 (m, 1H), 7.1 (s, 1H), 7.0 (m, 2H), 4.2 (m, 2H), 3.8 (s, 3H), 3.75 (m, 2H), 3.6 (m, 2H), 3.55 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14]O)=[NH:4].N[N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29].[ClH:30]>>[ClH:30].[ClH:30].[OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])=[NH:4]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: Cc1ccc(-c2cn(N)c(N)n2)cc1
Agent: Cl
Product: Cc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1
Temperature: 110 °C

Procedure:
A mixture of 1.20 g (5.848 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.10 g (5.844 mmol) of 1,2-diamino-4-(4-tolyl)-imidazole (Beyer H. et al., Chem. Ber. 101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 110° C. for 22 hours, with stirring, and is then concentrated in vacuo to approximately half its original volume. The product that has crystallized out is filtered off, washed with isopropanol and recrystallized from a mixture of 15 ml of methanol and 30 ml of isopropanol, yielding the title compound in the form of the dihydrate, m.p. 225°-232° C. (decomp.), 1H-NMR (D2O): δ=8.04 (d, 1H); 7.74 (d, 1H); 7.55 (t, 1H); 7.30 (s, 1H); 7.26 (d, 2H); 7.07 (d, 2H); 3.17-3.23 (m, 2H); 2.98-3.04 (m, 2H); 2.07 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br-:14].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][P+:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To bromide 1 (9.7 g, 35.0 mmol) in toluene (300 mL) was added triphenylphosphine (10.1 g, 38.5 mmol). The reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and the precipitate was filtered, washed twice with diethyl ether, and dried in vacuo to afford 17.4 g (92%) of 2 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].[I:17]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:17])[C:7]1=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: O=c1c(I)c(O)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.1 g, 5 mmol) in acetonitrile (15 mL) was added N-iodosuccinimide (1.1 g, 5.5 mmol) along with a ca. amount of dichloroacetic acid (0.1 mL). The reaction mixture stirred at room temperature for 1 hour under nitrogen. The mixture was chilled in an ice bath and filtered cold with fresh MeCl2. The beige solid was dried to afford the desired iodinated intermediate (1.21 g, 69%). ES-LRMS m/z 346.