Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C)C=O>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid, 20 g) in dimethylformamide was added (S)-2-amino-3-(4-iodophenyl)propanamide (Example 1, step (ii), 1.05 mol. eq.) and diisopropylethylamine (4 mol. eq.) at room temperature. The reaction mixture was cooled to 0-10° C. and stirred for 15 min. T3P (50% wt/wt in DMF; 1.7 mol. eq.) was added to the reaction mixture by dropwise addition at 0-10° C. over a period of 30 min and stirred for 1.5 h at the same temperature. The reaction mixture was quenched with water (2 rel. vol.) and stirred for 30 min at room temperature. 2-Methyltetrahydrofuran (15 rel. vol) and water (13 rel. vol) were added to the reaction mixture and extracted. The organic layer was separated and concentrated to 5 rel. vol. To the stirred organic portion was added toluene (10 rel. vol.) drop wise over a period of 30 min. The solution was stirred for 5 h at room temperature. The resulting solid material was filtered and washed with toluene (2 rel. vol), and dried the material at 50° C. under vacuum to afford the sub-titled compound (28.8 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64](OC2C=CC([N+]([O-])=O)=CC=2)=[O:65])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[C:76]([O:80][C:81]([NH:83][CH2:84][CH2:85][OH:86])=[O:82])([CH3:79])([CH3:78])[CH3:77].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64]([O:86][CH2:85][CH2:84][NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:82])=[O:65])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)Oc4ccc([N+](=O)[O-])cc4)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)OCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of the compound of Example 5A (83 mg, 0.081 mmol), 2-(tert-butyloxycarbonylamino)ethanol (26 mg, 0.161 mmol), DMAP (10 mg) and Hunig's base (0.1 mL) in acetonitrile (1 mL) was stirred at 90° C. overnight. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (73 mg, 86% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=3)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cscc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (106 μL; 1.26 mmol; 3 eq.), Intermediate 32 (120 mg; 0.42 mmol; 1 eq.), Intermediate 2 (92 mg; 0.42 mmol, 1 eq.) and DIEA (217 μL; 1.26 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from MeOH afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]1.[OH-].[Na+].[I:24]I>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[C:12][I:24])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]1
Reactant: C#CCOc1cc(-n2nnn(CCC)c2=O)c(Cl)cc1Cl
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1nnn(-c2cc(OCC#CI)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a cold solution of 0.5 g (0.00153 mole) of 1-[2,4-dichloro-5-(2-propynyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one in 20 mL of methanol was added 2 mL of a saturated aqueous solution of sodium hydroxide and an additional 10 mL of methanol. To this mixture was added a solution of 0.39 g (0.00153 mole) of iodine in 5 mL of methanol. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered and a solid collected. The solid was purified by column chromatography to yield 0.14 g of 1-[2,4-dichloro-5-(3-iodo-2-propynyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 134°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].I[CH2:29][CH3:30]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:29][CH3:30])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCI
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (250 mg, 0.705 mmol) in dry DMF (3 ml) was added slowly to the mixture of dry DMF (1 ml) and 55% NaH (61.4 mg, 1.41 mmol) at 0° C. under an nitrogen atmosphere. Thereafter the reaction mixture was stirred at RT for 30 min. The reaction mixture was recooled to 0° C. Iodoethane (0.057 ml, 0.712 mmol) was slowly added at 0° C. and then the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with brine (20 ml), pH was adjusted over 9 with NaOH and the product was extracted into ethyl acetate (3×30 ml). The combined organic layers were washed with water, dried and concentrated. Flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-99:1) afforded the title product. 1H NMR (400 MHz, DMSO-d6): 1.07 (3H, d), 1.34 (3H, t), 4.02 (2H, q), 4.20 (1H, distorted dd), 4.34 (2H, m), 6.95 (1H, d), 7.67 (1H, d), 7.76 (1H, d), 7.84 (1H, d), 8.00 (2H, m), 8.20 (1H, d), 8.27 (1H, d).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:30])[C@H:24]([C@H:26]([CH2:28][CH3:29])[CH3:27])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:30])=[O:22])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-isoleucine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>>[Cl:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: Cl
Product: O=C1OCc2ccccc2N1C1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1

Procedure:
The product was prepared from 1-piperidin-4yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (1.5 g) and 3-chloro-4-fluoronitrobenzene (1.23 g) using the method of example 115 step (ii). Yield 1.37 g.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[C:37]12([N:47]=[C:48]=[O:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2.C(N(CC)CC)C>CN(C)C=O>[C:37]12([NH:47][C:48]([NH:3][C:4]3[CH:36]=[CH:35][CH:34]=[C:6]([O:7][C:8]4[CH:9]=[CH:10][C:11]5[N:15]=[C:14]([CH2:16][O:17][C:18]6[CH:31]=[CH:30][C:21]([CH2:22][CH:23]7[S:27][C:26](=[O:28])[NH:25][C:24]7=[O:29])=[CH:20][CH:19]=6)[N:13]([CH3:32])[C:12]=5[CH:33]=4)[CH:5]=3)=[O:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)NC45CC6CC(CC(C6)C4)C5)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.9 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-adamantyl isocyanate (142 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→4:1→ethyl acetate as the eluant. The product insoluble in methanol was isolated by filtration and further purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→60:40→65:35→70:30 as the eluant to afford the title compound (66 mg, mp 227.1-231.4° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[CH:15]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3-chlorophenylboronic acid.
