Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=[O:2].[Na+].[CH:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20](N)[C:21]([OH:23])=[O:22])=[O:14])=[CH:7][CH:6]=1>O.OS(O)(=O)=O.C(#N)C>[CH2:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([OH:2])[C:21]([OH:23])=[O:22])=[O:14])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(NCCCCC(O)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaNO2 in water (200 ml) was added dropwise during 3 hr to an ice-cooled and stirred solution of N-ε-CBZ-L-lysine in 1 N H2SO4 and acetonitrile. The mixture was stirred for an additional 2 hr after the addition of 0-5° C. and left to stand overnight. The resulting clear solution was concentrated under reduced pressure. The residual semi-solid was extracted with ether, and the ether extract was then crystallized in ether/petroleum ether. The products recovered was α-(N-CBZ-4-aminobutyl) glycolic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH2:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl.Cl[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][C:31]([O:33][CH3:34])=[O:32])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(CNC(=O)OC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reaction time: 16 h

Procedure:
To a suspension of 3-aminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride (from Example 76.3., 0.2 mmole) in dichloromethane (2.0 ml) was added at 22° C. methyl chloroformate (0.22 mmole) and stirring was continued at 22° C. for 16 h. The mixture was washed with 1 N aqueous HCl, the organic layer was dried, evaporated and the residue was chromatographed on silica using n-heptane/AcOEt to give 5-fluoro-3-(methoxycarbonylamino-methyl)-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid. MS: 435.4 ([M+H]+).
Reaction SMILES: C([NH:8][S:9]([C:12]1[C:13]2[CH2:28][CH2:27][CH2:26][CH2:25][C:14]=2[C:15]2[NH:16][C:17](=[O:24])[C:18](=[O:23])[N:19]([OH:22])[C:20]=2[CH:21]=1)(=[O:11])=[O:10])(C(OCC)=O)=O>Cl>[OH:22][N:19]1[C:20]2[CH:21]=[C:12]([S:9](=[O:10])(=[O:11])[NH2:8])[C:13]3[CH2:28][CH2:27][CH2:26][CH2:25][C:14]=3[C:15]=2[NH:16][C:17](=[O:24])[C:18]1=[O:23]
Reactant: CCOC(=O)C(=O)NS(=O)(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2
Agent: Cl
Product: NS(=O)(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
A suspension of 6-ethoxalylaminosulfonyl-7,8,9,10-tetra-hydro-4-hydroxybenzo[f]quinoxaline-2,3(1H,4H)-dion g, 0.5 mmol) in 7 ml of conc. hydrochloric acid was heated to reflux with stirring for 1.5 h. The mixture was cooled to 0° C. and filtered. The isolated product was washed with water and dried to give 0.14 g (66%) of the title compound. M.p. 316° C. decomp. (DSC); IR (KBr): 1698 cm-1 ; 1H-NMR (DMSO-d6): 1.56-1.93 (m, 4H, 2CH2), 2.60-3.27 (m, 4H, 2CH2), 7.37 (broad s, 2H, SO ), 7.92 (s, 1H, ArH), 11.3 (broad s, 1H, NH or OH), ca. 10.7-12.1 (very broad s, 1H, NH or OH), MS m/e: 311 (M , 18%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=O.[I:20][C:21]1[CH:22]=[C:23]([CH2:27]C#N)[CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>CO>[I:20][C:21]1[CH:22]=[C:23]([C:27]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4([C:15]5[S:16][CH:17]=[CH:18][CH:19]=5)[O:14][CH2:13][CH2:12][O:11]4)=[CH:6][C:5]=23)[CH:24]=[CH:25][CH:26]=1
Reactant: N#CCc1cccc(I)c1
Reactant: O=[N+]([O-])c1ccc(C2(c3cccs3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Ic1cccc(-c2onc3ccc(C4(c5cccs5)OCCO4)cc23)c1

