Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:18])([CH2:14][CH2:15][CH2:16][CH3:17])[C:5](=[O:13])[CH2:6]P(=O)(OC)OC.[CH:19]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[CH2:27][CH2:28][S:29][C:30]1[S:31][CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=1)=O.Cl>O1CCCC1>[CH3:18][C:4]([CH3:3])([CH2:14][CH2:15][CH2:16][CH3:17])[C:5](=[O:13])/[CH:6]=[CH:19]/[C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[CH2:27][CH2:28][S:29][C:30]1[S:31][CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=1
Reactant: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2C=O)n1
Reactant: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To sodium hydride (60.0% in oil) (49.0 mg) was added slowly a solution of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate (332 mg) in anhydrous tetrahydrofuran (7.30 mL) at 0° C. and the solution was stirred at room temperature for 1 hour. To the reaction solution was added slowly a solution of the compound 5 (336 mg) in anhydrous tetrahydrofuran (2.90 mL) at room temperature and the solution was stirred for 2 hours. To the reaction solution was added 1N hydrochloric acid at 0° C. and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2), to give the title compound (211 mg) having the following physical data.
Reaction SMILES: [F:1][C@@:2]1([CH2:15][OH:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:20]1[N:29]=[C:28]([Cl:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>CN(C=O)C.C(Cl)Cl>[Cl:30][C:28]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[C:20]([O:16][CH2:15][C@:2]2([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]2)[N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CO)C1
Reactant: Clc1cc2ncccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(COc2nc(Cl)cc3ncccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To an ice cooled solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (1.406 g, 6.03 mmol) in DMF (20 ml) was added sodium hydride (0.313 g, 7.84 mmol) (60% dispersion in mineral oil). This was stirred for 15 min before adding 5,7-dichloro-1,6-naphthyridine (1.2 g, 6.03 mmol). This was warmed to room temp and stirred for 4 h. The reaction had gone to completion and so was cautiously quenched with aqueous ammonium chloride before partitioning between aqueous ammonium chloride and ethyl acetate. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine and concentrated in vacuo to give the crude product. This was dissolved in DCM and purified through silica (50 g), eluting with a gradient of 0-50% ethyl acetate in DCM. Appropriate fractions were concentrated in vacuo to yield the title compound as a cream foamy gum (1.91 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:21]([CH:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[CH2:12]2
Reactant: CN1CCC(N)CC1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCC(N2Cc3cc(Br)ccc3C2=O)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.3 g, 1 mmol; AstaTech Cat. No. 27012), 1-methylpiperidin-4-amine (0.14 g, 1.3 mmol)(Combi-blocks Cat. No. 4003460), and potassium carbonate (0.19 g, 1.4 mmol) in ethanol (5 mL) in a sealed reaction vial was stirred at 80° C. for 1 h. After cooling the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.1 g). LCMS (M+H)+=309.0/311.0.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:13][N:14]=[C:15](Cl)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[C:4]([O:3][C:1]([N:8]1[CH2:12][C@H:11]2[C@H:10]([C:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:14][O:13]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: ON=C(Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3cccnc3)[C@@H]2C1
Reaction time: 20 h

Procedure:
N-Boc pyrroline (270 mg; 1.60 mmol), chloro oxime 2f (470 mg; 3.00 mmol) and sodium bicarbonate (760 mg; 9.04 mmol) in isopropanol (10 mL) were heated at 40° C. overnight. An additional portion of chloro oxime and sodium bicarbonate was added and heating continued for 20 hours. After cooling, the volatiles were evaporated. The residue was dissolved in ethyl acetate (50 mL), and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. Cycloadduct 3f was isolated as a beige powder after chromatography with 70% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[S:17][CH:18]=[C:19](I)[CH:20]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[S:17][CH:18]=[C:19]([NH:31][CH2:30][CH2:29][N:26]4[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]4)[CH:20]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3cc(I)cs3)nc2)cc1
Reactant: CC1CCN(CCN)CC1
Product: CC1CCN(CCNc2csc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)c2)CC1

Procedure:
The product was obtained analogously to Example 20.1a starting from 5-(4-chlorophenyl)-2-(4-iodothiophen-2-ylethynyl)pyridine and 2-(4-methylpiperidin-1-yl)ethylamine. Yield: 3 mg (1% of theoretical); C25H26ClN3S (M=436.013); calc.: molpeak (M+H)+: 436/438 (Cl); found: molpeak (M+H)+: 436/438 (Cl); HPLC-MS: 5.10 minutes (method B).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:56]([O:55][C:54]([NH:53][CH2:52][CH2:51][CH2:50][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29])=[O:60])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 99.1 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (150 mg, 0.382 mmol) was dissolved in THF (7.5 mL), and the solution was treated with triphenylphosphine (200 mg, 0.764 mmol), tert-butyl N-(3-hydroxypropyl)carbamate (134 mg, 0.764 mmol) and 40% DEAD-toluene solution (0.348 mL), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 95/5) to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (208 mg, yield 99%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:7][C:8]=1[C:9]([CH3:13])=[CH:10][O:11]C)([CH3:3])[CH3:2].Cl>O1CCCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[S:7][C:8]=1[CH:9]([CH3:13])[CH:10]=[O:11])([CH3:2])[CH3:3]
Reactant: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Temperature: 50 °C

