Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:40]=[CH:39][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:22]=[CH:23][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([OH:29])=[O:28])=[CH:39][CH:40]=2)=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (230 mg, 0.43 mmol) in THF (5 ml) and methanol (2.5 ml) was added IN aqueous potassium hydroxide (1.3 ml, 1.3 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the object compound as an oily substance. 145 mg, (yield 66%)
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:23][CH2:22][CH2:21][CH2:20][N:14]1[CH2:13][CH2:12][C:11]2([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][NH:9][C:10]2=[O:17])[CH2:16][CH2:15]1
Reactant: NCCCBr
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Yield: 4 %

Procedure:
1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (5.00 g, 21.6 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (4.73 g, 21.6 mmol, 1.00 equiv) and potassium carbonate (2.99 g, 21.6 mmol, 1.00 equiv) were stirred in refluxing dioxane (70 mL) for 24 hours. After removal of the solvent, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1N aqueous NaOH. The mixture was extracted with CH2Cl2 (200 mL+3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3—MeOH—NH3 (2M in MeOH) 100:20:10 to 100:24:12) to give 250 mg (4%) of white solid, which was characterized spectroscopically.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)#[N:27]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (24.9 mg, 67.7%), MS (ISP) m/z=460.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 4-cyanobenzoic acid.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl>CCOCC>[CH:1]1([NH:6][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentyl amine (50.0 g, 587 mmols) was dissolved in anhydrous ether (500 ml) and triethylamine (69.3 g, 685 mols) was added. The resulting solution was cooled in an ice bath and then tert-butyl bromoacetate (95.4 g, 489 mmols) in ether (150 ml) was added slowly over approximately three hours. The reaction mixture was allowed to stir overnight at room temperature. The reaction was acidified to pH 1 with aqueous hydrochloric acid and the layers were separated. The aqueous layer was washed with ethyl acetate and then basified to pH 10 with aqueous ammonium hydroxide. The product was extracted several times into methylene chloride and the combined organic extract was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and evaporated to yield the desired product as a slightly yellow oil (56.9 g, 58.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(=O)C(=O)OCC(C)C
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.55 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:21]4[CH2:26][CH2:27][CH2:28][CH2:29][C:20]=4[CH:19]=[CH:18][C:17]=3[N:16]=2)[CH:14]=1)=[O:9])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:21]3[CH2:26][CH2:27][CH2:28][CH2:29][C:20]=3[CH:19]=[CH:18][C:17]=2[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)[NH:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85471152 %

