Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([CH:16]=O)[CH:3]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:23][O:24][NH2:25].CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])=[C:4]([CH:16]=[N:25][O:24][CH2:23][C:22]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=2)[CH:3]=1
Reactant: NOCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C=NOCc1ccc(Cl)c(Cl)c1)C(F)(F)F
Yield: 65.4 %

Procedure:
A solution of N-(4-chloro-2-formylphenyl)trifluoromethanesulfonamide 24 (163 mg, 0.57 mmol), O-(3,4-dichlorobenzyl)hydroxylamine hydrochloride (130 mg, 0.57 mmol) and anhydrous NaOAc (77 mg, 0.94 mmol) in EtOH (10 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CHCl3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded N-{4-chloro-2-[(3,4-dichlorobenzyloxyimino)methyl]phenyl}trifluoromethanesulfonamide 97 (172 mg, 66%), as a colorless oil. 1H n.m.r. (200 MHz, CDCl3) δ10.65, br s, 1H, 8.14, s, 1H, 7.66, d, J=8.8 Hz, 1H, 7.51-7.45, m, 2H, 7.35, dd, J=2.4 and 8.8 Hz, 1H, 7.27-7.22, m, 2H, 5.12, s, 2H. HRMS (M+) 459.9422.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15][CH2:16][CH:17]\2O)=[N:9][N:8]=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[C:38]([S:40][CH:17]1[CH2:16][CH2:15][NH:14][CH2:13]/[C:12]/1=[CH:11]\[C:10]1[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=[N:8][N:9]=1)(=[O:41])[CH3:39]
Reactant: COC(=O)Cn1nnnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1nnnc1/C=C1\CNCCC1SC(C)=O
Yield: 27 %

Procedure:
Following a procedure similar to that described in Example 150-(e), (E)-3-{[1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.5 g) was subjected to the reaction with thioacetic acid and N,N-dimethylformamide dineopentyl acetal. The product was purified by silica gel chromatography to afford (E)-4-(acetylsulfanyl)-3-{([1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (980 mg). This product was similarly treated with trifluoroacetic acid in dichloromethane, and the resulting product was purified by silica gel chromatography using dichloromethane and methanol (20:1) as an eluent to afford the title compound (342 mg, overall yield: 27%) as a yellow amorphous solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]1[CH:13]=[C:14]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][C:24]([N:26]1[CH2:32][CH2:31][C:30]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:29]=3[CH2:28][CH2:27]1)=[O:25])[CH2:15]2)=[O:10]>C(O)C.Cl>[CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]1[CH:13]=[C:14]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][NH:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:32][CH2:31][C:30]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:29]=3[CH2:28][CH2:27]1)=[O:25])[CH2:15]2)=[O:10]
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(OC(=O)N4CC5CCCC5C4)ccc31)C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3cc(OC(=O)N4CC5CCCC5C4)ccc31)CC2
Reaction time: 24 h

Procedure:
The product obtained in Step 1 is dissolved in 10 volumes of ethanol and 10 volumes of 3N ethanolic HCl solution. Stirring is carried out at ambient temperature for 24 hours and the precipitate obtained, which corresponds to the expected product, is filtered off.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.[OH:24]O.[OH-].[Na+]>CO.O.ClCCl>[O:24]1[C:8]23[C@:3]([CH3:23])([CH2:4][CH2:5][C:6](=[O:22])[C@H:7]12)[C@:2]1([F:1])[C@H:11]([C@H:12]2[C@@:16]([CH2:18][C@@H:19]1[OH:20])([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]2)[CH2:10][CH2:9]3
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@]12CCC(=O)[C@@H]3OC31CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 10g of 9-fluoro-11β-hydroxyandrost-4-ene-3,17-dione in 1.5 liter of methanol is stirred at room temperature with 30ml of 30% hydrogen peroxide and 20ml of 4N sodium hydroxide solution. The resulting solution is diluted with 4 liters of water and extracted with dichloromethane. The dichloromethane solution is washed with 5% hydrochloric acid, 5% sodium bicarbonate solution, water, dried, and evaporated in vacuo to give 9.1g of crude product. This material is dissolved in dichloromethane and chromatographed on a 100g-silica gel column. Elution with the same solvent gives 3.39g of the title compound and some impure material which is rechromatographed to give a further 1.71g of the title compound.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:1][CH3:2])([C:22]3[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:31])([CH3:32])[CH3:30])=[C:24]([CH3:36])[CH:23]=3)[CH2:4][CH3:5])=[CH:7][C:8]=2[CH3:21])[CH:46]=1
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 63.6 %

