Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[CH3:15][C:16]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1.Cl>C(=S)=S>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[O:20][C:16]=1[CH3:15])=[O:13]
Reactant: O=C(Cl)CCCCCBr
Reactant: Cc1cc2ccccc2o1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: Cc1oc2ccccc2c1C(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Tin tetrachloride (1.15 ml) was added to a solution of 6-bromohexanoyl chloride (2 g) and 2-methylbenzo[b]furan (1.24 g) in carbon disulfide (30 ml) under ice-cooling, the mixture was stirred at room temperature for 3 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2.2 g of 6-bromo-1-(2-methyl-3-benzo[b]furyl)-1-hexanone.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[O:20])[CH2:15][CH2:14]1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl>[Fe].C(O)(C)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:11]3[CH:30]=[CH:31][CH:32]=[C:9]([C:3]([OH:8])([C:2]([F:34])([F:33])[F:1])[C:4]([F:5])([F:6])[F:7])[CH:10]=3)[CH2:14][CH2:15]2)=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(Cc2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)CC1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(O)(C(F)(F)F)C(F)(F)F)c3)CC2)cc1
Yield: 76.7 %

Procedure:
(4-(3-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)(4-nitrophenyl)methanone (180 mg, 0.37 mmol), iron powder (205 mg, 3.66 mmol), 1 M hydrochloric acid (549 μL, 0.55 mmol) and isopropanol (10 mL) were stirred together, at ambient temperature, for 2 hours before being filtered and concentrated under vacuum. The residue was treated with strong cation exchange column chromatography and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol/dichloromethane). The product was recrystallised from benzonitrile to afford the title compound (131 mg). MS (ESI) m/z 462.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([CH3:12])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1ccc(Br)c(C=O)c1
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: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C)c(C=O)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a degassed solution of 2-bromo-5-methoxybenzaldehyde (1.5 g, 7.04 mmol, Fluorochem) and trimethylboroxine (0.98 mL, 7.04 mmol) in 1,4-dioxane (80 mL) was added potassium carbonate (2.91 g, 21.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.813 g, 0.70 mmol). The mixture was heated under reflux for about 20 h, then more tetrakis(triphenylphosphine)palladium(0) (0.200 g, 0.17 mmol) and trimethylboroxine (0.25 mL, 1.8 mmol) were added and the mixture was heated under reflux for about another 3 h. After cooling to rt the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:3) to give 5-methoxy-2-methyl-benzaldehyde (0.97 g, 92%) as a colorless liquid. 1H-NMR (CDCl3, Bruker 400 MHz) 2.60 (3 H, s); 3.83 (3 H, s); 7.04 (1 H, dd, J=8.5 Hz, 2.4 Hz); 7.16 (1 H, d, J=8.5 Hz); 7.33 (1 H, d, J=2.4 Hz); 10.2 (1 H, s).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OC(=O)[NH:15][C@@H:16]1[CH2:20][CH2:19][N:18](C2C(C(F)(F)F)=CC=CN=2)[CH2:17]1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[Cl:8][C:7]1[C:2]([N:18]2[CH2:19][CH2:20][C@@H:16]([NH2:15])[CH2:17]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Reactant: Clc1cccnc1Cl
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: N[C@@H]1CCN(c2ncccc2Cl)C1

Procedure:
The title compound was prepared from 2,3-dichloropyridine and 3R-(+)-3-(tert-butyloxycarbonylamino)pyrrolidine using the procedure outlined for Descriptions D1 and D2.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([Li])CCC.[C:16]1(=[O:40])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:32]=2)[CH2:27]1.Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].[Cl-].[NH4+]>O1CCCC1>[C:16]1(=[O:40])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:35](=[O:39])[C:36]([CH3:37])([CH3:38])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:32]=2)[CH2:27]1
Reactant: CC(C)C(=O)c1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)C(=O)c1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
