Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][OH:22])[CH3:17])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[O:2]1.O[C:24]1[CH:56]=[CH:55][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]2=[O:54])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][O:22][C:24]4[CH:56]=[CH:55][C:27]([CH2:28][CH:29]5[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]5=[O:54])=[CH:26][CH:25]=4)[CH3:17])=[CH:14][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccc3c(c2)OCO3)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc3c(c2)OCO3)cc1
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 600 mg of 2-(1-(3',4'-methylenedioxybiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 30), 907 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 550 mg of triphenylphosphine and 365 mg of diethyl azodicarboxylate, 1.12 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=1)[CH2:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1cnc(C(CN)CC2CC2)cn1
Product: Cc1cnc(C(CNC(=O)c2ccccc2Cl)CC2CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(5-methylpyrazin-2-yl)propylamine. LCMS (MH+): m/z=330.0, tR (minutes, Method E)=0.61
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[N:23]=[C:22]([NH:24][CH3:25])[N:21]=[C:20]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1>C(Cl)Cl>[CH3:25][NH:24][C:22]1[N:21]=[C:20]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CNc1nc(N)nc(OCC(F)(F)F)n1
Solvent: ClCCl
Product: CNc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2-Carbomethoxybenzenesulfonyl isocyanate (0.5 g) was dissolved in 5 ml of methylene chloride. The aminoheterocycle (0.46 g) prepared in Example 2 was added and the mixture was stirred overnight under nitrogen at room temperature. The resulting solids were filtered off, washed with methylene chloride and dried to give 0.54 g of ~80% pure subject compound; m.p. 195°-197° C. decomp. No attempt was made at further purification. The resulting product named above had the following characteristics: IR (nujol) showed carbonyl bands at 1723 cm-1 and 1740 cm-1. NMR (CDCl3, DMSO-d6): δ 2.9, m, (NHCH3); 3.8, s, (CO2CH3); 4.9, m, (OCH2CF3); 7.7-8.4, m, (aromatic H's) plus ~20% heterocycle.
Reaction SMILES: [CH2:1]([C:5]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH2:2][CH2:3][CH3:4].Br[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(F)(F)F)nc2nc[nH]c12
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(C(F)(F)F)nc2c1ncn2C1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of 6-(1-butyl)-2-trifluoromethylpurine (35 mg, 0.14 mmol), bromocyclopentane (89 mg, 0.60 mmol), potassium carbonate (83 mg, 0.6 mmol) and N,N-dimethylformamide (3 ml) was heated to 100° C. After 8 hours, the reaction mixture was cooled to 40° C. and concentrated under vacuum. The residue was treated with 15 ml of ethyl acetate and washed with 5% sodium bicarbonate (2×15 mL). The organic layer was concentrated and purified by chromatography (20% ethyl acetate in hexane) to give 6-(1-butyl)-9-cyclopentyl-2-trifluoromethylpurine (26.6 mg, 60% yield).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C@H:9]2[CH2:11][C@H:10]2[CH2:12][CH2:13][O:14][C:15]2[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][C:16]=2[CH3:29])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH:33]([CH3:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[Cl-].[Zn+2].[Cl-]>[CH:33]([C:32]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([C@H:9]3[CH2:11][C@H:10]3[CH2:12][CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:17][C:16]=3[CH3:29])[CH2:7][CH2:8]2)[O:30][N:31]=1)([CH3:35])[CH3:34]
Reactant: CC(C)C(=N)NO
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of tert-butyl (6-{2-[(1S,2R)-2-(cyanopiperidin-4-yl)cyclopropyl]ethoxy}-5-methylpyridin-3-yl)acetate (650 mg, 1.63 mmol), N-hydroxy-2-methylpropanimidamide (1.38 eq., 230 mg) and zinc chloride (1.58 eq., 350 mg) in 5 mL of DMF was stirred 2 hrs at 80° C., then PTSA (1.0 eq, 280 mg) was added and stirred for additional 2 hrs at 85° C. The mixture was cooled to room temperature and then quenched by said aq soln of NaHCO3. The mixture was extracted with EtOAc (2×75 mL), and the combined organics were then washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by ISCO column (40 g silica gel) using ethyl acetate in hexane (0-40% EA, 400 ml, and 40-100% EA 200 ml) to give the product. LCMS (ESI) m/z 485 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C:6]([CH3:15])([S:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:7])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:2]([O:4][C:5](=[O:16])[C:6]([S:8][CH:9]1[CH2:10][CH2:11][N:12]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([CH3:15])[CH3:7])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(C)SC1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)SC1CCN(S(C)(=O)=O)CC1
Yield: 41.9 %

