Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
Into a suspension of methyl 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (327.4 mg) in THF/methanol (4/2 ml) was added at room temperature an aqueous solution (1.0 ml) of potassium carbonate (240 mg), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (5 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (241 mg) as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](C)[CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:17][CH:18]([CH3:19])[CH3:10])=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 4-bromo-2-methylphenol (14.2 g) in DMF (75 ml) was added potassium carbonate (14.7 g), and to the mixture was added dropwise bromopropane (9.33 g). The mixture was stirred at 70° C. for 3 hours and cooled, and to the mixture was added water. The mixture was extracted with hexane, and the organic layer was washed with 1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give colorless oil of 4-bromo-2-methyl-propoxybenzene (10.6 g).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:10]1[CH:14](C(O)=O)[CH2:13][S:12][CH:11]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:36](=[CH2:39])[C:37]#[N:38]>ClCCl.O>[C:37]([C:36]1[CH:39]=[CH:8][N:10]2[C:14]=1[CH2:13][S:12][CH:11]2[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)#[N:38]
Reactant: C=C(Cl)C#N
Reactant: O=CN1C(C(=O)O)CSC1c1cccnc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccn2c1CSC2c1cccnc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Triethylamine (4.67 g) is added to a suspension of 3-formyl-2-(3-pyridyl)-4-thiazolidinecarboxylic acid (10 g) in dichloromethane (15 cc) at a temperature close to 20° C. A clear light yellow solution is obtained. This solution is added dropwise in the course of 1 hour at 40° C. to a mixture of tosyl chloride (8.8 g) in dichloromethane (17 cc). The reaction mixture becomes homogeneous and orange-red in colour. 2-Chloroacrylonitrile (4.10 g) is then added quickly, followed, while the reaction medium is maintained at reflux, by triethylamine (9.37 g). The reaction mixture is maintained refluxing for a further 1 hour and 25 minutes. After cooling to room temperature, the reaction medium is hydrolysed with water (12 cc). The organic phase is decanted and the aqueous phase extracted with dichloromethane. The organic extracts are combined and dried overnight over sodium sulphate. After filtering, the solvent is evaporated under reduced pressure (20 mm Hg; 2.7 Pa) at 20° C. A crude product (11.11 g) is obtained, and is purified by chromatography on a column (diameter 4.5 cm) containing silica (100 g) (0.063-0.2 mm), eluting with a mixture of ethyl acetate and dichloromethane. 7-Cyano-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole (8.36g) is thereby obtained in the form of light beige-coloured crystals, m.p. 110° C. (yield 88.4% relative to the acid used).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH:16]=[CH:15][O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([CH:15]2[CH:16]=[CH:17][CH:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:14]2)=[CH:24][CH:23]=1)[CH3:19]
Reactant: COc1cc(C2CC=CO2)cc(OC)c1OC
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C2C=CC(c3cc(OC)c(OC)c(OC)c3)O2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 287 (200 mg, 0.846 mmol) and 4-Iodo-benzoic acid ethyl ester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were added PPh3 (20 mg, 0.076 mmol), Ag2CO3 (467 mg, 1.69 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol). The reaction mixture was stirred 18 h at 80° C. The reaction mixture was filtered through celite and washed with AcOEt. Water was added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 30/70) to afford the title compound 288 (280 mg, 0.728 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 6.61 (s, 2H), 6.18-5.95 (m, 4H), 4.38 (q, J=7.0 Hz, 2H), 3.88 (s, 6H), 3.84 (s, 3H), 1.39 (t, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[OH:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][C:41]2([C:44]([OH:46])=[O:45])[CH2:43][CH2:42]2)=[CH:38][CH:37]=1.[CH3:49]N(C)C(N=NC(N(C)C)=O)=O>>[CH3:49][O:45][C:44]([C:41]1([O:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:14][CH:13]([N:12]3[C:11]4[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=4[N:9]=[C:8]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:48][CH:47]=2)[CH2:43][CH2:42]1)=[O:46]