Lithium bis(trimethylsilyl)amide prepared from 1.78 g of 1,1,1,3,3,3-hexamethylsilazane and n-butyl lithium (6.9 ml of 1.6M hexane solution), dissolved in 50 ml of tetrahydrofuran was cooled to -40° C., and 3.30 g of 2-(1,3-isoindolinedion-2-yl)-5-(2-methylpropionyl)indane dissolved in 50 ml of tetrahydrofuran was added dropwise thereto over 15 minutes. The mixture was stirred at 0° C. for 20 minutes and cooled to -30° C. To the mixture was added dropwise 1.68 g of methyl bromoacetate dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added a saturated ammonium chloride solution, the mixture was extracted with ethyl acetate, the extract was dried, and then the solvent was removed. The residue was purified by silica gel column chromatography (eluted by n-hexane:ethyl acetate =4:1). The resulting crystals were recrystallized from ethyl acetate-n-hexane to obtain 2.06 g of 2-(1,3-isoindolinedion-2-yl)-5-(2,2-dimethyl-3-methoxycarbonyl-propionyl)indane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](=[S:33])[NH:24][C@H:25]([CH:30]([CH3:32])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](=[S:33])[NH:24][C@H:25]([CH:30]([CH3:31])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[O:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(N)cc2)no1)C(C)C
Product: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(C)C
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carbothioamido)-3-methylbutanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 65% of the title compound. MS (ESI): m/z 471(M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 10.935 (s, 1H), 9.355 (s, 1H), 8.640 (s, 1H), 8.161 (s, 1H), 7.891 (s, 2H), 7.634 (d, 3H), 7.256 (s, 1H), 7.162 (s, 1H), 7.038 (s, 1H), 4.835 (s, 1H), 3.689 (s, 3H), 2.507 (s, 1H), 1.049 (d, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1>O1CCOCC1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCc1ccc(N)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-(1H)-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and IN NaOH at 0° C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 hr then at room temperature for an additional hour. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi-solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium bicarbonate (12 ml) and cooled to 0° C. Benzyl chloroformate(1.5 ml, 10.5 mmol) was once again added and after stirring for 30 min, thereaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave 2.64 g of the title compound as a white powder: 1H NMR (CDCl3) δ0.96 (t, J=7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J=7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H),8.05 (brd,J=5.3Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11]Cl>C(O)(=O)C>[Cl:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([Br:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: ClCl
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CC(=O)O
Product: O=Cc1cc(Br)cc(Cl)c1O

Procedure:
Scheme II illustrates methodology useful for preparing the ethyl N-gly-amino-3-(3,5-dihalo-2-hydroxy)phenyl propionate portion which can be coupled to the tetrahydropyrimidinobenzoic acid moiety. Briefly, 3,5-halo substituted salicylaldehydes may be prepared by direct halogenation as, for example, would be the case where 5-bromosalicylaldehyde is slurried in acetic acid and an equivalent or more of chlorine is added to yield 3-chloro-5-bromo-2-hydroxybenzaldehyde. Some product precipitates and can be recovered by filtration. The remainder may be recovered by diluting the filtrate with water and isolating the precipitate. Combining the solids and drying gives 3-chloro-5-bromo-2-hydroxybenzaldehyde. 3-iodo-5-chlorosalicylaldehyde may be prepared by reacting 5-chlorosalicylaldehyde with N-iodosuccinimide in DMF and subjecting the reaction mixture to usual work-up conditions. 3-iodo-5-bromosalicylaldehyde may be prepared by reacting 5-bromosalicylaldehyde in acetonitrile with potassium iodide and chloramine T. Work-up gives a material that when treated with hexanes gives the desired 3-iodo-5-chlorosalicylaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[C:18]([CH2:21]O)[N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:23]([NH2:25])=[O:24])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[C:18]([CH2:21][S:31]([CH3:30])(=[O:33])=[O:32])[N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:23]([NH2:25])=[O:24])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccccc1COc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CS(C)(=O)=O)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 49 (step 1), 210 mg of 3-[(2-ethylbenzyl)oxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 112 mg of methanesulfonyl chloride, and 104 mg of triethylamine in 5 ml DMF give 3-[(2-ethylbenzyl)oxy]-5-{6-[(methylsulfonyl)methyl]-1H-imidazo[4,5-c]pyridin-1-yl}thiophene-2-carboxamid as crude material that is used for step 2 without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccnc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cncc(-c2cccc3c2OCCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