Procedure:
4-Isopropyl-5-(2-methoxy-1-methyl-vinyl)-2-(4-trifluoromethyl-phenyl)-thiazole is dissolved into anhydrous tetrahydrofuran (100 mL) and concentrated hydrochloric acid (5 mL) is added with stirring under nitrogen. The reaction is heated to 50° C. and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully neutralized with sodium hydroxide, extracted with diethyl ether, washed, dried, and concentrated. The 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde (4.6 g, 14.05 mmol), 82% two steps, is obtained in pure form after flash column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH2:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1.FC(F)(F)C(=O)CC(C1C=CC(C2OC=CC=2)=CC=1)=O.Cl.[NH:43]([C:45]1[CH:46]=[CH:47][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[N:49][CH:50]=1)[NH2:44]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:43]([C:45]3[CH:46]=[CH:47][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[N:49][CH:50]=3)[N:44]=[C:15]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ncco2)c(Cl)c1
Agent: Cl
Agent: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ccco2)cc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ncco3)c(Cl)c2)cn1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 (step 2) using 1-[3-chloro-4-(1,3-oxazol-2-yl)phenyl]-4,4,4-trifluoro-1,3-butanedione, instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione and 5-hydrazino-2-pyridinesulfonamide hydrochloride instead of 2-hydrazino-5-sulfamoylpyridine dihydrochloride.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:32][C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]2)=[O:34])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O>[OH-].[Na+]>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:32][C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]2)=[O:34])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)N1CCC(C(=O)OCC)CC1)Cc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)N1CCC(C(=O)O)CC1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg (0.1 mmol) of ethyl 1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylate were suspended in 1N sodium hydroxide solution in a 9:1 mixture of methanol and water and stirred at room temperature for 3 hours. Thereafter, the solvent was evaporated and the residue was recrystallized from methanol/methylene chloride/hexane, to obtain 1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylic acid as white crystals, melting point 169°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: ClCCCl
Product: CCOC(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To a solution of N-t-butyloxycarbonyl-(S)-prolinol (5.0 g, 25 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture was heated to 80° C. Ethyldiazoacetate (3.9 ml, 37 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 90 min and the mixture was heated at 80° C. for 3 hours. Then another portion of ethyl diazoacetate (1.3 ml, 12 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature and washed with saturated sodium bicarbonate (2×100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated in vacuo. The crude product was chromatographed on silica (300 g) with petrol ether/ethyl acetate 4:1 as eluent to give 4.7 g of (2S)-2-(((ethoxycarbonyl)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester. The obtained product was dissolved in 1 M lithium hydroxide in water/methanol 1:3 (50 ml) and stirred at room temperature overnight. The mixture was concentrated in vacuo, water (20 mL) was added and washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1 M aqueous hydrogen chloride, extracted with ethyl acetate (2×100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo to give 3.6 g of (2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2cccnc12
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 5-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. Title compound: ESI-MS: 534.1 [M+H]+; tR=3.56 min (System 1); TLC: Rf=0.14 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]([NH:48][C@H:49]1[CH2:53][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:51]([C:61](O)=[O:62])[CH2:50]1)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>ClCCl.C(Cl)(Cl)Cl>[CH2:23]([C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:61](=[O:62])[C@@H:51]2[CH2:50][C@@H:49]([NH:48][C:46](=[O:47])[CH2:45][NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:53][N:52]2[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Nc2ccc(Cc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
1-Hydroxybenzotriazole (21 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg) were added to a solution of 4-benzylaniline (57 mg) and trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 120 mg) in dichloromethane (3 mL) at 0° C. The mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1, v/v) to give the title compound (158 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 18H), 2.01 (m, 1H), 2.70 (m, 1H), 3.26 (m, 1H), 3.75 (m, 3H), 3.91 (s, 2H), 4.50 (m, 2H), 5.53 (m, 1H), 6.79 (m, 1H), 7.08-7.28 (m,7H), 7.40 (d, J=7.8 Hz, 2H), and 9.28 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][C:14]([OH:16])=O)[C:11](=O)[C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:10]3[CH2:9][CH2:8][CH2:7][C:5]4[S:6][C:2]([CH3:1])=[CH:3][C:4]=4[C:11]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: Cc1cc2c(s1)CCCC(CC(=O)O)C2=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)CCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Yield: 74.6 %