Procedure:
Lithium hydroxide monohydrate (9.3 mg, 0.22 mmol) and water (0.19 mL) were added to 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (25.0 mg, 73.9 pmol) in THF (0.28 mL). The reaction mixture was stirred at room temperature for 18 h and was then concentrated. The residue was redissolved in water (3 mL) and this solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield the titled compound (19.6 mg, 85% yield). MS (ESI/Cl): mass calcd. for C16H14N4O3, 310.1; m/z found, 311.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.98 (s, 1H), 12.42 (s, 1H), 8.92 (s, 1H), 8.23 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 3.37 (t, J=5.8 Hz, 2H), 2.83 (t, J=5.3 Hz, 2H), 1.84-1.67 (m, 4H).
Reaction SMILES: Cl.C([O:4][C:5]([CH2:7][N:8]([S:34]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2)(=[O:36])=[O:35])[C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([CH2:16][C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH2:28])=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])C.[OH-].[Na+]>C(O)C.O>[C:5]([CH2:7][N:8]([S:34]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2)(=[O:36])=[O:35])[C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:28])=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=3)=[N:15][C:11]=2[CH:10]=1)([OH:6])=[O:4]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCC)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N=C(N)c1ccc(Cc2nc3cc(N(CC(=O)O)S(=O)(=O)c4cccc5cccnc45)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-ethyloxycarbonyl-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)[C:13]#[N:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]([C:13]#[N:14])([CH3:28])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1cccc(Br)c1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-bromobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=485, RT=0.75 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][O:18][NH2:19]>C(OCC)(=O)C.CCCCCC>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][O:18]/[N:19]=[C:10](/[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)\[CH3:11]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: NOCc1ccccc1F
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(/C(C)=N/OCc2ccccc2F)cc1O
Yield: 90.7 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(2-fluorobenzyl)hydroxylamine hydrochloride (32) (58 mg, 0.327 mmol) according to the general procedure II-B defined above. After being heated for 36 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL) and the resulting solution washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane) to afford the title compound CP30280 (79 mg, 91%) as a pale-yellow oil, Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Br:14][C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1>CN(C=O)C.CCOC(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of phenol (2.35 g, 25.0 mmol) and K2CO3 (9.4 g, 68.1 mmol) in 40 mL of DMF was heated at 100° C. with 4-bromo-1-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 15% EtOAc/hexane giving a yellow oil (6.6 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[C:18]([F:19])([F:20])[F:21]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2′-methyl-2-(trifluoromethyl)biphenyl-4-carboxylate (5 g; 17 mmol) in EtOH (150 mL) at RT was treated with sodium hydroxide (10.2 mL; 5 M; 51 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid which was taken up in water (300 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2, then it was concentrated until precipitation (half of the volume). The suspension was filtered affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 13.55 (br s, 1H), 8.31 (s, 1H), 8.26-8.23 (d, J=7.9 Hz, 1H), 7.51-7.48 (d, J=7.9 Hz 1H), 7.37-7.12 (m, 4H), 1.99 (s, 3H). LC/MS (Method A): 278.9 (M−H)−. HPLC (Method A) Rt 4.57 min (Purity: 98.7%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH3:15])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1.[OH-].[Na+]>CC#N.O>[CH3:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[C:2]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[N:3]=1
Reactant: O=C(O)C1CCNCC1
Reactant: CNc1nc(Cl)nc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-N-methyl-6-phenyl-1,3,5-triazin-2-amine (10.0 g, 45.3 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (60 mL) was cooled (0° C.), and 4-piperidinecarboxylic acid (11.7 g, 90.6 mmol, 2.00 equiv) was added. The pH of the reaction mixture was adjusted to 9-10 by treating with 1 N NaOH. The pH was maintained at 9-10 for 24 hours (product formation monitored by LCMS). The mixture was diluted with water, and filtered to provide the crude product (filtered solid was washed with additional water). The resulting solid was purified by HPLC to afford 9.1 g of the title compound. MS (ES+): m/e 314.2 [M+H]+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][CH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: C[C@H](O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of (S)-1,3-butanediol (1.0 g) and triethylamine (1.12 g) in dichloromethane (30 ml) was added portionwise p-toluenesulfonyl chloride (2.12 g) at 0° C., and then the mixture was stirred at ambient temperature for 3hours and stand overnight. The resulting solution was dilueted with dichloromethane (30 ml) and the organic layer was washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded (S)-3-hyrdoxybutyl p-toluenesulfonate (2.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[C:10](I)[C:3]=12.C([Li])(C)(C)C.[CH3:27][Sn:28](Cl)([CH3:30])[CH3:29].[F-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[C:10]([Sn:28]([CH3:30])([CH3:29])[CH3:27])[C:3]=12
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Agent: [F-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc([Sn](C)(C)C)c3c(Cl)ccnc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a Schlenk flask (dried by heating under high vacuum and venting with argon), 1.0 g of 4-chloro-3-iodo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (2.31 mmol) is initially charged in anhydrous THF (30 ml) and cooled to −78° C. 2.85 ml of tert-butyllithium (1.7 M in pentane) (4.85 mmol) is then slowly added dropwise, and the mixture is stirred at −78° C. for 30 min. 2.42 ml of a 1 M solution of trimethyltin chloride in THF are then added dropwise, and the mixture is allowed to warm to RT overnight. 10 ml of a saturated potassium fluoride solution are then added, and the organic phase is separated off and extracted once with ethyl acetate. The combined organic phases are dried over magnesium sulfate, and the solution is concentrated. The product is purified by column chromatography on silica gel (mobile phase: toluene/ethyl acetate 20:1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:24](CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:24][C:17]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-tert-leucine (prepared according to the procedure in the literature; Emily, M. S. et al. Tetrahedron 2001, 57, 5303-5320.; 3.7 g, 14 mmol) in DMF (80 mL) were added ammonium chloride (900 mg, 17 mmol), triethylamine (5.9 mL, 42 mmol), HOBt (2.8 g, 18 mmol) and EDAPC (3.1 g, 18 mmol) and stirred at rt. After 17 h, the reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×3), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 3.0 g (82%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:38][S:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[Cl:28])(=[O:37])=[O:36])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)O)ccc32)c1
Product: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4Cl)ccc32)c1

Procedure:
Using a similar procedure to that described in Example 29, the carboxylic acid (Example 28) was reacted with 2-chlorobenzene sulphonamide to give N-{1-[3-(isobutoxycarbonylamino)benzyl]indol-5-ylcarbonyl}-2-chlorobenzene sulphonamide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[F:10][CH:11]([F:13])I.CN(C=O)C.[H-].[Na+]>O>[F:10][CH:11]([F:13])[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: FC(F)I
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1C(F)F

Procedure:
Was prepared from stirred a mixture of methyl 1H-pyrrole-2-carboxylate (3.04 g, 23.5 mmol), difluoroiodomethane (4.4 g, 24.7 mmol) and DMF (40 ml). Sodium hydride (1.41 g, 35.2 mmol) was added in portions during 30 minutes. The mixture was stirred for additional 15 minutes. Water (50 ml) was added and the mixture was extracted with dichloromethane. The mixture was purified by silica gel chromatography, using dichloromethane as solvent. The product was dried and evaporated. Yield 3.21 g (78%).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH:50]1([SH:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:50]1([S:56][C:2]2[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]4[NH:25][N:24]=[N:23][N:22]=4)=[CH:13][CH:14]=3)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SC2CCCCC2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 52 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), cyclohexylmercaptan (0.12 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 5 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.2 g, 52%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>[N+](C)([O-])=O>[N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCOCC2)nc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
In step c, the t-butyl ester functionality of 16 is hydrolyzed, with for example, HCl in nitromethane, to give the corresponding 6-(morpholine-4-carbonyl)nicotinic acid 17.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8].[OH:25]OS([O-])=O.[K+]>CO.O>[CH3:1][S:2]([C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8])=[O:25]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)N(C)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(O)C(=O)C=Cc1cc(CCCc2ccccc2)ccc1S(C)=O
Reaction time: 0.58 h

Procedure:
In methanol (15 ml) is placed 2-(methylthio)- 5-(3-phenylpropyl)-N-hydroxy-N-methylcinnamamide (0.35 g, 1.02 mmol) prepared according to Example 27 and the solution cooled in an ice bath. In 3 ml of water is placed oxone (0.33 g, 0.533 mmol) which is then added to the cooled methanol solution and stirred for 35 minutes. The reaction mixture is poured into 80 ml of water and extracted twice with 75 ml portions of ethyl acetate. The organic layers are washed with brine and dried over MgSO4 to afford the title compound.