A mixture of tert-butyl 9-(pyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (190 mg, 0.582 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (109 mg, 62.6%) as a solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[N:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[BH4-].[Na+].O>C(O)C>[C@@H:1]1([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC1=NC(=O)N([C@H]2C[C@H](O)[C@@H](CO)O2)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
Method A (Reduction of 2). To a suspension of 2′-deoxy-5-azacytidine (2) (0.045 g, 0.2 mmol) in 96% ethanol (2.9 mL) was added NaBH4 (40 mg, 1.06 mmol), and the mixture was stirred for 10 min at RT. Water (4 mL) was added to the mixture giving a clear solution that was directly used for RP HPLC purification using a gradient of MeCN in 0.1 M triethylammonium bicarbonate buffer. The main fraction after evaporation provided 0.04 g of 9 as a solid. MS ES+231 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][OH:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:44](O)(=[O:46])[CH3:45]>O1CCCC1>[C:44]([O:27][CH2:26][C:10]1[C:11]2[C:12](=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:28])(=[O:46])[CH3:45]
Reactant: CC(=O)O
Reactant: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 55 %

Procedure:
0.1 g (0.26 mmol) of 1-benzyl-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 0.164 g (0.8 mmol) of dicyclohexylcarbodiimide and 0.046 ml (0.8 mmol) of glacial acetic acid are reacted in 5 ml of anhydrous tetrahydrofuran as described for Example 7a. Yield: 55%, m.p.: 109°-110° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)([Cl:18])=O>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(Cl)c1ccccc1-c1ccccc1

Procedure:
A mixture of 5.6 g of 2-biphenylcarboxylic acid and 29 ml of thionyl chloride is heated on a steam bath for 0.5 hour and the volatiles removed under vacuum. Toluene (40 ml) is added (twice) and the solvent removed under vacuum to give 6.8 g of a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5](=[NH:7])[SH:6])(=[O:3])[CH3:2].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.N1C=CC=CC=1>CC(C)=O>[Cl:8][CH2:9][C:10]1[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:11]=1
Reactant: CC(=O)NC(=N)S
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
N-(4-(chloromethyl)thiazol-2-yl)acetamide was prepared following a literature procedure (Silberg, A.; Frenkel, Z.; Bull. Soc. Chim. Fr.; 1967; 2235-2238). A suspension of 1-acetylisothiourea (3.55 g, 0.03 mol), 1,3-dichloropropan-2-one (3.8 g, 0.03 mol) and pyridine (1.96 g, 2 ml, 0.025 mol) in acetone (10 ml) was heated at 100 C in an oil bath for 20 minutes. A flocculent white solid formed. After cooling to room temperature, the reaction mixture was filtered to collect the white solid. The filtrate was evaporated, and the resulting residue was taken into water resulted in a white suspension which was stirred for a couple of minutes. The suspension was filtered. The collected solid was washed with water, dried under vacuum and combined with the above-mentioned white solid to give 2.89 g (51% yield) of N-(4-(chloromethyl)thiazol-2-yl)acetamide. LC/MS m/z 191.05, 193.05 (M+H)+); HPLC Rt: 1.71 min.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C:11]2[C:12]([OH:27])=[N:13][C:14]([C:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[O:19][N:18]=3)=[N:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O>[C:28]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([NH:10][C:11]2[C:12]([OH:27])=[N:13][C:14]([C:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[O:19][N:18]=3)=[N:15][CH:16]=2)=[O:9])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc(-c2ncc(NC(=O)C(c3ccccc3)c3ccccc3)c(O)n2)no1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2ncc(NC(=O)C(c3ccccc3)c3ccccc3)c(O)n2)no1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a suspension of compound 3-2 (60 mg, 0.135 mmol) in H2O (100 mL) was added KOH (75 mg, 1.35 mmol) and stirred at 50° C. for 30 min. The reaction mixture was extracted with EA (20 mL). The aqueous layer was adjusted to pH 3 by addition of HCl. The solids were filtered to afford compound 3-3 as a white solid (40 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ 13.61 (br s, 1H), 10.02 (s, 1H), 8.99 (s, 1H), 7.35-7.26 (m, 12H), 5.76 (s, 1H). LC-MS: (M+H)+ 417.
