Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1
Reactant: BrCCOC1CCCCO1
Reactant: Fc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc2cnn(CCOC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-fluoro-1H-indazole (2.0 g, 14.7 mmol), and 2-(2-bromo-ethoxy)-tetrahydro-pyran (3.38 g, 16.2 mmol) in DMF (25 mL) was treated with caesium carbonate (6.1 g, 18.7 mmol) and stirred at RT for 18 h. The solvent volume was reduced in vacuo, and the residue partitioned between EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted into EtOAc (3×). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-50% cyclohexane in EtOAc, to afford the title product and a yellow oil. LCMS (Method 1): Rt 3.42 min, m/z 181 [MH+] (M-THP). 1H NMR (300 MHz; CDCl3) 1.52-1.56 (6H, m), 3.39-3.49 (1H, m), 3.57-3.68 (1H, m), 3.89-3.91 (1H, m), 4.19-4.21 (1H, m), 4.56-4.57 (3H, m), 6.88 (1H, td, J 9.15 and 2.26), 7.30 (1H, m), 7.62 (1H, m), 8.04 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH:9](OC)(OC)OC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9]
Reactant: COC(OC)OC
Reactant: Nc1cnccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-pyridin-3-ylamine (2 g, 11.56 mmol, CAS RN 239137-39-4) in trimethyl orthoformate (19 mL, 173.4 mmol, CAS RN 149-73-5) and a catalytic amount of TFA (1 drop) was heated to reflux for 2 hours. Volatiles were removed in vacuo, the resultant dark brown material was dissolved in THF (40 mL), treated portionwise with LiAlH4 (440 mg, 11.56 mmol) at 0° C. and then left stirring at 0° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL), filtered through a bed of celite, and the residue further washed with EtOAc (30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated off in vacuo. The residue was purified by column chromatography over alumina (10% EtOAc in n-hexane) to afford the title compound. Light yellow oil (875 mg, 40%). MS (ESI): m/z=187.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[O:14]>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:13]([C:12]2[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])[OH:14])=[CH:7][N:6]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: Clc1ncc(Br)c(Cl)n1
Product: OC(c1cnc(Cl)nc1Cl)c1c(F)cccc1F
Yield: 88 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and 2,6-difluorobenzaldehyde (Aldrich) in 88% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.35 (m, 1H, 7.92 (m, 2H), 6.35 (s, 1H), 2.67 (br. s, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH3:19][O:20][C:21](=[O:38])[C@@H:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:38])[C@@H:22]1[CH2:26][C@@H:25]([O:27][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:24][N:23]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
37.5 ml (270 mmol) of triethylamine, 49.04 g (257 mmol) of p-toluenesulfonyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine were added in turn to a solution of 77.70 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-4-hydroxyproline methyl ester in 600 ml of methylene chloride, and the resulting mixture was then stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 106.18 g (quantitative yield) of (2S,4R)-1-benzyloxycarbonyl-4-(p-toluenesulfonyloxy)proline methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]([CH2:33][CH2:34][O:35][CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]([CH2:33][CH2:34][O:35][CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[CH:19][CH:18]=3)[S:10][C:3]=12
Reactant: COCCN(CCc1ccc(Br)nc1)C(=O)OC(C)(C)C
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCN(CCc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (4.26 g, 25.09 mmol) in THF (64 mL) at −15° C. was added n-BuLi (10.77 mL, 25.09 mmol). After 30 min, ZincCl2 (3.42 g, 25.09 mmol) was added at −15° C. and the reaction mixture was allowed to warm to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.387 g, 0.335 mmol) and bromide 285 (6.01 g, 16.73 mmol) in THF (20 mL) was added and the mixture was heated to reflux for 1 h and concentrated. The reaction was quenched by addition of water and ammonium hydroxide and the mixture was extracted with DCM. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; AcOEt/Hex:50/50 to 100/0 over 20 CV), to afford title compound 286 (3.74 g, 8.35 mmol, 50% yield) as yellow oil. MS (m/z): 448.48 (M+H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[N:32][N:33]=2)[N:30]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([N:31]=[N:32][N:33]=4)[N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1ccc2nnnn2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nnnn4n3)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.12 h
Yield: 65.5 %

Procedure:
