Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@H:10]1[NH:14][C:13](=[O:15])[C@H:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]1)=[O:9])#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][NH:35]1>O1CCOCC1.C(Cl)Cl>[CH2:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][N:35]1[C:17](=[O:19])[CH2:16][C@H:12]1[C:13](=[O:15])[NH:14][C@H:10]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:9])[CH2:11]1
Reactant: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](CC(=O)O)C(=O)N1
Reactant: c1ccc2c(c1)CNC2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](CC(=O)N2Cc3ccccc3C2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred solution of [(3S,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}-2-oxopyrrolidin-3-yl]acetic acid (265 mg, 0.50 mmol) and HOBt (42 mg, 0.55 mmol) in 1,4-dioxane (3 mL) was added a solution of EDC (105 mg, 0.55 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 10 min at room temperature. Isoindoline (65 mg, 0.55 mmol) in CH2Cl2 (2 mL) was added with stirring. After 16 h, the reaction mixture was washed with saturated aqueous NaHCO3 (10 mL), 1 N aqueous citric acid (10 mL), and brine (10 mL). The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified over silica gel using CH2Cl2/MeOH (98:2) as an eluent to yield compound 1 (128 mg, 0.35 mmol, 70%). 1H NMR (300 MHz, CDCl3): (6/1 mixture of trans/cis amide rotomers) δ 7.30-7.26 (m, 4H), 6.56 (s, 0.86H), 6.06 (s, 0.14H), 4.82-4.77 (m, 4.86H, overlapped two singlet at 4.82, 4.77), 4.60 (d, J=6.6 Hz, 0.14H), 4.55 (d, J=9.0 Hz, 0.14H), 4.40 (dd, J=3.0, 9.0 Hz, 0.86H), 3.61-3.04 (m, 2H), 3.02-2.88 (m, 2H), 2.68-2.36 (m, 3H), 2.29-2.12 (m, 4H). MS (ES+) m/z calcd. for C20H22N4O3: 366.17. found: 367.1 (M+H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[CH:15]1[C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:20][C:19]=2[C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.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>[CH:15]1[C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:20][C:19]=2[C:18]([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: OB(O)c1cccc2c1Oc1ccccc1S2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1cc(-c2cccc3c2Oc2ccccc2S3)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 40.9 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (3)(863 mg, 4 mmol), phenoxathiin-4-boronic acid (1.07 g, 4.4 mmol), and ground potassium carbonate (1.1 g, 8 mmol) were suspended in dioxane (10 ml) and degassed (sonication for 5 minutes then saturated with N2). Pd(PPh3)4 (231 mg, 0.2 mmol) was then added and the reaction mixture was then heated at 90° C. for 24 hours under a vigorous stirring and a N2 atmosphere. The solvent was removed in vacuo and the residue was then suspended in water (50 ml) and extracted with ethyl acetate (3×50 ml). The organics were combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography (silica; ethyl acetate:ethanol; 9:1) to give the title compound as a white solid (620 mg, 41%). 1H-NMR (300 MHz, DMSO-d6): δ=3.38 (4H, t, J 5 Hz); 3.71 (4H, t, J 5 Hz); 5.49 (1H, d, J 2 Hz); 6.49 (1H, d, J 2 Hz); 7.06 (1H, dd, J 1 and 8 Hz); 7.26 (4H, m); 7.46 (1H, dd, J 1.5 and 8 Hz); 7.55 (1H, dd, J 1.5 and 8 Hz). m/z (LC-MS, ESP): 380 (M++1).
Reaction SMILES: [OH-].[Na+].[Cl-].[CH3:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:38]=O.Cl>>[CH3:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]=[CH2:38]
Reactant: C=O
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OC)c2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: C=Cc1cc(OC)c2ccccc2c1OC
Reaction time: 1 h