Reaction SMILES: [CH2:1]([P:3](Cl)([CH2:5][CH3:6])=[O:4])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:17][O:18][C:19]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:20]=1[CH2:21][N:22]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:23]([C:25]1[C:26](=[O:37])[N:27]([CH3:36])[C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:20]=1[CH2:21][N:22]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:23]([C:25]1[C:26](=[O:37])[N:27]([CH3:36])[C:28]2[C:33]([C:34]=1[O:35][P:3]([CH2:5][CH3:6])([CH2:1][CH3:2])=[O:4])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24]
Reactant: CCP(=O)(Cl)CC
Reactant: COc1ccc(CN(C(=O)c2c(O)c3ccccc3n(C)c2=O)c2ccccc2)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCP(=O)(CC)Oc1c(C(=O)N(Cc2ccc(OC)cc2OC)c2ccccc2)c(=O)n(C)c2ccccc12
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
Diethylphosphorylchloride (150 mg, 0.87 mmol) was added to a solution of EtNiPr2 (129 mg, 1.00 mmol), DMAP (10 mg, 0.08 mmol) and N-(2,4-dimethoxybenzyl)-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (222 mg, 050 mmol) in CH2Cl2 (3.0 mL). The reaction mixture was stirred for 30 min and was then concentrated at reduced pressure. The residue was purified by silica column chromatography (EtOAc) to give the title compound (196 mg, 68%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13].[CH3:18][O:19][C:20]1[C:21]([N+:32]([O-:34])=[O:33])=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=[O:24]>O1CCCC1>[OH:24][CH:23]([C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[C:21]=1[N+:32]([O-:34])=[O:33])[C:13]#[C:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C#CC(=O)OCC
Reactant: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Temperature: -58 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A 1.0 M solution (1.9 ml) of lithium bistrimethylsilylamide in tetrahydrofuran was added to tetrahydrofuran (4.0 ml) at -78° C. under an argon atmosphere, and the mixture was stirred for 30 min. A solution of ethyl propiolate (176 μl, 1.74 mmol) in tetrahydrofuran (1.0 ml) was added thereto, and the mixture was stirred for 30 min. A solution of 3,4,5-trimethoxy-2-nitrobenzaldehyde (280 mg, 1.16 mmol), prepared in the step (b), in tetrahydrofuran (2.5 ml) was added thereto, and the temperature was raised to -58° C., followed by stirring for 30 min. The reaction mixture was poured into an ice-cold 10% aqueous ammonium chloride solution, and the mixture was vigorously stirred for 5 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(3,4,5-trimethoxy-2-nitrophenyl)-2-butynoate as an oil (268 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:6][C:7]1([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.CC(C)=O.O.C(OCC)(=O)C>O1CCCC1.B>[OH:13][CH2:12][C:7]1([CH2:6][C:5]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(CC2(C(=O)O)CCCC2)cc1OC
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CC2(CO)CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
1.50 g of 1-[3-methoxy-4-(methoxycarbonyl)-benzyl]cyclopentanecarboxylic acid was dissolved in 15 mL of tetrahydrofuran, to which 10.3 mL of a 1M solution of borane in tetrahydrofuran was added dropwise at 5 to 10° C., and then this mixture was stirred for one hour at room temperature. Then, acetone and water were successively added dropwise to the reaction mixture, which was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to yield 0.564 g of methyl 4-{[1-(hydroxymethyl) cyclopentyl]methyl}-2-methoxybenzoate as colorless oil.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:34]([O:36]C)=[O:35])[CH2:21][C:22]3[CH:32]=[C:31]([CH3:33])[C:25]4[NH:26][C:27]([O:29][CH3:30])=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:34]([OH:36])=[O:35])[CH2:21][C:22]3[CH:32]=[C:31]([CH3:33])[C:25]4[NH:26][C:27]([O:29][CH3:30])=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (4.18 mmol) LiOH in 6 mL water was added to a solution of 980 mg (1.83 mmol) (R)-1-methoxycarbonyl-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 18 mL THF and the reaction mixture was stirred overnight at RT. 1.05 mL of 4 M HCl was added, the THF was evaporated down i.vac., whereby the crude product was produced in the form of an oil. The water was decanted off, the residue was dissolved in DCM/MeOH and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.