Procedure:
A solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example 31; 0.06 g, 0.12 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 41.8 mg, 0.18 mmol), tetrakistriphenylphosphine palladium (19.5 mg, 0.0169 mmol) and potassium phosphate (38.6 mg, 0.18 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane) to give the title compound (39.5 mg, 62%).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]1.[CH3:12][Mg]I>CCOCC>[CH3:12][C:6]1([OH:10])[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][CH:2]([CH3:11])[CH3:1])[CH2:5]1
Reactant: C[Mg]I
Reactant: CC(C)CC1CCCC(=O)C1
Solvent: CCOCC
Product: CC(C)CC1CCCC(C)(O)C1
Yield: 62 %

Procedure:
A solution of 62.7 g (0.407 mol) of the distilled ketone in 200 ml ether was added dropwise to a stirred solution of 0.6 mol methyl magnesium iodide in 200 ml ether at such a rate that the reaction mixture was allowed gradually to reach and then maintain a steady reflux. When the addition was complete heat was applied to maintain reflux for a further 30 minutes. Thereafter the reaction mixture was quenched with 1.01 of water and the resulting precipitate in the aqueous phase dissolved by the addition of saturated aqueous ammonium chloride (1.01). The organic phase was separated, washed, dried and the solvent was removed in vacuo. The crude consisted of a mixture of trans and cis 1-methyl-3-(2-methylpropyl)cyclohexan-1-ol in a ratio of 2:1. It could be purified by distillation under reduced pressure to obtain a mixture of about the same isomer distribution. Alternatively it could be separated into the cis and trans isomers by column chromatography over silica (200 g for 4 g of crude) using a mixture of diethyl ether and pentane (1.5 v/v ratio) as the eluent. It could also be separated into the isomers by fractional distillation under reduced pressure over a 1 m Sulzer column using a reflux: take off ratio of 10:1. Thus, 217 g of crude yields 102 g (>94% pure on gc) of the trans isomer (head temperature 69° C. at 0.04 kPa) and 50 g (>97% pure on gc) of the cis isomer (62° C. at 0.01 kPa) and 43 g of an intermediate fraction consisting of a mixture of the two isomers.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:7][CH:8]1[CH2:10][CH2:9]1)C.[OH-].[K+].O>CO>[CH:8]1([CH2:7][CH:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:5][C:4]([OH:15])=[O:3])[CH2:9][CH2:10]1
Reactant: CCOC(=O)CC(CC1CC1)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(CC1CC1)C[N+](=O)[O-]
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 4-cyclopropyl-3-nitromethyl-butanoic acid ethyl ester (1.34 g, 7.27 mmol) in 50 mL of MeOH is added to 10 mL of 10% KOH/H2O at room temperature and stirred overnight. The MeOH is evaporated, and the pH of the solution is adjusted to ca. 7 by the addition of KH2PO4. The aqueous solution is extracted with EtOAc (3×100 mL), and the combined extracts are dried over Na2SO4. Evaporation of the solvents gives 1.3 g of 4-cyclopropyl-3-nitromethyl-butanoic acid as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[C:43]1=[O:55]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[C:43]1=[O:55])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)CCN1CCCC[C@H](N)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)CCN1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C(=O)OC)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-methoxy-3-oxopropyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (5.0 mg, 0.0088 mmol) and Intermediate 27 (4.4 mg, 0.018 mmol) to give a white solid (2.1 mg, 29% yield). Anal. Calcd. for C41H54N4O8S m/z 762.5. found: 763.5 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.26-7.06 (m, 10H), 5.50 (d, J=3.3 Hz, 1H), 5.15 (d, J=6.6 Hz, 1H), 4.98 (dd, J=8.8, 4.4 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 3.67-3.62 (m, 6H), 3.62-3.48 (m, 2H), 3.36 (dd, J=15.4, 4.4 Hz, 1H), 3.12 (d, J=9.3 Hz, 1H), 2.89-2.72 (m, 3H), 2.72-2.59 (m, 4H), 2.59-2.50 (m, 2H), 2.36 (d, J=12.1 Hz, 1H), 2.06 (d, J=7.1 Hz, 1H), 1.97 (d, J=11.5 Hz, 1H), 1.87 (d, J=12.1 Hz, 1H), 1.84-1.54 (m, 10H), 1.54-1.40 (m, 2H), 1.39-1.27 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13])=[O:7].[I-].[Na+].[CH3:22][O-:23].[Na+]>CO>[CH3:22][O:23][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13])=[O:7]
Reactant: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COCCCCC(=O)c1oc2ccc(OC)cc2c1C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution (20 mL) of 5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one (1.93 g) synthesized in Example A120(1) in methanol were added sodium iodide (1.54 g) and sodium methoxide (1.86 g), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (797 mg, 42%) as a white solid.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.C=CC(=O)CCC.[CH2:28]([CH:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36])[CH3:29]>[OH-].[K+]>[CH2:28]([C:30]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36])[CH3:29]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Reactant: CCC1C(=O)CCC1=O
Agent: C=CC(=O)CCC
Agent: [K+]
Agent: [OH-]
Product: CCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride a 70°C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH:27]=[CH2:28])[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[C:19]([C:17]1[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH:27]=[CH2:28])[C:14]([CH3:29])=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=2)[CH:18]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C=Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1c(C)c(C#Cc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.5 %

