Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=2.[CH2:15]([O:17]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:15]=[O:17])=[CH:8][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=2
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: CCCOc1ccc2[nH]c(C)cc2c1
Product: CCCOc1ccc2[nH]c(C)c(C=O)c2c1
Reaction time: 1 h

Procedure:
This compound was prepared from 408b (263 mg, 1.39 mmol) in a manner similar to that for 409a except for after the drop-wise addition of substituted indole, the solution was stirred for 1 h. A cream-colored powder was obtained (228 mg, 75%): mp 156-158° C. TLC Rf 0.52 (75% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.85 (s, 1H), 10.00 (s, 1H), 7.55 (d, 1H, J=2.46 Hz), 7.27-7.25 (d, 1H, J=8.7 Hz), 6.79-6.77 (dd, 1H, J1=8.7 Hz, J2=2.52 Hz), 3.92-3.90 (t, 2H, J=6.54 Hz), 2.64 (s, 3H), 1.77-1.71 (sex, 2H, J=7.38 Hz), 1.00-0.98 (t, 3H, J=7.38 Hz). NMR (150 MHz, d6-DMSO) δ 184.0, 154.9, 148.5, 130.0, 126.4, 113.6, 112.26, 112.04, 103.2, 69.3, 22.2, 11.5, 10.5. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.74; H, 6.81; N, 6.42.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)NC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
TFA (0.3 mL, 4.03 mmol) was added to a solution of 1-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-cyclopentylurea (6 mg, 0.013 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (4 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.36 (s, 1H), 7.81 (m, 2H), 7.60 (d, 1H, J=8.8 Hz), 7.46 (m, 3H), 4.11 (t, 1H, J=6.4 Hz), 2.00 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.51 (m, 2H); ESI-MS [M+H]+: 361.3.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:15])[NH:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:5]1=[O:16])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27](OCC)(=[O:33])[C:28](OCC)=[O:29]>CN(C=O)C.C1COCC1>[OH:33][C:27]1[C:28](=[O:29])[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[N:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:16])[C:6]=12
Reactant: C=CCN1CCN(C(=O)NC(C)C)CC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(2-propenyl)-4-(N-2-propylcarbamoyl)-2-piperazinone (8.0 g, 35 mmol) in DMF (80 mL) at 0° C. was added lithium bis(trimethylsily)amide (40 mL of a 1.0 M solution in THF, 40 mmol). Diethyl oxalate (5.84 g, 40 mmol) was added and the mixture was stirred for 1 h at 0° C. More lithium bis(trimethylsily)amide was added (35 mL of a 1.0 M solution in THF, 35 mmol) and the mixture was stirred for 1 h at 0° C., and then at ambient temperature for 18 h. The reaction was quenched by the addition of 0.5 N aqueous HCl to pH 3 and the solvents were removed in vacuo. The residue was vigorously stirred in methanol-water, and the precipitate was collected by filtration and dried in vacuo to give the title compound. HPLC RT=2.72 min (Method A); ES MS (M+H)=280; 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 5.80 (ddt, 1H), 5.29 (d, J=17 Hz, 1H), 5.22 (d, J=10 Hz, 1H), 5.05 (septet, J=7 Hz, 1H), 4.10 (d, J=7 Hz, 2H), 3.94 (t, J=7 Hz), 3.58 (t, J=7 Hz, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:38]4[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2cccc(F)c2)OC1=O
Reactant: Cn1ccc(I)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2cccc(F)c2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 23 Step 9. LC-MS Method 2 tR=1.57 min, m/z=501, 479, 421.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[O:10][N:9]=1)(=[O:3])[CH3:2].[I:27]N1C(=O)CCC1=O>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:27])=[C:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)on1
Solvent: C1CCOC1
Product: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-3-isoxazolyl]oxy}ethyl acetate (Preparation 24) (1.17 g) in tetrahydrofuran (10 ml) was added N-iodosuccinimide (0.76 g). The reaction mixture was left stirring at room temperature overnight. The solvent was removed in vacuo to yield the crude material as a brown oil (1.5 g). The crude material was purified using the Biotage™ Flash 40i system (silica, 90 g) and eluted with hexane:ethyl acetate (1:9) to yield the product as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:37]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(Cl)Cl.[N-:19]=[N+:20]=[N-:21].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:10])=[N:21][N:20]=[N:19]2)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g, 8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride (5 mL) to obtain a clear solution at 25° C. The resulting solution was treated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixture was then cooled to 0° C. The reaction mixture was then treated with trifluoromethanesulfonic anhydride (3.59 g, 12.7 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%) as a white solid: EI-HRMS m/e calcd for C9H6BrF3N4 (M+) 305.9728, found 305.9733.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=[O:12])([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[NH2:14][C@H:15](C(O)=O)[CH2:16][CH2:17][C:18](O)=O>>[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:10]([N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: NCCCCC(C(=O)O)N(CC(=O)O)CC(=O)O