Procedure:
To a solution of 4.47 g (16.74 mmol) of 2-methyl-2-(piperidin-4-ylsulfanyl)-propionic acid ethyl ester hydrochloride salt in anhydrous THF (30 mL) are added 13.45 mL (77.36 mmol) of N,N-diisoproylethylamine, followed by 2.98 mL (38.58 mmol) of methanesulfonyl chloride. The reaction mixture is heated for 2 d to 60° C. The mixture is concentrated under reduced pressure and the residue is partitioned between saturated aqueous NaHCO3 solution (75 mL) and ethyl acetate (75 mL). The basic aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layer is separated and washed with brine (50 mL), dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography (silica, eluent: heptanes, 30% ethyl acetate) to give 2.17 g of 2-(1-methanesulfonyl-piperidin-4-ylsulfanyl)-2-methyl-propionic acid ethyl ester as a brown solid. Yield: 42%, ES-MS: m/z 310 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.22 (3H, t, J=7.11 Hz), 1.47 (6H, s), 1.59-1.69 (2H, m), 1.92-2.00 (2H, m), 2.70 (3H, s), 2.90-2.99 (3H, m), 3.39-3.47 (2H, m), 4.10 (2H, q, J=7.12 Hz)
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(Cl)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[C:1](#[N:4])[CH:2]=[CH:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccccc1
Yield: 540 %

Procedure:
The procedure described in Example 1 is repeated, except that 3.31 g (0.0625 mol) of acrylonitrile, 7.02 g (0.05 mol) of benzoyl chloride, 11.6 g (0.0625 mol) of tri-n-butylamine, 100 ml of p-xylene and 0.1122 g (0.0005 mol) of palladium acetate are used. After a reaction time of 2 hours at 120° C., 3.47 g (0.27 mol) of cinnamonitrile are obtained, corresponding to a yield of 54% of theory. Boiling point=134°-136° C./17×102Pa.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[NH:14][N:13]=[C:12]([CH2:15][CH3:16])[CH:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:15]([C:12]1[NH:13][N:14]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:11]=1)[CH3:16]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCc1cc(N)[nH]n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 60 °C
Yield: 34.7 %