Procedure:
A solution of [4-(5-tert-butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 146, 0.02 g, 0.049 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 1M lithium hydroxide (0.5 mL, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.020 g, ˜100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([CH:21]2[CH2:23][CH2:22]2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:30](=[O:31])[NH:20][C:19]2[C:14]1=[N:15][C:16]([CH:21]1[CH2:22][CH2:23]1)=[N:17][CH:18]=2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@@H](Nc1nc(C2CC2)ncc1N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C3CC3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
(R)-3-(5-Amino-2-cyclopropyl-pyrimidin-4-ylamino)-3-phenyl-propionic acid ethyl ester (880 mg, 2.7 mmol) was dissolved in THF (10 ml). To the solution CDI was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with Ethyl acetate (100 ml) washed with water, dried over MgSO4, filtered and evaporated to dryness. The black residue obtained was purified by chromatography, eluded with 3% methanol in dichloromethane to give oil (427 mg, 45%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[C:10](=O)[CH2:9][CH2:8][CH:7]4[CH2:6]2)[CH2:3][CH2:2]1.[CH2:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[CH:10]([CH3:25])[CH2:9][CH2:8][CH:7]4[CH2:6]2)[CH2:3][CH2:2]1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1OC1C(=O)CCC3CN(CC4CC4)CCC231
Product: COc1cccc2c1OC1C(C)CCC3CN(CC4CC4)CCC231