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Reactant: O=C(O)C1(Oc2ccc(O)cc2)CC1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Product: COC(=O)C1(Oc2ccc(OCC(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4cc(F)c(F)cc43)cc2)CC1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid (CAS RN: 857903-44-7) and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow foam (31%). MS (Turbo Spray): m/z=581.2 [M+H].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]1[C:13]([NH2:14])=[N:12][C:10](=[O:11])[N:9]([C@@H:15]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:17]([OH:22])[C:16]2([F:24])[F:23])[CH:8]=1.Cl>>[F:24][C:16]1([F:23])[C@H:17]([OH:22])[C@@H:18]([CH2:20][OH:21])[O:19][C@H:15]1[N:9]1[CH:8]=[CH:7][C:13]([NH:14][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[N:12][C:10]1=[O:11]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 64 %

Procedure:
Using Method A and ethyl chloroformate, gemcitabine hydrochloride was converted to 8 (white solid, 64% yield): 1H NMR (400 MHz, DMSO-d6)δ10.88 (s, 1H), 8.24-8.27 (d, 1H), 7.13-7.16 (d, 1H), 6.34-6.37 (d, 1H), 6.18-6.22 (t, 1H), 5.32-5.36 (t, 1H), 4.17-4.23 (m, 3H), 3.90-3.94 (m, 1H), 3.82-3.86 (m, 1H), 3.65-3.72 (m, 1H), 1.25-1.29 (t, 3H); MS (HR-ESI): m/z 334.0853 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[CH:16][CH:17]=1)=[O:23])([CH3:39])[CH3:35]
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol) and TBTU (92 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (221 μL, 1.29 mmol). Then isopropylamine (25 μL, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (84 mg, 88%) as a light yellow solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:36])=[C:11]2[C:16](=[CH:17][N:18]=1)[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14](=[O:26])[C:13]([C:27]1[CH:28]=[N:29][C:30]([N:33]([CH3:35])[CH3:34])=[N:31][CH:32]=1)=[CH:12]2)=[O:8].[OH-].[Na+].C1COCC1>CO>[CH2:19]([N:15]1[C:16]2[C:11](=[C:10]([OH:36])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:8])=[N:18][CH:17]=2)[CH:12]=[C:13]([C:27]2[CH:32]=[N:31][C:30]([N:33]([CH3:35])[CH3:34])=[N:29][CH:28]=2)[C:14]1=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCNC(=O)c1ncc2c(cc(-c3cnc(N(C)C)nc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ncc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 3-{[1-benzyl-3-(2-dimethylamino-pyrimidin-5-yl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-propionic acid methyl ester (30 mg, 0.060 mmol), 2 M NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at r.t. overnight. The mixture was concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound as a pale yellow solid. MS: (+) m/z 489.29 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].CO.[OH-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: ClCc1ccccc1Cl
Reactant: O=C(CO)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(COCc1ccccc1Cl)Nc1ccccc1
Reaction time: 2 h

Procedure:
2-Hydroxyacetanilide (15.1 parts) is added to methanol (60 parts). Into this mixture is further added a solution of sodium hydroxide (4.8 parts) in water (14 parts). The resulting mixture is kept at 0° to 5° C. and add dropwise 2-chlorobenzyl chloride (18.3 parts) within 30 minutes, and the reaction is continued for 2 hours at 0° to 5° C., for additional 6 hours at 30° to 40° C. and further for additional 2 hours at 65° C. After completion of the reaction, the reaction mixture is poured into cold water (250 parts) and is then filtered. The filter cake obtained is washed with water and the resulting white cake is dried at 80° C. to yield the intended product (22.3 parts) having melting point 130° to 132° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[CH3:28][N:24]1[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=[C:19]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[N:16][CH:15]=[N:14][CH:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:29]=[C:23]12