2.72 g of 7-aminocephalosporanic acid was suspended in 16 ml of water and 8 ml of acetone, and a suspension of 2.1 g of sodium bicarbonate in 16 ml of water was dropwise added thereto over a period of 7 minutes time. The inside temperature of a reactor was then increased to 50° C., and a suspension of 2.3 g of 6-mercaptotetrazolo[4,5-b]pyridazine in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 6 hours at a stable inside temperature of reactor of 61° C. followed by allowing the refluxed mixture to stand. The pH of the solution was 8 and thereafter, the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid under ice cooling, in which the pH was measured by means of a pH meter and then stirred for 1 hour. The precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.39 g of the titled compound having a melting point (decomposition) of 202° to 205° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8](N(OC)C)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Reactant: CON(C)C(=O)c1ncccc1F
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1ncccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-fluoro-N-methoxy-N-methylpyridine-2-carboxamide (4.8 g) in THF (100 mL) was added dropwise [4-(benzyloxy)phenyl]magnesium bromide (1 M solution in THF, 27.4 mL) at 0° C. After stirring at 0° C. for 2 h, the mixture was warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (3.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH2:21][NH:22][CH3:23].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]([CH3:23])[CH2:21][C:13]1[N:12]([CH3:11])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:5]
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
A solution of 2-bromobenzoyl chloride (1.85 g, 8.45 mmole) in CH2Cl2 (10 mL) was added dropwise to a solution of 1-methyl-2-(methylaminomethyl)indole (1.47 g, 8.45 mmole) and Et3N (3.6 mL, 25.8 mmole) in CH2Cl2 (50 mL) at 0° C. The reaction was stirred at 0° C. for 15 min, then was allowed to warm to RT. After 2 hr, the mixture was concentrated in vacuo, and the residue was diluted with H2O. The mixture was extracted with Et2O, and the combined Et2O layers were dried (MgSO4) and concentrated in vacuo. The oily residue was triturated with Et2O/petroleum ether to afford the title compound (2.6 g, 87%) as a white solid: MS (ES) m/e 357 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>C1COCC1>[CH2:11]([O:18][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccccc2)c(Br)c1
Yield: 90 %

Procedure:
3-Bromo-4-flurobenzonitrile (3.00 g, 15 mmol), benzyl alcohol (1.71 ml, 16.5 mmol) and THF (40 ml) are combined and treated with 60% sodium hydride in oil (0.66 g, 16.5 mmol). The reaction mixture is heated to reflux under nitrogen for 3 hours. Aqueous workup and chromatographic purification (cyclohexane:dichloromethane, 3:1) yields 4-benzyloxy-3-bromobenzonitrile as a white solid (3.88 g, 13.5 mmol). A portion of this material (2.64 g, 9.16 mmol) in THF (25 ml) is treated with a 1 M solution of borane in THF (18.3 ml, 18.3 mmol). After the exotherm subsides the reaction is refluxed a couple of days under nitrogen. The excess borane is destroyed by the addition of methanol and 4-benzyloxy-3-bromobenzylamine is precipitated as the hydrochloride salt (1.58 g, 4.8 mmol). This material is suspended in dichloromethane (30 ml) and treated successively with triethyl amine (1.68 ml, 12.02 mmol) and di-tert-butyl dicarbonate (1.26 g, 5.77 mmol). The reaction mixture is stirred under nitrogen four hours; aqueous workup and chromatographic purification (ethyl acetate:cyclohexane, 3:7) yields the title compound as a white solid (1.69 g, 4.3 mmol). MS(EI): 394(M+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:2].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1>O1CCOCC1>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:4]5[CH2:5][CH2:6][CH2:7][N:3]5[CH2:1][CH3:2])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc43)cn12
Temperature: 60 °C

Procedure:
To a solution of Intermediate 61c (72.0 mg, 0.19 mmol) in 1,4-dioxane (2.00 mL) was added DIPEA (66 μL, 0.38 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 77.0 mg, 0.19 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further purification by HPLC (C18 X-select column, 20-70% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (37 mg, 31%). LCMS (Method 5): Rt 3.73 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 0.94 (3H, t, J 7.2), 1.30 (9H, s), 1.89-2.16 (6H, m), 2.22-2.31 (2H, m), 2.31-2.38 (2H, m), 2.38 (3H, s), 2.49 (1H, m), 3.32 (1H, m), 4.11 (1H, t, J 8.0), 4.90 (1H, dd, J 9.0, 5.6), 5.28 (1H, t, J 4.1), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.65 (1H, dd, J 10.0, 0.7), 8.37 (1H, d, J 1.9).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:11]2[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)[nH]c2c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CCO[Si](C)(C)C(C)(C)C)c2c1Cl
