Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C:11](=[O:12])[N:10](C2C=CC(OC)=CC=2)[C@H:9]1[CH2:21][O:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])[CH3:3].N1C=CC=CC=1.Cl[S:42]([CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:44])=[O:43]>C1COCC1.C(OCC)(=O)C>[CH3:49][O:48][C:46](=[O:47])[CH2:45][S:42]([NH:23][O:22][CH2:21][C@H:9]1[C@@H:8]([NH:7][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:34])[C:11](=[O:12])[NH:10]1)(=[O:44])=[O:43]
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CS(=O)(=O)NOC[C@@H]1NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of the oxyamine produced in Example 1 (495 mg, 2.1 mmol) in dry THF containing pyridine (1.1 eq.) was added ClSO2CH2CO2CH3 and the solution was stirred for 1 hour at 0° C. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl, 5% sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The product was purified by flash chromatography (ethyl acetate-hexane, 1:2) to afford 426 mg (54%) of [[[[cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-2-azetidinyl]methoxy]amino]sulfonyl]acetic acid methyl ester: mp 128°-129° C. (CH2Cl2); IR (KBr) 3340, 3210, 2975, 1780, 1740, 1685, 1525, and 1160 cm-1 ; NMR (DMSO-d6) δ 1.40 (9H, s), 3.75 (3H, s), 3.90 (1H, m), 4.00 (2H, m), 4.34 (1H, d, J=15 Hz), 4.42 (1H, d, J=15 Hz), 4.94 (1H, d, J=9, 6 Hz), 7.68 (1H, d, J=9 Hz, exchangeable), 8.44 (1H, s, exchangeable).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[NH2:7][C:8]1[S:12][N:11]=[C:10](/[C:13](=[N:17]/[O:18][CH2:19][F:20])/[C:14](O)=[O:15])[N:9]=1.C(OC(C)C)(C)C>C(Cl)Cl>[ClH:2].[NH2:7][C:8]1[S:12][N:11]=[C:10](/[C:13](=[N:17]/[O:18][CH2:19][F:20])/[C:14]([Cl:2])=[O:15])[N:9]=1
Reactant: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: Cl
Product: Nc1nc(/C(=N/OCF)C(=O)Cl)ns1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
Phosphorus pentachloride (500 mg) was dissolved in dry methylene chloride (5 ml). After cooling the resulting solution to -10° C., 2-(5-amino-1,2,4-thidiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid (325 mg) was added and the resulting mixture was stirred at the same temperature for 30 minutes. Isopropyl ether (20 ml) was added to the reaction mixture, and the resulting precipitate was collected by filtration to obtain the target product (130 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:8])=[CH:5][CH:4]=1.[CH2:22]1[CH2:27][CH2:26][CH:25](C=O)[CH2:24][CH2:23]1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCCl>[CH:22]1([CH2:1][N:2]([CH3:30])[C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:8])=[CH:20][CH:21]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CNc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CC1CCCCC1
Agent: C[N+](C)(C)C
Solvent: ClCCCl
Product: CN(CC1CCCCC1)c1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-methylamino-N-quinolin-3-yl-benzamide (0.075 g, 0.27 mmol), cyclohexylcarboxaldehyde (0.049 mL, 0.405 mmol) and tetramethylammonium triacetoxyborohydride (0.213 g, 0.81 mmol) in 1,2-dichloroethane was heated to 85° C. in a sealed tube for 18 hours. The solution was cooled to room temperature and washed with a solution of ammonium hydroxide in water. The product was preabsorbed on silica gel and purified by flash chromatography, using ethyl acetate/hexane (1/1) as the eluant, to give the product as a colorless solid, 0.051 g (51%). MS: m/z 374 (MH+). 1H NMR (DMSO-d6): 0.90-1.05 (m, 2 H), 1.10-1.23 (m, 3 H), 1.58-1.77 (m, 6 H), 3.02 (s, 3 H), 3.27 (d, 2 H), 6.77 (d, 2 H), 7.54-7.67 (m, 2 H), 7.91 (d, 2 H) superimposed on 7.95 (t, 2 H), 8.81 (d, 1 H), 9.15 (d, 1 H) and 10.28 (s, 1 H).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[N:22]1([C:28](=[S:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:29]=[C:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[S:30][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)N1CCCCC1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2sc(N3CCCCC3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.462 g, 1.24 mmol) (Example 26, Step 2) in ethanol (10 mL) in a 25 mL round bottom flask was added piperidine thiocarboxamide (0.198 g, 1.37 mmol) and the solution was heated to reflux for 14 hours. The reaction was cooled to room temperature and concentrated in vacuo yielding a foam. This foam was dissolved in methylene chloride and washed successively with NaHCO3 saturated solution (3 portions) and brine, dried over Na2SO4, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-piperidinyl)-thiazole (0.371 g, 72%) as a yellow-green fluffy solid: mp 173°-175° C., 1H NMR (CDCl3) 400 mHz δ7.77 (d, J=8.56 Hz, 2H), 7.46 (dd, J=5.60, 8.80), 7.38 (d, J=8.56 Hz, 2H), 6.99 (t, J=8.80 Hz, 2H), 3.53 (s (broad), 4H), 3.05 (s, 3H), 1.70 (s (broad), 6H). MS (EI): m/z 417 (MH+). HRMS Δ=-1.5 mmu.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1
Reactant: CC1CN(C(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)CC(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC1CN(C(=O)c2ccc(Sc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)CC(C)O1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A solution of the product of Example 179A (56 mg, 0.0795 mmol) in 1,4-dioxane (2 mL) was treated with a solution of sodium hydroxide (8 mg, 0.1988 mmol) in water (1 mL), and heated at 60° C. for 30 minutes. The reaction was then cooled to room temperature and diluted with ethyl acetate (50 mL) and water (25 mL). The aqueous pH was adjusted to 5 with 1N aqueous hydrochloric acid, the layers were separated, and the organic phase washed with water (2×25 mL) and brine (25 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 5% methanol/methylene chloride provided the title compound as an off-white solid (18 mg, 43%). 1H NMR (300 MHz, DMSO-d6/TFA) δ ppm: 0.91-1.25 (m, 6 H) 1.37 (d, J=6.99 Hz, 6 H) 2.70-2.97 (m, 1 H) 3.25-3.40 (m, 1 H) 3.45-3.64 (m, 4 H) 4.20-4.52 (m, 1 H) 5.72 (s, 2 H) 7.29 (d, J=8.09 Hz, 1 H) 7.35 (d, J=8.46 Hz, 2 H) 7.48 (dd, J=7.91, 2.02 Hz, 1 H) 7.50 (d, J=8.45 Hz, 2 H) 7.60 (d, J=1.84 Hz, 1 H) 7.96 (d, J=8.82 Hz, 1 H) 8.97 (s, 1 H) 9.07 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 529 (M+H)+, (ESI−) m/z 527 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[CH2:7](Br)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1(/[CH:9]=[CH:8]/[CH2:7][O:5][CH2:4][CH2:3][OH:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCO
Reactant: BrCC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOC/C=C/c1ccccc1
Yield: 40.5 %