Procedure:
A suspension of 2.5 g of 2-methyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-5-acetic acid and 1.95 g of 4-chlorophenyl hydrazine in 50 ml of toluene is refluxed under heating for 4 hours. After cooling, the mixture is concentrated under reduced pressure and the precipitated crystals are recrystallzed from ethanol to give 2.7 g of 2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one, melting at 119°-121° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:14][OH:15]>>[CH3:14][O:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: O=C1CCCCCO1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCO
Temperature: 25 °C

Procedure:
A solution of ε-caprolactone (11.4 g, 0.100 mol), MeOH (300 mL) and concentrated H2SO4 (5 mL) was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated. Water was added to the residue and the pH was adjusted to 7 with solid NaHCO3. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried and concentrated to give 6-hydroxy-hexanoic acid methyl ester as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc(S)cc1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(O)cc2)s1
Temperature: 120 °C
Yield: 56.5 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 4-hydroxythiophenol (1.3 g) and potassium carbonate (2 g) in N,N-dimethylformamide (30 ml) was heated at 120° C. for 2.5 hours with stirring. The reaction mixture was poured into ice water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-hydroxyphenylthio)thiazole (1.5 g, yield: 56.6%). mp: 265°-267° C.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][C:20]=1[F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: C1CNCCN1
Agent: COc1ccc(Br)cc1C
Product: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Yield: 54.1 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 1-benzyloxy-4-bromo-2-fluorobenzene (6.742 g) and piperazine (12.404 g), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=2:1) to provide 1-(4-benzyloxy-3-fluorophenyl)piperazine (3.716 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][N:9]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:39][CH2:40][CH3:41])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN([C@@H]1C[C@@H](C(C)C)N(OCc2ccccc2)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
N-[(3R,5S)-1-(Benzyloxy)-5-isopropyl-2-oxopyrrolidinyl]-4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonamide (0.047 g, 0.088 mmoles, Example 27a), 1-iodopropane (0.052 mL, 0.53 mmoles), cesium carbonate (0.043 g, 0.13 mmoles) and anhydrous N,N-dimethylformamide (0.50 mL) was stirred at 55° C. (oil temperature) over night, concentrated by rotary evaporation, taken up diethylether and washed with water once. The aqueous phase was washed with a second portion of diethylether, the combined organic phases were washed with brine, dried with potassium carbonate, filtered and concentrated by rotary evaporation. Flash chromatography of the crude product on silica using dichloromethane-methanol (99:1) as eluent gave the title compound as a colourless oil. LC-MS (APCI) m/z 575 (M+1). 1H NMR (CDCl3) δ 8.12 (d, J=8 Hz, 2H), 7.74–7.69 (m, 5H), 7.72 (d, J=8 Hz, 2H), 7.44–7.34 (m, 4H), 5.01 (s, 2H), 4.48 (dd, J1=8 Hz, J2=10 Hz, 1H), 3.45 (dt, J1=3 Hz, J2=9 Hz, 1H), 3.10–2.98 (m, 2H), 2.24 (ddd, J1=2 Hz, J2=10 Hz, J3=14 Hz, 1H), 2.20–2.10 (m, 1H), 2.03 (dt, J1=9 Hz, J2=14 Hz, 1H), 1.73–1.51 (m, 2H), 0.87 (d, J=7 Hz, 3H), 0.84 (d, J=7 Hz, 3H) and 0.82 (obscured t, J=7 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:17].[OH-].[K+]>O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[NH:22]1[CH:21]=[CH:20][N:19]=[C:18]1[C:16]1[S:17][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:15]=1
Reactant: COc1ccc(C2CCOCC2)cc1NC(=S)c1ncc[nH]1
Agent: [Fe+6]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COc1ccc(C2CCOCC2)c2sc(-c3ncc[nH]3)nc12
Yield: 41.1 %

Procedure:
0.085 g of 1H-Imidazole-2-carbothioic acid [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-amide (0.27 mmol) was taken up in water (6.0 ml) and treated with 0.06 g KOH (1.07 mmol) and 0.331 g of potassium hexacyano ferrate (1.0 mmol) at reflux for 16 h. After cooling to ambient temperature water (10 ml) was added and the reaction mixture was extracted with methylene chloride and dried over sodium sulfate. The residue was dried in vacuo at 40° C. One obtained 0.035 g of 2-(1H-imidazol-2-yl)-4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazole (41%) as a light brown solid; M.p.: 220–224° C.