Reaction SMILES: C(C1C=CC(C)=[N:7]C=1)C.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:45]=[CH:44][C:24]([C:25]([NH:27][C:28]3[C:37]4[O:36][C:35]([C:38](OCC)=[O:39])=[CH:34][C:33](=[O:43])[C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O)(=O)=O>CO>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:45]=[CH:44][C:24]([C:25]([NH:27][C:28]3[C:37]4[O:36][C:35]([C:38](=[O:39])[NH2:7])=[CH:34][C:33](=[O:43])[C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCc1ccc(C)nc1
Reactant: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc(OCCCCc4ccccc4)cc3)c2o1
Agent: CS(=O)(=O)O
Solvent: CO
Product: NC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc(OCCCCc4ccccc4)cc3)c2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a mixture containing 120 ml of 5-ethyl-2-methylpyridine and 75 ml of methanol was added 29.5 g of 8-[4-(4-phenyl-1-butoxy)benzoyl]amino-2-ethoxycarbonyl-4-oxo-4H-benzopyran, into which 8.2 g of ammonia gas was bubbled around 0° C., and the mixture was stirred below 30° C. for 3 hours. Then, the temperature was increased to 80° C., and excess ammonia and part of the methanol were removed and recovered into methanol in another vessel. The recovered ammonia and/or methanol can be used again in the subsequent production. The temperature was increased to 80° C., and the remaining methanol and part of 5-ethyl-2-methylpyridine were removed by reducing a pressure down to 30 mmHg. Subsequently, 60.8 mmol (5.84 g) of methane sulfonic acid was added, and the mixture was stirred at 100° C. for 6 hours. Then, the temperature was decreased to 60° C., and methanol was added dropwise at 50° to 60° C. The mixture Was cooled to 0° C., and the deposited crystals were collected by filtration, which afforded 27.7 g of 8-[4-(4-phenyl-1-butoxy)benzoyl]amino-2-carbamoyl-4-oxo-4H-benzopyran (yield 99%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO.[OH-].[Na+]>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (5.13 g, 12.0 mmol) in pyridine (50 mL) were added cyclopropanecarbonyl chloride (2.5 mL, 27.6 mmol) and N,N-dimethylpyridine-4-amine (89.3 mg, 731 μmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with methanol (50 mL), 2N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (300 mL), and washed successively with water (150 mL), dilute hydrochloric acid (100 mL), saturated aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=95/5→50/50) and recrystallized from ethyl acetate/diisopropyl ether to give the title compound (4.4 g, 88%) as colorless crystals.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH2:8][CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[I:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCI
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated rotary evaporation (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)-tetrahydro-2-H-pyran (~100 g, 68.9%) was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 140 °C

Procedure:
4-Chloro-N-isobutylphthalimide is prepared as described in Example 2, starting with 10 g of 4-chlorophthalic anhydride, 5.4 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 16 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is taken up in 100 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 12 g of 4-chloro-N-isobutylphthalimide are thus obtained in the form of a white powder. (Rf=0.85, thin layer chromatography on silica gel, eluent: cyclohexanelethyl acetate (75/25 by volume)).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:13](=O)[CH3:14]>>[CH2:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[CH3:14]
Reactant: CC=O
Reactant: Nc1ccc(-n2ccnc2)cc1
Product: CCNc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 8, react 4-(1H-imidazol-1-yl)benzenamine with acetaldehyde to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 ml RB flask containing a solution of lauroyl chloride (19.38 g., 89 mM) in dry chloroform (200 ml) was cooled to 0° C. on an ice bath. A solution of N,N-dimethyl-1,3-propanediamine (10.40 g., 51 mM) and triethylamine (9.40 g., 93 mM) in dry chloroform (25ml) was added dropwise to the cold solution through an addition funnel, then allowed to warm to room temperature and stirred for 2 hours. The chloroform was removed under reduced pressure and the residue redissolved in an ethanol/water mixture (1:1) and neutralized with sodium bicarbonate, followed by extraction with chloroform (4×50 ml). The combined extracts were dried (MgSO4), concentrated, and the residue distilled under reduced pressure (bp 171° C., 10μ) to give 23.92 g. (68%) of the subject compound as an amber solid.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:17](=[O:25])[C:16]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34]>C(OCC)(=O)C>[CH2:12]([O:11][C:9]([O:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:17](=[O:25])[C:16]=1[C:26]1[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32])=[O:10])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C)c(-c2c(O)cc(C(C)(C)C)oc2=O)c(C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(C(C)(C)C)oc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
2.0 g (20 mmol) of triethylamine and subsequently 2.2 g (20 mmol) of ethyl chloroformate in 20 ml of ethyl acetate are added dropwise at 0° C. to 5.7 g (20 mmol) of 4-hydroxy-6-tert.-butyl-3-(2,4,6-trimethylphenyl)pyrone in 50 ml of ethyl acetate. The mixture is stirred for 20 hours at 20° C. and filtered, the organic phase is washed with semi-concentrated sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35-70 μm) using toluene/acetone (20:1 parts by volume). 6.0 g of 4-ethoxycarbonyloxy-6-tert.-butyl-3-(2,4,6-trimethylphenyl)pyrone are obtained (yield: 84% of theory). M.p.=92°-94° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([OH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CCOC(C)=O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:22])[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C(O)c3ccccn3)cc2OCc2ccccc2)S1(=O)=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C(=O)c3ccccn3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
To a solution of 5-[2-benzyloxy-4-(hydroxypyridin-2-yl-methyl)-phenyl]1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (45 mg, 0.085 mmol) in acetic acid (2 mL) is added iron powder (24 mg, 0.43 mmol) and the mixture is refluxed for 2 h. The reaction is diluted with EtOAc and filtered. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography using a gradient of 0-50% EtOAc/hexane to afford the title compound as a yellow oil: (M+H)+=524.