Procedure:
8 Milliliters of 85% sodium hydroxide aqueous solution mixed with 46 g of ethylene glycol was heated at 40°-50° C., and 15 g of cinnamyl bromide was added dropwise thereto. After the addition was finished, the reaction mixture was heated at 100°-110° C. for 2 hours. The reaction mixture was allowed to cool, and poured into 50 ml of water then extracted with ether. The ether extract was washed with water and a saturated aqueous solution of sodium chloride in this order, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform) to yield 5.5 g of 2-[3-phenyl- 2(E)-propenyloxy]ethanol.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.COC1C=CC([Mg]Br)=CC=1.[O:21]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:44])[C:36]=2[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:31][CH:30]=1)[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CCOCC.CCOCC.C1COCC1>[O:21]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]([OH:44])([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)[C:36]=2[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:33][CH:34]=1)[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc2C1(O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 113.8 %

Procedure:
To dry magnesium turnings (119 mg, 4.9 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (0.61 ml, 4.9 mmol) in 9: 1 Et2O/THF (10 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl 3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindene-2-carboxylate (1.00 g, 2.5 mmol) in Et2O (60 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 5 min. The mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide the title compound (1.47 g) which was used without further purification.
Reaction SMILES: [N:1]([C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][N:7]1[C@H:16]([C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C@H:14]2[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C@@H:4]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:5]([OH:24])[CH2:6][N:7]1[C@H:16]([C:17]([NH:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][C@H:14]2[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8]1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 99.6 %