Procedure:
Compound 11 is prepared using a procedure analogous to the procedure of Example 5 for the preparation of Compound 7, except that glutamic acid is used instead of N-(5-amino-1-carboxypentyl)iminodiacetic acid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]4C[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:25])[NH:4][CH2:3]1.[OH:26][C@@H]1CCNC1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[OH:26][C@@H:21]1[CH2:22][CH2:23][N:19]([CH2:18][CH2:17][CH2:16][O:15][C:11]2[CH:10]=[CH:9][C:8]3[N:7]4[C@H:2]([CH3:1])[CH2:3][NH:4][C:5](=[O:25])[C:6]4=[CH:14][C:13]=3[CH:12]=2)[CH2:20]1
Reactant: O[C@@H]1CCNC1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(OCCCN4CCCCC4)ccc3n21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C[C@@H]1CNC(=O)c2cc3cc(OCCCN4CC[C@@H](O)C4)ccc3n21
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to example 2 from (R)-8-(3-chloro-propoxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 9, intermediate), (R)-3-hydroxy-pyrrolidine (commercially available), potassium carbonate and potassium iodide, to give the desired product as a light brown foam (39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[CH2:20]([O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27](F)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[CH3:21].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][C:7](=[O:15])[CH:8]([C:27]1[CH:28]=[CH:29][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:34])=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32])[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)CC(=O)NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C(C(=O)NCc2ccc(F)c(F)c2)C(=O)C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-4,4-dimethyl-3-oxopentanamide (Compound 112, 126 mg, 0.47 mmol) and ethyl4-fluoro-3-nitrobenzoate (Compound 113, 100 mg, 0.47 mmol) in DMSO (1 ml) was added K2CO3 (130 mg, 0.94 mmol). The mixture was stirred at room temperature for 16 h, diluted with EtOAc, washed with 1 M HCl, H2O, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17]CC)=[O:16])=[O:8])=[O:4].[Li+].[OH-]>CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8])=[O:4]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)O)C(C)C
Yield: 56 %

Procedure:
(2S,5 S)-Ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (39.3 mmol, assuming complete conversion from the previous transformation) was suspended in MeOH (200 mL) and aqueous LiOH (1.0 M, 100 mL, 100 mmol) was added. The reaction mixture was stirred o/n, then concentrated under reduced pressure to remove most of the MeOH. The aqueous solution was washed 2× with DCM before being acidified to pH˜1-2 with 10% HCl. The acidic aqueous phase was then extracted 5× with EtOAc. The combined EtOAc extracts were dried over MgSO4 filtered and concentrated under reduced pressure to afford (2S,5S)-1-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid (6.89 g, 56% over 2 steps).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:14]([CH2:13][CH2:12][NH:11][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])([OH:16])=[O:15]
Reactant: NCCC(=O)O
Reactant: CC(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(Cc1ccccc1)NCCC(=O)O
Reaction time: 18 h
Yield: 60.2 %

Procedure:
Phenylacetone (100 mg, 0.745 mmol) was dissolved in anhydrous methanol (2.0 ml). Beta-alanine (398 mg, 4.47 mmol) was added, followed by sodium cyanoborohydride (94 mg, 1.49 mmol). After 18 hours of stirring under nitrogen, the reaction mixture was filtered, and the filtrate solvent was removed in vacuo. The resulting crude material was purified on four 1.0 millimeter C18 reverse-phase preparative thin layer chromatography plates eluted with H2O/methanol/acetic acid (40/60/0.4). The material obtained was dissolved in ethyl acetate (20 ml) and was extracted with 1.0M sodium bicarbonate (3×20 ml). The aqueous extracts were combined, the pH was adjusted to 4 with 1.0M hydrochloric acid, and the solvent was removed in vacuo. The resulting crystalline solid was then triturated twice with 50-milliliter portions of ethyl acetate and filtered. The filtrates were combined, and the solvent was removed in vacuo to yield 93 milligrams of N-carboxyethyl-amphetamine.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Na].[C:11]([C:14]1[N:15]2[CH:18]([S:19][CH2:20][C:21]=1[CH2:22][S:23][C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1)[CH:17]([NH:30][C:31](=[O:39])[CH2:32][C:33]1[S:34][C:35](=[O:38])[S:36][CH:37]=1)[C:16]2=[O:40])([OH:13])=[O:12]>CN(C)C=O>[CH3:29][N:28]1[C:24]([S:23][CH2:22][C:21]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:40])[CH:17]3[NH:30][C:31](=[O:39])[CH2:32][C:33]3[S:34][C:35](=[O:38])[S:36][CH:37]=3)[C:14]=2[C:11]([O:13][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:12])=[N:25][N:26]=[N:27]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Temperature: 5 °C
Yield: 30.7 %