Procedure:
If one were to take 10 mmole of the dioxolane from Step A and treat it with 1.5 equivalents of (3-iodophenyl)acetonitrile and 5 equivalents of sodium hydroxide in anhydrous methanol and then refluxed the resulting reaction mixture for 2-3 hours, one would obtain after aqueous work-up the resulting 3-(3-iodo-phenyl)-5-(2-thiophen-2-yl-[1,3]dioxolan-2-yl)-benzo[c]isoxazole (3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.O[CH2:44][CH2:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48]>>[C:47]([CH2:46][CH2:45][CH2:44][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)([OH:49])=[O:48]
Reactant: CC(C)(C)OC(=O)CCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with tert-butyl 4-hydroxybutanoate to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 3-carboxy-propyl ester after removal of the Boc protection group by trifluoroacetic acid. MS (ES+) m/z calcd. for C35H36Cl2F2N3O6: [(M+H)+]: 702. found: 702.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)ncc(-c3cccnc3)c2s1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.05 mmol) was dissolved in 8 ml toluene. 4-Chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (280 mg, 0.90 mmol) (Example B), 3-pyridineboronic acid (133 mg, 1.08 mmol), 2M sodium carbonate (2.70 ml, 5.4 mmol) and 2 ml ethanol were added and the mixture stirred at 80° C. for 6 hrs. The reaction mixture was extracted with water and two times ethyl acetate. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 9:1->0:100 gradient). The desired compound was obtained as a light yellow solid (100 mg, 42%), MS: m/e=263.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis/trans-Ethyl 4-(ethyloxy)cyclohexanecarboxylate (D2, 21 g, 105 mmol) was dissolved in MeOH-THF (100 mL-100 mL) and NaOH (5 eq., 0.5 mol, 40 mL, 12.5 N aqueous solution) was slowly added at room temperature. The mixture was stirred at room temperature overnight. The THF/MeOH was then evaporated and the crude was washed with Et2O. The aqueous phase was acidified and extracted with EtOAc (2×); organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound as a pale-yellow oil, 17.3 g, 96%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][C:24]=1[NH2:35]>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[CH:25][C:24]=1[NH:35][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8]
Reactant: O=C(O)c1ncc[nH]1
Reactant: COc1ccc(N2CCOCC2)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(N2CCOCC2)cc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
According to scheme 1, to a suspension of a imidazole-2-carboxylic acid (X) was added CDI (1,1′-carbonyl-diimidazole) and stirred at ambient temperature for about 1 h. Then the mixture was refluxed and cooled to ambient temperature. 2-Methoxy-5-morpholin-4-yl-phenylamine (for R1=morpholinyl, IX) was added and the reaction mixture was heated to reflux for about 16 h. After workup 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (XI) was obtained, which was then treated with the Lawesson reagent. The reaction mixture was then heated to reflux for about 22 h. The obtained 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (II) was taken up in water and treated with KOH and potassium hexacyano ferrate to give 2-(1H-imidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (Ia for R1=morpholinyl).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[C:12]([CH3:18])[C:11]=1[CH3:19])=[O:8].[CH2:20](Cl)[C:21](=[CH2:23])[CH3:22]>CN(C)C=O>[CH:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:22][C:21]([CH3:23])=[CH2:20])=[C:12]([CH3:18])[C:11]=1[CH3:19])=[O:8]
Reactant: C=C(C)CCl
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C)c(NC=O)c(C)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Potassium carbonate (74.0 g, 0.54 mol) was added to a solution of 4-formylamino-2,3,5-trimethylphenol (85.5 g, 0.48 mol) and methallyl chloride (45.3 g, 0.5 mol) in dimethylformamide (300 ml) and the mixture was stirred at 80° C. for 3 hours under an argon atmosphere. The reaction mixture was poured into ice-cold water. Crystals precipitated were filtered, washed with water and dried. The crude crystals obtained were recrystallized from isopropyl ether to obtain the desired compound (80.0 g, yield: 71.6%), m.p. 144°-145° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[N:3]=1.[C:15]([C:19]1[O:23][N:22]=[C:21]([NH2:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(O)(C)C.Cl>[C:15]([C:19]1[O:23][N:22]=[C:21]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=3[N:3]=2)[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cn1c(Cl)nc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)c1cc(N)no1
Agent: Cl
Solvent: CC(C)O
Product: Cn1c(Nc2cc(C(C)(C)C)on2)nc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Yield: 317.1 %

Procedure:
To a solution of 2-Chloro-1-methyl-5-nitro-1H-benzoimidazole (200 mg, 0.19 mmol) and 5-tert-Butyl-isoxazol-3-ylamine (265 mg, 1.90 mmol) in isopropanol (15 ml) was added a solution of HCl (3 drops, 4.0 m in dioxane). The reaction was heated to 80° C. and after 20 h. the reaction mixture was cooled to rt. The solvent was evaporated to dryness and the resultant solid was dissolved in EtOAc and neutralized by a 10% NaHCO3 water solution. The combined organic layers were washed with water, dried over MgSO4 and concentrated to give a foam. The crude material was purified through silica gel to give the title compound as a yellow solid (190 mg, 63%). MS (ESI) m/z=316 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]([CH2:11][OH:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+]=[N-])[CH3:15]>ClCCCl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][O:12][CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:9][CH3:10])[CH3:15]
Reactant: CCC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCCl
Product: CCOC(=O)COCC(CC)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of (1-(hydroxymethyl)propyl)carbamic acid tert-butylester (7.2 g, 39 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture was heated to 80° C. Ethyldiazoacetate (6.0 ml, 57 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 60 min and the mixture was heated at 80° C. for 6 hours. Then another portion of ethyldiazoacetate (2.0 ml, 19 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 7 hours. The mixture was cooled to room temperature and washed with sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) is with pentane/ethyl acetate 7:3 as eluent to give 4.3 g of (2-(tert-butoxycarbonylamino)butoxy)acetic acid ethylester. The product was dissolved in of 1 M lithium hydroxide in water/methanol 1:3 (40 ml) and stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and water (100 mL) was added and the solution was washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1 M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 2.46 g of (2-(tert butoxycarbonylamino)butoxy)acetic acid.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:33]=[CH:32]2.C(=O)(O)[O-].[Na+]>CS(C)=O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([N:39]1[CH2:40][CH2:41][N:42]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:43][CH2:44]1)[CH:33]=[CH:32]2
Reactant: Brc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4cc(Br)ccc4n2)CC1)O3
Temperature: 75 °C
Yield: 39.3 %