Procedure:
50 ml of a 10% aqueous solution of sodium hydroxide were added dropwise, with stirring, to a mixture of 7.36 g of 1,4-dimethoxy-2-naphthylmethyltriphenylphosphonium chloride [prepared as described in step (a) above] and 75 ml of a 30% V/v aqueous solution of formaldehyde, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was neutralized with 3N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 24:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.45 g of the title compound as a pale yellow oil.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[C:17]=1[CH3:18])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:18][C:17]1[C:13]2[CH2:14][CH2:15][O:16][C:12]=2[CH:11]=[C:10]([CH3:19])[C:9]=1[NH2:8]
Reactant: Cc1cc2c(c(C)c1NCc1ccccc1)CCO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1N)CCO2
Yield: 86 %

Procedure:
Using N-benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 270, the title compound was synthesized in the same manner as in Reference Example 30. Yield 86%. Melting point: 85-86° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[CH:2]([CH3:4])[CH3:3].CS([C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=1)(=O)=O.S([O-])([O-])(=O)=O>CN(C=O)C>[CH2:1]([C:5]1[O:6][C:7]([C:10]2[C:15]([O:16][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC(C)Cc1ncc(-c2c(O)cccc2Cl)o1
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2-c2cnc(CC(C)C)o2)n1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
2 ml DMF solution containing 0.5 g 2-isobutyl-5-(2-chloro-6-hydroxyphenyl)oxazole, 0.41 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.55 g pottasium sulfate was stirred for 14 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and was then extracted with ethyl acetate. The organic layer obtained was washed with water and was then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduce pressure. The residue obtained was purified by using silica gel column chromatography, where hexane-ethyl acetate solution in a mixing ratio of 6:1 is used, affording the objective substance in an amount of 0.64 g.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].O=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Reaction time: 0.67 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL, 15 mmol) was added dropwisely to a stirred solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (50 mL) at 0° C. and stirred for 40 min at the same temperature. A solution of ethyl 4-oxocyclohexanecarboxylate (2.04 g, 12 mmol) in THF (20 mL) was added slowly at 0° C. and stirred for 2 h from 0° C. to room temperature. The reaction was quenched with saturated NH4Cl aq. and extracted with hexane. The collected organic layer was dried over MgSO4 and concentrated under reduced pressure. The solvent (100 mL, hexane/Et2O=5/1) was added to the residue and stirred for 30 min. The suspension was filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by silicagel chromatography (5% EtOAc/hexane as eluent) to provide compound A122-1 (1.478 g, 73%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH2:24][CH3:25])C>>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:7]/[CH:6]=[CH:5]/[C:25]2[CH:24]=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Reactant: CCOCC
Product: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1C/C=C/c1ccccc1
Yield: 69 %

Procedure:
Using 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one, the title compound was synthesized in substantially the same manner as in Working Example 21 in a yield of 69%, m.p. 152°-154° C. (diethyl ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([C@H:7]([OH:10])CO)[C@@H:4]([C@H:11]([OH:14])CO)[O:3]1.I([O-])(=O)(=O)=O.[BH4-].[Na+]>>[CH3:1][C:2]1([CH3:15])[O:3][C@H:4]([CH2:11][OH:14])[C@@H:5]([CH2:7][OH:10])[O:6]1
Reactant: CC1(C)O[C@H]([C@H](O)CO)[C@@H]([C@H](O)CO)O1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CC1(C)O[C@H](CO)[C@@H](CO)O1

Procedure:
Such a reaction sequence is illustrated for R=methyl by way of example in Scheme 1, for the preparation of the (4R, 5R)-compound. The starting material, the known 3,4-O-isopropylidene-D-mannitol (1), is reacted with periodate ion, and the product of glycol cleavage is reduced with sodium borohydride to afford 2,3-O-isopropylidene-D-threitol (2). Sulphonylation of (2) with methanesulphonyl chloride affords the di-methanesulphonate (3), which undergoes displacement with azide ion to yield the diazide(4). Catalytic reduction of (4) gives the (4R,5R)-diamine (5), which is reacted, generally without isolation, with potassium tetrachloroplatinate, to afford (4R,5R)-(I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]2[N:43]([CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[O:41][N:40]=2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43]([CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[O:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]1=[O:18]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: COCCOCn1c(-c2ccccc2-c2ccc(CBr)cc2)noc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-4-[(2-methoxyethoxy)methyl]-1,2,4-oxadiazol-5(4H)-one (14.5 g), potassium carbonate (8 g) and acetonitrile (500 mL) was stirred at 50° C. for 4 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (15.5 g, 79%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH2:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:13][C:14]([CH3:16])=O.N1CCCC1>CO.CCOCC.O>[CH3:1][C:2]1([C:8]2[CH:12]=[CH:11][C:10](=[C:14]([CH3:16])[CH3:13])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)=O
Reactant: CC1(C2=CC=CC2)CCCCC1
Solvent: CCOCC
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)=C1C=CC(C2(C)CCCCC2)=C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.3 %