Procedure:
A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 5-amino-3-ethyl-1H-pyrazole (2.44 g, 22 mmol) and N,N-diisopropylethylamine (3.8 ml, 22 mmol) in dry THF (75 ml) was heated at 60° C. for 18 hours. The volatiles were removed by evaporation, and the residue was triturated with a mixture of DCM and water. The solid product was collected by filtration, washed with water and ether, and dried to give the title compound (1.55 g, 35%) as a colourless crystalline solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13](Cl)[N:12]=1.C(N(CC)CC)C>C(#N)C>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: NCCc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
Phenethylamine (7.0 g, 58.4 mmol) was added to a stirred solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (14.5 g, 53.1 mmol) (preparation 5) and triethylamine (21 g, 212.5 mmol) in acetonitrile (200 ml). The reaction mixture was stirred for 3 hr at room temperature and then more phenethylamine (1 g, 8.3 mmol) was added. The reaction mixture was stirred for a further 1 hr and then the solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether (500 ml) and water (250 ml). The diethyl ether layer was washed with more water (300 ml). The solvent was removed from the organic phase under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with diethyl ether to give the title compound (17.9 g) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)#[N:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: N#Cc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 4-cyanobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 8.02 (d, J=8.8 Hz, 2 H), 8.42 (d, J=8.8 Hz, 2 H), 8.57 (dt, J=8.1, 1.9 Hz, 1 H), 8.75 (dd, J=4.7, 1.7 Hz, 1 H), 9.31 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:62][C@H:63]([C:68](O)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH2:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66]
Reactant: NC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(N)=O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
To a solution of 4-{[(1′S,2′S)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}benzamide (20, 150 mg, 0.26 mmol), DCC (64 mg, 0.31 mmol) and DMAP (3 mg, 0.026 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (91 mg, 0.26 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (180 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (86%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 201 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (500 mg, 1.29 mmol) was dissolved in methanol (30 mL). A 4 N hydrochloric acid/ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for one hour. Concentration under reduced pressure gave 419 mg of the title compound as a white solid (100%). (159b) Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)pyridine-4-carboxylate
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:39][C@@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.O>CN(C)C=O>[CH3:45][C:42]1([CH3:46])[O:41][C@H:40]([CH2:39][N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]([CH:13]3[CH2:12][CH2:11][N:10]([CH2:9][C@H:4]4[CH2:5][CH2:6][CH2:7][CH2:8][C:3]54[CH2:2][CH2:1]5)[CH2:15][CH2:14]3)[C:17]2=[O:25])[CH2:44][O:43]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C[C@H]2CCCCC23CC3)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@@H](Cn2c(=O)n(C3CCN(C[C@H]4CCCCC45CC5)CC3)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (2.94 g) was dissolved in dimethylformamide (60 mL), and to which 60-72% sodium hydride (oil dispersion) (706.6 mg) was added at room temperature and stirred for 30 minutes. To the reaction mixture, [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzene-sulfonate (7.25 g) was added and stirred at 80° C. for 7 hours. After cooling the reaction mixture to room temperature, water was added, followed by extraction with ethyl acetate. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=2/1−1/2) to provide 3.43 g of the title compound as a pale yellow, oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CCNC1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(3-pyrrolidin-1-yl-propoxy)-benzo[d]isothiazole, MS: 418 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH:11]=[N:12][C:13]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]3[C:14]=2[CH2:15][NH:16][C:17]3=[O:23])[CH:7]=1.B(Br)(Br)Br.CO.ClCCl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]2[C:7]=1[CH:11]([NH:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]3[C:14]=1[CH2:15][NH:16][C:17]3=[O:23])[C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:9][C:8]2([CH3:30])[CH3:29]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cc(F)cc2c1CNC2=O)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cc(F)cc3c2CNC3=O)c2c(F)ccc(O)c21
Reaction time: 1 h
Yield: 2.5 %