Procedure:
(A)(iii) A solution of 17 mg (0.04 mmol) of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 2 or Example 3) in 5 ml of ethanol was hydrogenated at about 3.4 atmospheres and at room temperature for 2 hours over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and washed twice with ethanol. The combined filtrate and washings were evaporated to give 16 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 402 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:14][N:13]=[C:12]([CH2:15][NH:16][CH3:17])[N:11]=1)=[O:8].CO.[CH3:23][C:24]1[C:28]([CH:29]=O)=[C:27]([CH3:31])[O:26][N:25]=1.C([BH3-])#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:23][C:24]1[C:28]([CH2:29][N:16]([CH2:15][C:12]2[N:11]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)=[O:8])[S:14][N:13]=2)[CH3:17])=[C:27]([CH3:31])[O:26][N:25]=1
Reactant: Cc1noc(C)c1C=O
Reactant: CNCc1nsc(NC(=O)NCc2cccc(F)c2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1CN(C)Cc1nsc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C

Procedure:
1-(3-Fluoro-benzyl)-3-(3-methylaminomethyl-[1,2,4]thiadiazol-5-yl)-urea (Intermediate XXVII) was taken up in DCM and methanol with 3,5-Dimethyl-isoxazole-4-carbaldehyde (2 eq.) and acetic acid (several drops). Reaction was stirred for several hours at ambient temperature. Sodium cyanoborohydride (2 eq.) was added at once and the reaction was stirred overnight at ambient temperature. An additional equivalent of 3,5-Dimethyl-isoxazole-4-carbaldehyde and sodium cyanoborohydride (2 eq.) was added and stirred 4 more hours. Crude r×n mixture was loaded directly onto a silica plug and eluted with 10% saturated NH3/MeOH in DCM. Purified by column chromatography (silica, DCM, 0-10% MeOH saturated with NH3) to give the title compound. 1H NMR (400 MHz, DMSO): 11.45 (br s, 1H), 7.43-7.35 (m, 2H), 7.17-7.05 (m, 3H), 4.38 (d, 2H), 3.58 (s, 2H), 3.33 (s, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.[CH:15]1([C:18]([CH2:20]Br)=[O:19])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([C:18](=[O:19])[CH2:20][N:11]2[N:10]=[C:9]([O:8][CH3:7])[S:13][C:12]2=[O:14])[CH2:17][CH2:16]1
Reactant: COc1n[nH]c(=O)s1
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1nn(CC(=O)C2CC2)c(=O)s1
Reaction time: 20 h

Procedure:
55 g of potassium carbonate are added to a solution of 26.4 g of 5-methoxy-3H-[1,3,4]-thiadiazol-2-one in 700 ml of dioxane and the reaction mixture is heated to 60°. Then 35 g of bromomethyl cyclopropyl ketone are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. The residue is stirred with diisopropyl ether and filtered with suction. 41 g of crystals of the title compound having a melting point of 98-100° are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C)nc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Commercially available 6-Methyl-2-nitro-pyridin-3-ol (Aldrich) (5.09 g, 33 mmol) in acetone (50 mL) was treated with K2CO3 (5.47 g, 39.6 mmol) and MeI (3.09 mL, 49.5 mmol). The orange suspension was heated to 50° C. for 90 hours. After evaporation of the solvent in vacuo the crude mixture was treated with 1N NaOH (50 mL) and extracted with EtOAc (2×50 mL) the combined organic phases was washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. 3-Methoxy-6-methyl-2-nitro-pyridine was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[NH:8][C:7]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]1[CH:38]=[C:37]([C:39]2[S:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[O:36][N:35]=1.C(O)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH2:19]2)[N:8]([CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[O:36][N:35]=2)[C:7]=1[CH3:24]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)NC2CCN(C(C)C)CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)CCc1c(C)c(C(=O)NC2CCN(C(C)C)CC2)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
55 mg (0.16 mmol) of 3-[5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester were dissolved in DMF (5 mL). Subsequently 103 mg (2 equiv.) of Cs2CO3 and 65.8 mg (1.5 equiv.) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 4 h at 800 C. Because of low conversion 206 mg (4 equiv.) of Cs2CO3 were added stirring was continued for 7 h at 80° C. The reaction mixture was acidified by the addition of acetic acid and concentrated. The residue was purified by preparative HPLC(CH3CN/H2O gradient+0.05% formic acid) to give 3-[1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester (34 mg) as a colorless amorphous material. MS (ESI+): m/e=548 [M+H]+, chloro pattern.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])(=[O:19])=[O:18].[CH2:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31]>>[CH2:30]([C:32]1[CH:38]=[CH:37][C:35]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[S:17]([CH3:16])(=[O:19])=[O:18])(=[O:28])=[O:27])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:33]=1)[CH3:31]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4S(C)(=O)=O)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 413.20 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methanesulfonyl-benzenesulfonyl chloride and 4-ethylaniline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.C(N(CC)C(C)C)(C)C>ClCCl>[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]([C:7]([C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([I:13])=[CH:4][C:5]=3[O:11][CH3:12])=[O:9])[CH2:30][C:29]=12
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(I)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
To a mixture of 5-chloro-4-iodo-2-methoxy benzoic acid of Step C (0.900 g, 2.88 mmol) and N,N-dimethylformamide (6.7 mL, 86.4 mmol) in anhydrous dichloromethane (14.4 mL) was added dropwise oxalyl chloride (0.263 mL, 3.02 mmol). The mixture was heated to reflux for 1 hour, then cooled to room temperature and evaporated to dryness. Fresh anhydrous dichloromethane (25 mL) was added, the resulting solution was concentrated and the residue dried in vacuo. The crude acid chloride thus obtained and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.584 g, 3.17 mmol) were combined in anhydrous dichloromethane(14.4 mL), and N,N-diisopropylethylamine (0.447 mL, 3.46 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was diluted with dichloromethane (15 mL) and washed sequentially with 1 N hydrochloric acid, 1 N sodium hydroxide, and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude title amide which was recrystallized from diethyl ether to provide 1.23 g of pale orange crystals, m.p. 191-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](OB(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(OB(O)O)c1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: COc1cccc(-c2ccc(S(=O)(=O)n3cccc3)s2)c1
Yield: 93 %