Procedure:
To a solution of 2.71 g (16.7 mmol) of (1-methyl-1-cyclohexyl)cyclopentadiene in 30 ml of methanol, 25 ml (340.5 mmol) of acetone and 2.8 ml (33.5 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for 3 days. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.95 g (14.58 mmol) of a yellow liquid (yield: 87%). The analyzed values are given below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1=Cc2cc(OCc3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (25.0 g, 0.14 mol) and potassium carbonate (39.2 g, 0.28 mol) in 500 ml of DMF is treated with benzyl bromide (26.7 g, 0.16 mol). The mixture is stirred overnight at room temperature. Water is added and three extractions with dichloromethane are carried out. The extract is dried (MgSO4) and evaporated to dryness. The residue is crystallized from hot ethyl acetate to give 6-benzyloxy-2H-1-benzopyran-3-carboxaldehyde, m.p. 112°-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][N:35]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:34][NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN=[N+]=[N-])C(C)C)cc1OCCCOC
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN)C(C)C)cc1OCCCOC

Procedure:
According to the procedure described for Example 130/reaction step C, by hydrogenation of (3S,4R)-3-azidomethyl-4-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.95 g, 7.48 mmol), dissolved in absolute EtOH (100 mL), in the presence of Pd/C 10% (0.8 g; Engelhard 4505) at room temperature under atmospheric pressure to give, after filtration and drying in vacuo, the title compound as colorless oil. MS: 492.2 [M+H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.62 min.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[OH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C1C=CN=CC=1)C.O1CCOCC1>[I:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]([N:32]3[CH2:33][CH2:34][C:29]([OH:28])([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:30][CH2:31]3)=[N:3][CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(O)(c4ccccc4)CC3)nc2)cc1I
Yield: 65 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (100 mg, 0.26 mmol), a catalytic amount of DMAP, diisopropylethyl amine (0.14 mL, 8.1 mmol), 4-hydroxy-4-phenyl piperidine (140 mg, 8.1 mmol) in 5 mL in dioxane was heated at 95° C. in a sealed tube for about 48 h. The reaction mixture was then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was then collected, dried over Na2SO4 filtered and concentrated. The residue was chromatographed with a silica gel column and 20-100% EtOAc in hexanes to afford the product (90 mg. Yield: 65%). HRMS m/z calcd for C24H24N3O2I [M+H]+: 514.0986. Found: 514.0987.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C(F)=CC(F)=CC=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([CH2:25][N:15]([C:16]2[C:17]([F:24])=[CH:18][C:19]([F:23])=[CH:20][C:21]=2[F:22])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2c(F)cc(F)cc2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1cc(F)c(NCC2CCCC2)c(F)c1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2c(F)cc(F)cc2F)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,4,6-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:16])[NH:5][S:6]2(=[O:8])=[O:7].[H][H]>O.[Pd]>[CH3:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:16])[NH:5][S:6]2(=[O:8])=[O:7]
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])ccc2c1C(=O)NS2(=O)=O
Agent: [Pd]
Solvent: O
Product: Cc1c(N)ccc2c1C(=O)NS2(=O)=O
Temperature: 25 °C