Procedure:
380 mg (0.832 mmol) of 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-one is mixed at room temperature with 8.3 ml of a 1 M solution of BBr3 in dichloromethane and stirred for one hour at ice bath temperature. The working-up of the batch is carried out as described in Example 4. After chromatography of the crude product on a Flashmaster (amine phase; mobile solvent:methanol/dichloromethane), 9.2 mg (2.7%) of the desired compound is obtained.
Reaction SMILES: I[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[C:20]2[S:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O1CCCC1.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[S:19]1[C:20]2[C:12]([O:11][C@@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][NH:24][CH3:23])=[CH:13][CH:14]=[CH:15][C:16]=2[CH:17]=[C:18]1[C:21]#[N:22]
Reactant: N#Cc1cc2cccc(O[C@H](CCI)c3ccccc3)c2s1
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCC[C@@H](Oc1cccc2cc(C#N)sc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 7-{[(1R)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (156 mg, 0.37 mmol) in tetrahydrofuran (1.5 mL) was added 40% aqueous methylamine (0.5 mL) and the solution was stirred at room temperature for 16 hours. The solvent removed in vacuo and the residue purified by flash chromatography with a gradient of 0–15% methanol in dichloromethane. To a solution of free base (96 mg, 0.3 mmol) in methanol (1 mL) and added a warm solution of fumaric acid (26 mg, 0.3 mmol) in methanol (1 mL). The solvent removed in vacuo, and the solid residue triturated with ether (5 mL), then dried in a vacuum oven at 40° C. for 1 hour to give the title compound (120 mg, 74%); δH (300 MHz, DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 7.05–6.98 (1H, m, ArH), 6.45 (2H, s, CHCO2H), 5.85–5.75 (1H, m, CHO), 3.05–2.90 (2H, m, 1-CH2), 2.52 (3H, s, NHCH3) and 2.46–2.07 (2H, m, 2-CH2).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH:4]([OH:12])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(Cl)Cl.[CH2:17]([N:24]=[C:25]=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[OH:12][CH:4]([CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][O:2][NH:1][C:25]([NH:24][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26]
Reactant: NOCC(O)CN1CCCCC1
Reactant: CCCCCCCN=C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCNC(=O)NOCC(O)CN1CCCCC1
Reaction time: 20 h

Procedure:
To the solution of 1.23 g (7.1 mmol) of l-aminooxy-2-hydroxy-3-(1-piperidinyl)-propane dissolved in 20 ml of chloroform 1.0 g (7.1 mmol) of heptyl isocyanate was added and the reaction mixture was stirred for 20 hours. Solvent was evaporated in vacuum and the residue was purified by chromatography to give pure colorless oil. White crystalline product was obtained by triturating with petroleum ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][C:12](OC)=[S:13]>>[NH2:1][CH2:2][CH2:3][NH:4][C:12](=[S:13])[CH2:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: COC(=S)CC1CCCCO1
Reactant: NCCN
Product: NCCNC(=S)CC1CCCCO1
Temperature: 75 °C

Procedure:
1,2-Diaminoethane (21 g, 350 mmol) was added to methyl tetrahydropyran-2-ylthioacetate (20 g, 105 mmol) and the mixture heated at 75° C. for 2 h. Volatile components were then removed from the reaction mixture in vacuo to give the N-(2-aminoethyl)-tetrahydropyran-2-ylthioacetamide in essentially quantitative yield. This product was contaminated with a small quantity of 1,2-diaminoethane, but it was sufficiently pure to be used without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:11]>O>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([Cl:11])[CH3:5])[CH3:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Product: CCOC(=O)C=C(C)Cl
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl acetoacetate (150.0 g, 0.86 mol) in hexanes (200 mL) was added phosphorus pentachloride (95.0 g, 0.456 mol) at 23° C. under nitrogen and stirred for 3 h. Water (300 mL) was added to the reaction mixture while cooling in an ice-bath. The organic layer was separated, washed with an aqueous solution of 20% potassium carbonate (3×200 mL) followed by a saturated sodium chloride solution (2×100 mL), dried over sodium sulfate and concentrated in vacuo to afford 3-chloro-but-2-enoic acid ethyl ester which was purified by distillation (95.8 g, 75%): boiling range 160°-170° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].[CH3:9][C:10]([CH3:12])=O>CO.[Pd]>[CH:10]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7])([CH3:12])[CH3:9]
Reactant: CC(C)=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCC[C@H]1C(=O)O
Reaction time: 9 h
Yield: 101.8 %

Procedure:
A suspension of (S)-pyrrolidine-2-carboxylic acid (5 g, 50 mmol), acetone (5.52 mL, 50 mmol) and 10% Pd/C (2.5 g) in methanol (100 mL) was stirred under hydrogen atmosphere for 6 to 12 hours. The reaction mixture was filtered on a pad of celite and the filtrate was concentrated. The residue obtained was filtered through a column of silica gel to afford (S)-1-isopropylpyrrolidine-2-carboxylic acid (8.0 g, 94%) as a colorless solid.