Procedure:
N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-methoxyphenylboric acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in 93% yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: C([O-])C.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](#[N:18])[CH:16]=[CH2:17].Cl>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH2:17][CH2:16][C:15]([NH2:18])=[N:8]2)[CH:10]=1
Reactant: C=CC#N
Reactant: NNc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: NC1=NN(c2cccnc2)CC1
Temperature: 20 °C
Yield: 73.5 %

Procedure:
To a 4-neck, round bottomed flask (250 mL) was charged sodium ethanolate (21 wt % in ethanol, 32 mL). 3-Hydrazinopyridine.dihydrochloride (5.00 g, 27.5 mmol) was added, causing an exotherm from 20° C. to 58° C. The mixture was allowed to cool to 20° C. and acrylonitrile (2.91 g, 54.9 mmol) was added. The reaction was heated at 60° C. for 5 hours and cooled to 20° C. The excess sodium ethanolate was quenched with hydrochloric acid (4 M in 1,4-dioxane, 6.88 mL, 27.5 mmol) at <20° C. The mixture was absorbed on silica gel (10 g) and concentrated to dryness. The crude product was purified by flash column chromatography using 0-10% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to dryness to afford the title compound as a yellow solid (3.28 g, 74%): mp 156-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=2.8, 0.8 Hz, 1H), 8.01 (dd, J=4.6, 1.4 Hz, 1H), 7.22 (ddd, J=8.4, 2.8, 1.5 Hz, 1H), 7.12 (ddd, J=8.4, 4.6, 0.8 Hz, 1H), 4.20 (s, 2H), 3.70 (t, J=9.3 Hz, 2H), 2.92 (t, J=9.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 154.23, 144.78, 139.22, 135.08, 123.44, 119.44, 49.23, 32.74; ESIMS m/z 163 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][Cl:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:30]([CH3:31])=[N:29][N:28]=[C:27]1[SH:32].[I-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[ClH:20].[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:32][C:27]3[N:26]([CH3:25])[C:30]([CH3:31])=[N:29][N:28]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnc(S)n1C
Reactant: CC(C)(C)c1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(SCCCN2CCN(c3cc(C(C)(C)C)nc(C(C)(C)C)n3)CC2)n1C
Product: Cl
Yield: 44 %

Procedure:
1 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-pyrimidine (2.83 mmol), 0.4 g of 4-Methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3.09 mmol), 0.2 g of lithium-hydroxide (8.35 mmol) and a spatula tip of potassium iodide werde stirred in 20 ml of dimethylformamide for 2 h at 80° C. After addition of water and ethyl acetate, the organic phase was separated and dried over magnesium sulfate. After filtration and evaporation of the solvent, the crude product was purified by column chromatography on silica gel using dichloromethane-methanol (1-6%). Fractions containing the product were combined and the solvent was evaporated. The residue was dissolved in isopropanol, and a solution of HCl in isopropanol was added. On addition of diisopropylethylether, the product formed an oily mass. The solvent was decanted and the remaining oil evaporated to dryness to yield 0.6 g (41%) of the title compound as a white solid.