Procedure:
33.6 g (0.13 mol) of 4-methyl-5-nitrosaccharin are dissolved in 1.2 l of water with warming and 5 g of Pd/C (10 percent on active carbon) are added. Hydrogen gas is then passed in with vigorous stirring (pressureless hydrogenation). 9 l of H2 are absorbed in the course of 4.5 hours. After cooling to 25° C., the catalyst is filtered off, and the filtrate is concentrated to a volume of 200 ml on a Rotavapor and then acidified to pH 1. The deposited precipitate is filtered off with suction, washed with water and dried under reduced pressure at 50° C. 23.4 g (0.11 mol=85% of theory) of a white solid of m.p.: 272°-273° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](OC)=[O:21].[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[CH:20][OH:21])[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-benzyloxyphenylacetate (26.99 g) and methyl formate (126.62 g) in dry DMF (300 ml) was added dropwise to a stirred suspension of sodium hydride (50% disp. in oil, 10.13 g) in DMF (300 ml) at 0° C. After stirring at 0° C. for two hours the mixture was poured into water (1000 ml) and washed with ether (2×150 ml). The aqueous layer was acidified to pH4 with 6M hydrochloric acid then extracted with ether (2×350 ml). The extracts were dried and concentrated under reduced pressure to afford crude methyl 2-[2'-benzyloxyphenyl]-3-hydroxyacrylate as a yellow oil, infrared max. (film): 1720, 1660 cm-1.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:24][C:25]4[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1ccc(CBr)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 23.2 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-methylbenzyl bromide (18.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(4-methylbenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (9.2 mg).
Reaction SMILES: C[C:2](C)([O:29][SiH2]C(C)(C)C)[C:3]1[CH:28]=[CH:27][C:6]2[C:7](=[O:26])[NH:8][C:9]3[CH:25]=[CH:24][CH:23]=[N:22][C:10]=3[N:11]([C:12](=[O:21])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl.C1COCC1>[OH:29][CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[C:7](=[O:26])[NH:8][C:9]3[CH:25]=[CH:24][CH:23]=[N:22][C:10]=3[N:11]([C:12](=[O:21])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=1
Reactant: CN1CCN(CC(=O)N2c3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc3C(=O)Nc3cccnc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC(=O)N2c3cc(CO)ccc3C(=O)Nc3cccnc32)CC1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Compound l , 15 (15 mg, 0.03 mmol) was dissolved in 1 mL CHCl3, and a solution of 1M tetrabutylammonium fluoride in THF (40 μl) was added. The solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo, and the remaining residue was dissolved in saturated NaHCO washed with ether to remove non-polar impurities, and extracted with CHCl3. The CHCl3 extracts were combined, evaporated, and purified on a short silica gel column to yield 10 mg (86%) of 16 as a waxy solid: 1H NMR (CDCl3) δ 2.05-2.50 (m, 60 H), 2.20 (s, 3 H, CH3), 3.22 (d, J=14 Hz, 1 H), 3.60 (m, 1 H), 4.80 (s, 2 H, CH20), 7.30 (dd, J=7.8, 4.7 Hz, 1 H), 7.44 (d, J=8.1 Hz, 1 H), 7.50 (dd, J=1.6, 7.8 Hz, 1 H), 7.62 (s, 1 H), 7.96 (d, J=8.1 Hz, 1 H), 8.02 (m, 1 H); MS (CI/NH3) m/e 382 (MH+, base), 242, 141, 113.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:20][N+:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:23]([F:35])[CH:22]=1.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[C:37]#[CH:38]>C1COCC1>[C:31]([O:30][C:28]([NH:27][C:24]1[CH:25]=[CH:26][N:21]2[N:20]=[CH:38][C:37]([C:36]([O:40][CH2:41][CH3:42])=[O:39])=[C:22]2[C:23]=1[F:35])=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cc[n+](N)cc1F
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(NC(=O)OC(C)(C)C)c(F)c12
Reaction time: 0.5 h

Procedure:
K2CO3 (36.96 g, 267 mmol) was added to a solution of 1-amino-4-((tert-butoxycarbonyl)amino)-3-fluoropyridin-1-ium 2,4-dinitrophenolate (50 g, 121 mmol) in THF (500 mL) at 28° C. and continued stirring at same temperature for 30 min. Ethyl propiolate (14.3 g, 145 mmol) was added to above solution and stirring was continued at 28° C. for 16 hr. Reaction mixture was filtered to remove the salt, filtrate collected was diluted with EtOAc washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60-120 silicagel and 10% EtOAc in Hexane as eluant) to afford the title compound.