Procedure:
A solution of iodomethyl pivalate (8.65 g.) in dimethylformamide (70 cc.) is added to a solution of the sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (18.2 g.) in dimethylformamide (115 cc.) over the course of 15 minutes, whilst maintaining the temperature at 5° C. The mixture is allowed to react for one hour at 5° C. and is then concentrated to dryness under reduced pressure (0.5 mm Hg). The residue is taken up in ethyl acetate (500 cc.). The mixture is washed successively with water (600 cc.), a saturated aqueous sodium bicarbonate solution (500 cc.) and water (900 cc.). It is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is chromatographed on silica (450 g.), elution being carried out successively with a mixture of cyclohexane and ethyl acetate (6/4 by volume) (1 liter) and then with a mixture of cyclohexane and ethyl acetate (4/6 by volume) (4 liters). The eluates are concentrated to dryness under reduced pressure (20 mm Hg). A residue (12.7 g.) is obtained in the form of a frothy solid which is crystallised from a mixture of ethyl acetate and ether (1/1 by volume) (120 cc.). A white crystalline product (7.4 g.) is obtained, which when dried at 30° C. under 0.5 mm Hg retains about 3% of ethyl acetate. The product is treated overnight with water (250 cc.) while stirring and the crystals are filtered off and then dried (35° C.-0.5 mm Hg). 3-[(1-Methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-2-pivaloyloxymethoxycarbonyl-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (6.6 g.), m.p. 100° C. is thus obtained. [α]D20 = -21.6° ± 0.8° (c= 1, dimethylformamide).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1.CS(C)=O.[H-].[Na+].Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[CH2:19][CH2:18]1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1coc(Cn2c(NC3CCN(CCOc4nccs4)CC3)nc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5.1 parts of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineethanol and 100 parts of dimethyl sulfoxide were added portionwise 0.9 parts of a sodium hydride dispersion 50%. After stirring for 1 hour at room temperature, 2.5 parts of 2-bromothiazole were added dropwise. Upon completion, stirring was continued overnight at room temperature. Water was added and the product was extracted twice with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was taken up in 4-methyl-2-pentanone. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methylbenzene, yielding 0.3 parts of 1-(2-furanylmethyl)-N-[1-[2-(2-thiazolyloxy)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 136.4° C. (compound 71).
Reaction SMILES: [C:1]([NH+:9]([O-:11])[NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](O)(=[O:14])[CH3:13].C(OC(=O)C)(=O)C>C(OCC)C>[C:12]([N+:9]([O-:11])([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[NH2:10])(=[O:14])[CH3:13]
Reactant: N[NH+]([O-])C(=O)c1cccnc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)[N+](N)([O-])C(=O)c1cccnc1
Reaction time: 1 h

Procedure:
A mixture of nicotinoyl hydrazine-N-oxide (25.3 g; 0.166 m), acetic acid (85 ml) and acetic anhydride (16.9 g; 0.166 m) was heated at reflux. After one hour, the reaction mixture was cooled and poured into diethylether to yield 32 g of N-acetylnicotinoylhydrazine N-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:22]([F:25])([F:24])[F:23])=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:26]([O-])=O)[CH:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:26][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:22]([F:24])([F:25])[F:23])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 98.4 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-chloro-2-nitro-N-(5-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 254) (370 mg, 0.86 mmol), SnCl2 (967 mg, 5.15 mmol), conc.HCl (4-5 drops) and EtOH (15 ml) gave the title compound (340 mg, 98%) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=O.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[N:18][OH:19]
Reactant: COc1ccccc1C(=O)c1sccc1Br
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=NO)c1sccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 20 g of (3-bromothien-2-yl) (2-methoxyphenyl)methanone in 200 g of pyridine containing 10 g of hydroxylamine hydrochloride was heated at 100° for 10 minutes and thereafter allowed to cool. After standing at room temperature for 16 hours, the solution was poured onto 600 g of ice water and the organics were extracted into ether. The combined ether solution was washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under vacuum left a solid residue which was recrystallized from ether/hexane to give prisms, m.p. 129°-130° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][C:20]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33][N:34]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:28]=2)=[N:21][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[CH3:26][O:25][C:23]([C:22]1[N:21]=[C:20]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33][N:34]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:28]=2)[CH:19]=[CH:18][C:17]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1O
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (1.93 g, 6.86 mmol) was added dropwise to tert-butyl 7-(5-hydroxy-6-(methoxycarbonyl)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29D) (2.40 g, 6.23 mmol) and TEA (0.95 g, 9.35 mmol) in anhydrous DCM (25 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hours, diluted with DCM, washed with 10% citric acid, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 88:12-82:18 to provide tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E): 1H NMR (300 MHz, CDCl3) δ 8.40 (1H d), 7.95 (1H, d), 7.71 (1H, d), 7.66 (1H, dd), 7.19 (1H, d), 4.04 (3H, s), 3.75 (2H, m), 2.82 (2H, t), 1.96 (2H, m), 1.56 (9H, s).