Reactant: N#Cc1cc(CO)ccc1Oc1cncnc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cncnc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-(pyrimidin-5-yloxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C(OC(=O)CNC[C:8]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9])C.[OH2:18].[OH-:19].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C>[OH:16][C:15]1[C:10]([C:8]([N:11]([CH2:10][C:8]([OH:19])=[O:18])[CH3:12])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O
Reactant: [OH-]
Reactant: CCOC(=O)CNCC(=O)c1ncccc1O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CN(CC(=O)O)C(=O)c1ncccc1O
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of [(3-hydroxy-pyridine-2-carbonyl)methylamino]acetic acid ethyl ester, 32, (0.10 g, 0.42 mmol) in THF (4 mL) is added H2O (1 mL) and NaOH (0.90 g, 2.25 mmol). The reaction is stirred for 3 hours then concentrated under reduced pressure. The remaining oil is acidified to pH˜1 with 1M HCl and the solution is concentrated under reduced pressure to give an off-white solid. The solid is suspended in CHCl3:isopropanol (1:1) then collected by filtration. The solid is washed with additional CHCl3:isopropanol (1:1) then transferred to a flask and triturated with Et2O to afford 0.075 g (85% yield) of the desired compound as a pale yellow solid. 1H NMR (250 MHz, MeOD) δ ppm (rotamers) 8.26 (1H, br s), 7.63-7.74 (1H, m), 7.56-7.63 (1H, m), 4.38 (1H, s), 4.32 (1H, s), 3.20 (1.5H, s), 3.12 (1.5H, s). HPLC-MS: m/z 211 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:7](=O)[CH2:6][CH2:5]2.[NH2:22][C:23]1[CH:31]=[C:27]([C:28]([OH:30])=[O:29])[C:26]([OH:32])=[CH:25][CH:24]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>>[C:28]([C:27]1[CH:31]=[C:23]([N:22]2[C:7]3[CH2:6][CH2:5][C:4]4[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=4[C:8]=3[CH:12]=[C:13]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:24]=[CH:25][C:26]=1[OH:32])([OH:30])=[O:29]
Reactant: O=C(CC1C(=O)CCc2cc(Cl)ccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2cc(Cl)ccc2-3)ccc1O

Procedure:
A mixture of 10.1 g. (0.03 mole) of 6-chloro-1-phenacyl-2-tetralone, 4.5 g. (0.03 mole) of 5-aminosalicylic acid and 30 ml. of glacial acetic was heated under reflux for 70 minutes, cooled and filtered. The collected solid was washed with acetic acid and petroleum ether and recrystallized from acetonitrile to give 4.3 g. (59%) of colorless crystals, m.p. 249°-251°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[C:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[N:15]=[CH:16][CH:17]=2)[N:12]=[C:11](C(O)=O)[CH:10]=1.C1(P([N:44]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[C:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[N:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([NH2:44])[CH:10]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)c2ccnc(-c3c(F)cccc3F)c2n1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1cc(-c2ccc(F)cc2F)c2ccnc(-c3c(F)cccc3F)c2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 114.8 %

Procedure:
To a suspension of the title compound from Example 1 (100 mg, 0.25 mmol) in tert-butanol (2.4 mL) were added diphenylphosphoryl azide (DPPA) (0.07 mL, 0.32 mmol) and triethylamine (0.045 mL, 0.32 mmol). The mixture was heated at 100° C. for 75 minutes. The solvent was evaporated and the mixture redissolved in HCl (4M in dioxane, 2 mL) and stirred at room temperature for 2.5 hours. Subsequently, 4% aqueous sodium bicarbonate (40 mL) was added to the mixture and the reaction was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give 106 mg of a yellowish oil. The mixture was purified by column chromatography (C-18 silica from Waters©, reverse phase water/(acetonitrile/methanol 50:50) as eluent [0.1% v/v ammonium formate buffered] 0% to 100%). The organic solvent from the appropriate fractions was evaporated and the aqueous phase basified to pH 10 with ammonium hydroxide. This was extracted with ethyl acetate, dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a white solid (55 mg, 60%).