Procedure:
To a solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4 bromobenzene sulfonate (2.31 g, 5.13 mmol) in dimethylsulfoxide (123 mL) is added the 6-bromo-2-piperazin-1-yl-quinoline of Step B (1.5 g, 5.13 mmol) and the mixture is heated at 75° C. under nitrogen overnight. The mixture is poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (0.5–2%) in ethyl acetate-hexane (55:45) to provide the title compound as an off-white solid (1.02 g), m.p. 153–154° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[NH2:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[C:29]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:26])=[CH:32][CH:31]=1)#[N:28]
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: N#Cc1ccc(CN)cc1
Agent: [Li+]
Product: N#Cc1ccc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)cc1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 4-(aminomethyl)benzonitrile (30 mg, 0.22 mmol). Yield: 66 mg (63%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)[CH3:21].[Li+].C(I)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH2:20][CH3:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.63 g, 1.86 mmol) in anhydrous THF (10 mL), at −35° C., was added a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.86 mL, 3.77 mmol) dropwise. The reaction mixture was stirred at −35° C. for 30 min and then ethyl iodide (0.90 mL, 11.18 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 4 h. The reaction mixture was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane 0:100 to 70:30). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.27 g, 40%). LCMS (Method H): RT=4.65 min, [M+H]+ 367 (79Br), 369 (81Br)
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@H:29]1[CH2:34][C:33]2[C:35]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>CN(C)C=O>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([C:35]2[C:33]3[CH2:34][C@H:29]([NH:28][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:15][CH:14]=4)[CH2:30][O:31][C:32]=3[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCCCC4)cc2)CO3)CC1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 36.3 %

Procedure:
A suspension of 4-piperidinobenzoic acid (276 mg, 1.35 mmol; described in: Weringa, W. D.; Janssen, M. J. Recl. Trav. Chim. Pays-Bas 1968, 87(12), 1372–1380) and 1,1′-carbonyldiimidazole (229 mg, 1.41 mmol) in anhydrous N,N-dimethylformamide (11 mL) was placed in an oil bath at 75° C. After 45 min of stirring, the mixture was allowed to cool. A solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (317 mg, 1.28 mmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at room temperature for 40 h. Another portion of 1,1′-carbonyldiimidazole (83 mg, 0.51 mmol) was added, and the reaction was stirred for 3 days. At this time, the reaction was not complete and a final amount of 1,1′-carbonyldiimidazole (42 mg, 0.25 mmol) was added. The reaction mixture was heated for 3 h at 50° C. after which the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% NH3) affording 202 mg (36% yield) of the title compound as a white solid: mp 178–180° C.; [α]22D−159° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (35, M+).
Reaction SMILES: [N:1]([CH:4]([C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.C1COCC1>[CH3:10][C:9]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1]
Reactant: COC(=O)C(N=[N+]=[N-])C(C)(C)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H](N)C(C)(C)c1ccccc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of methyl 2-azido-3-methyl-3-phenylbutanoate (2.6 g, 11.2 mmol) and PPh3 (4.4 g, 16.7 mmol) in H2O (400 uL) and THF (100 mL) was stirred at 25° C. over 2 d then at 50° C. for 12 h. The solution was concentrated and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)) yielding the title compound (1.4 g, quant.): LCMS (ES) m/e 208 (M+H)+.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]=[CH:13]1.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1.C(O)(C)C>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH2:1]([NH:9][C:10]([N:20]1[CH2:19][CH2:18][CH:17]([C:15]2[N:14]=[CH:13][NH:12][CH:16]=2)[CH2:22][CH2:21]1)=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C=NCCc1ccccc1
Reactant: c1nc(C2CCNCC2)c[nH]1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: S=C(NCCc1ccccc1)N1CCC(c2c[nH]cn2)CC1
Temperature: 80 °C

Procedure:
A solution of 1.63 g (0.01 mol) of phenethyl isothiocyanate in 60 ml of toluene and 1.51 g (0.01 mol) of 4-(4-imidazolyl)piperidine is heated to reflux for 1h 30 min. After cooling, the solution is evaporated under reduced pressure and the residual oil obtained is dissolved in 60 ml of isopropanol in the presence of 1.2 equivalents of oxalic acid. After 30 minutes of heating at 80° C., the white precipitate formed is drained, washed with ether and recrystallised in acetonitrile.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:9]1(=[O:10])[N:5]([O:4][CH2:3][CH2:2][O:1][C:17]2[CH:49]=[CH:48][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:47])=[CH:19][CH:18]=2)[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1OCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 80.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 2.0 g of N-(2-hydroxyethoxy)-phthalimide [prepared as described in step (a) above], 4.4 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 2.53 g of triphenylphosphine and 1.68 g of diethyl azodicarboxylate, 5.00 g of the title compound were obtained as a foam-like solid.