Procedure:
Oxidation of XI ##STR97## with chromium trioxide gives 3-cyclopropylmethyl-9-methoxy-2,4,4a,5,6,7-hexahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-7[3H]-one ##STR98## Reaction of this compound with methylenetriphenylphosphorane followed by catalytic hydrogenation of the resulting 7-methylene derivative gives 3-cyclopropylmethyl-9-methoxy-7-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR99##
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[O:5][N:4]=1.[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][S:24]([CH2:27][CH2:28][NH:29][C:30]([C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[O:31])(=[O:26])=[O:25])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]>>[Cl:13][C:10]1[S:9][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:23]([CH:20]3[CH2:21][CH2:22][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:18][CH2:19]3)[S:24]([CH2:27][CH2:28][NH:29][C:30]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:31])(=[O:25])=[O:26])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc(Cl)s3)on2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 141 mg (2 equiv.) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and 100 mg (0.25 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-Chloro-thiophene-2-carboxylic acid {2-[[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]2([CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:12](=[O:14])[N:13]=1
Reactant: BrCCOCCBr
Reactant: O=C1CSC(N[C@H]2C[C@@H]3CC[C@H]2C3)=N1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC12CCOCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To the mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (840 mg, 4.0 mmol) in THF (5.0 mL) was added LDA (2.0 M, 20 mL) at −78° C. The resulting mixture was stirred for 10 min at −78° C., and then 1-bromo-2-(2-bromoethoxy)ethane (3.71 g, 16 mmol) was added. The mixture was allowed to warm to room temperature and then stirred overnight. A sat'd solution of NaH2PO4 was added, and it was extracted with EtOAc. The organic layer was washed with sat'd NH4Cl, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified through flash chromatography (4:1:0.05; CH2Cl2/EtOAc/MeOH) to give the title compound as off-white solid. MS (ES+): 281 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH2:9]([CH2:13][C:14](=O)[CH3:15])[C:10]([CH3:12])=O.O>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=2)[C:10]([CH3:12])=[CH:9][CH:13]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(O)cc1

Procedure:
A mixture of 4.0 g of p-aminophenol and 4.0 g of acetonylacetone is heated under reflux in toluene for 3 hours using a Dean Stark water separator to yield 4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenol. Condensation with ethyl alpha-bromoisobutyrate in ethyl alcohol in the presence of potassium carbonate gives ethyl 2-[4-(2,5-di-methyl-1H-pyrrol-1-yl)-phenoxy]-2-methylpropanoate. Hydrolysis with 1.5 N sodium hydroxide solution yields 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenoxy]-2-methyl-propanoic acid, m.p. 178°-180°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][N:18]3[S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)(=[O:23])=[O:22])=[CH:14][CH:13]=2)=[O:11])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:35]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH:20]=[C:19]4[C:15]([CH2:16][CH2:17][N:18]4[S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)(=[O:22])=[O:23])=[CH:14][CH:13]=3)=[O:11])=[CH:5][C:4]=2[C:31]([F:34])([F:32])[F:33])=[N:2][N:37]=[N:36]1
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)c(C(F)(F)F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CC2
Yield: 45.5 %

Procedure:
A solution of 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (30 mg, 0.06 mmol) in dimethylformamide (0.8 ml) was treated with sodium azide (71 mg, 1.1 mmol, 18 equiv.) and ammonium chloride (58 mg, 1.1 mmol, 18 equiv.). The solution was flushed with argon, then sealed and irradiated in microwave oven at 170° C. for 1 hour. The mixture was diluted with concentrated NaHCO3 and washed with ethyl acetate. The aqueous phase was acidified with HCl 1N to pH 1, then extracted twice with ethyl acetate. The combined organic phases were dried with Na2SO4 and the solvent evaporated to yield 15 mg (46% yield) of 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-3-trifluoromethyl-phenyl]-amide as an orange foam, MS (ISP): m/e=547.2 (M−H), δH (300 MHz; d6-DMSO) 10.75 (1H, s), 8.41 (1H, s), 8.21 (1H, d), 7.97 (1H, s), 7.61-7.84 (5H, m), 7.56 (1H, t), 7.32 (1H, d), 3.98 (2H, t), 2.95 (2H, t).