Reaction SMILES: N1[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si](Cl)(C)C.[NH2:11][C:12]1[C:33]([Cl:34])=[CH:32][C:15]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH:26]3CCN[CH2:28][CH2:27]3)[CH2:21][CH2:20]2)=[O:17])=[C:14]([O:35][CH3:36])[CH:13]=1.[OH2:37]>CN(C)C=O>[NH2:11][C:12]1[C:33]([Cl:34])=[CH:32][C:15]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH:26]3[CH2:5][CH2:4][N:3]([CH:2]=[O:37])[CH2:28][CH2:27]3)[CH2:21][CH2:20]2)=[O:17])=[C:14]([O:35][CH3:36])[CH:13]=1
Reactant: O
Reactant: c1c[nH]cn1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C=O)CC2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of imidazole (330 mg) in dimethylformamide (0.74 ml) is added trimethylsilyl chloride (0.61 ml) at room temperature, and the mixture is stirred for 20 minutes. To the solution is added 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]-benzamide (610 mg), and the mixture is stirred at room temperature for 24 hours. To the reaction mixture is added a small amount of water, and the mixture is concentrated to dryness under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The organic layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=30:1→20:1) to give the desired compound (200 mg) as amorphous.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C@H:8]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[S:7][CH:6]1[C:32]1[S:36][C:35]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:34][CH:33]=1.[CH:45](=O)[CH:46]([CH3:48])[CH3:47].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C@H:8]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[S:7][CH:6]1[C:32]1[S:36][C:35]([CH:37]2[CH2:38][CH2:39][N:40]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:41][CH2:42]2)=[N:34][CH:33]=1
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cnc(C2CCNCC2)s1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN1CCC(c2ncc(C3S[C@@H](CC(=O)N4CCC(N5CCc6ccccc6NC5=O)CC4)C(=O)N3CCC(C)(C)C)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To a solution of (5S)-3-(3,3-dimethylbutyl)-5-(2-oxo-2-(4-(2-oxo-4,5-dihydro-1H-benzo[d][1,3]diazepin-3(2H)-yl)piperidin-1-yl)ethyl)-2-(2-(piperidin-4-yl)thiazol-5-yl)thiazolidin-4-one (30 mg, 0.04 mmol, 1 eq) in DCM (3 mL) was added isobutyraldehyde (6 mg; 0.08 mmol, 2 eq) and NaBH(OAc)3 (27 mg, 0.12 mmol, 3 eq). The reaction mixture was stirred at RT for 18 h, then quenched with MeOH (0.1 mL) and sat. NaHCO3 (1 mL). The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL), brine (5 mL), dried (MgSO4) and then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with 2 to 10% MeOH in DCM to afford (5S)-3-(3,3-dimethylbutyl)-2-(2-(1-isobutylpiperidin-4-yl)thiazol-5-yl)-5-(2-oxo-2-(4-(2-oxo-4,5-dihydro-1H-benzo[d][1,3]diazepin-3(2H)-yl)piperidin-1-yl)ethyl)thiazolidin-4-one (23 mg, 79% yield). (M+1) 695. 1H NMR (CDCl3) δ 7.70 (m, 3H), 6.90 (t, J=7.2 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 6.49 (NH, 1H), 5.65 (m, 1H), 4.74 (m, 1H), 4.44 (m, 1H), 3.93 (m, 1H), 3.65 (m, 1H), 3.45-3.35 (m, 3H), 3.17-2.59 (m, 9H), 2.09-1.41 (m, 15H), 1.35 (m, 1H), 1.00-0.85 (m, 15H) ppm.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:16][C@@H:15]([CH:17](C(=O)C)[OH:18])[C@:13](C(=O)C)([OH:14])[C@:11]2(C(=O)C)[OH:12])[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:16][C@@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@@H:11]2[OH:12])[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C(O)[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)c(Cl)c(Cl)cc32)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
2-(Isopropylamino)-4,5,6-trichloro-1-(2,3,5-triacetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.00 g, 1.86 mmol), sodium carbonate (0.26 g, 2.45 mmol), water (4 mL), methanol (6 mL) and ethanol (8 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.57 g (75%) of a white powder; m.p. 223-224° C. Anal. Calcd. for C15H18Cl3N3O4: C, 43.87; H, 4.42; N, 10.23. Found. C, 43.63; H, 4.55; N, 9.98.
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:32]=[CH:31][C:25](/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([C:28](=[O:29])/[CH:27]=[CH:26]/[C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:33])([F:34])[F:19])=[CH:32][CH:31]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: O=C(Cl)/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)SC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SC1CCN(C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)CC1
Yield: 95.2 %

Procedure:
In 17 ml of dichloromethane were suspended 1.28 g (6.53 mmol) of 4-(acetylthio)piperidine hydrochloride, and 2.27 ml (16.3 mmol) of triethylamine were added dropwise to the suspension with stirring under ice-cooling. Then, a solution in which 1.80 g (7.18 mmol) of (E)-4-(trifluoromethoxy)cinnamoyl chloride were dissolved in 6 ml of dichloromethane was added dropwise to the reaction mixture, followed by stirring of the mixture at the same temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography and eluted with a mixed solvent of hexane-ethyl acetate (2:1 to 1:1) to obtain 2.32 g (yield: 95%) of the desired compound as a slightly yellow solid.