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a mixture of Methyl-7-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate (115.7 mgs, 291 μmol) in 2 mL of DMSO under N2 was added NaH (95%, 2 equivalents, 582 μmol, 14.0 mgs), and the reaction mixture was stirred for 20 minutes. (2-bromoethoxy)-tert-butyldimethylsilane (1.5 equivalents, 436 μmol, 94 μL) was then along with KI (1.5 equivalents, 72.4 mgs), and the reaction was stirred at room temperature overnight. The crude product was acidified with 1 M HCl, diluted with water and extracted with dichloromethane. The extracted product was concentrated en vacuo then purified by automated flash chromatography (Biotage Horizon™, gradient elution, 5 to 40% Ethyl Acetate/Hexane) to give 136.0 mgs (86%) of Methyl-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylate as a oily colorless solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 2 minute hold at a rate of 5 mL/minute. The NMR spectra was recorded at room temperature using a Bruker DRX300 spectrometer. Chemical shifts were reported in ppm relative to the deuterated solvent used. Coupling constants were reported in hertz. Peak multiplicity was reported using the following abbreviations: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), br (broad). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.05 Hz, 1H), 7.73 (d, J=8.05 Hz, 1H), 7.50 (d, J=8.42 Hz, 2H), 7.24 (d, J=8.42 Hz, 2H), 4.69 (t, J=6.40 Hz, 2H), 4.17 (s, 3H), 4.12 (s, 3H), 3.95 (t, J=6.40 Hz, 2H), 2.79 (m, 1H), 1.96 (m, 6H), 1.41-1.56 (m, 3H), 1.11-1.20 (m, 1H), 0.95 (s, 9H), 0.03 (s, 6H). MS m/z 557.23 (M+H), Rf 3.05 min., 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=1)=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]([O:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=3)=[O:33])[CH:7]=2)[CH:18]=[CH:17][N:16]=1)=[O:20]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(NC(=O)c4cccc(Cl)c4)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-(5-aminonaphthalen-2-yloxy)-N-methylpicolinamide (40 mg, 0.14 mmol) and NaHCO3 (33 mg, 0.44 mmol)in CH2Cl2, 3-chlorobenzoyl chloride (17 □L, 0.14 mmol) was added. The reaction was stirred at RT for 12 h then taken up into CHCl3 and washed with water and brine, dried over Na2SO4, and filtered. The title compound was isolated after purification by column chromatography. MS (ESI pos. ion) m/z: 432.4 (M+H). Calc'd for C24H18ClN3O3−431.87.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32]C)=O)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[OH:34][NH2:35].Cl.NO.C[O-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[C@@H:8]([C:30]([NH:35][OH:34])=[O:32])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC(C)(C)C)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of dimethyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (0.038 g, 0.000082 mol) in methanol (0.30 mL, 0.0074 mol) was added 1.640 M of N-hydroxyamine in methanol (1.004 mL), freshly made from the corresponding hydroxylamine HCl salt and sodium methoxide. The mixture was stirred at rt for 1 h then acidified with 1N HCl. The resulting mixture was applied directly on RP-HPLC to give the targeted product as a TFA salt (10 mg, 45%). MS (ESI): (M+H)+=463.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[Cl-]>N1C=CC=CC=1.C(Cl)Cl>[S:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:31]1[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCO
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In a mixed solvent of 15 ml pyridine and 120 ml methylene chloride was dissolved methyl 22-hydroxydocosanoate (1.70 g, 4.59 mmoles) . P-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was gradually added to the obtained solution under ice-cooled condition, over a period of 1 hour, and the mixture was stirred for 14 hours in a refrigerator. Then, ptoluenesulfonyl chloride (1.75 g, 9.18 mmoles) was added to the reaction mixture, and reaction was effected for 24 hours. After the completion of reaction, the reaction mixture was treated in the same manner as in Reference Example 1, to give methyl 22-tosyloxydocosanoate (2.28 g, 75%) having the following properties.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1.ClCCl>[CH2:27]([O:26][C:24]([NH:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1sc2cc(OC)ccc2c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1c(C(=O)OC)sc2cc(OC)ccc12
Yield: 87.7 %

Procedure:
A mixture of 27.4 g (0.115 mol) of methyl 3-amino-6-methoxybenzo[b]thiophene-2-carboxylate, 38 g (0.275 mol) of potassium carbonate and 13.2 ml (0.138 mol) of ethyl chloroformate in 330 ml of toluene is heated at reflux for three hours. 7 ml (0.069 mol) of ethyl chloroformate are then added and the mixture is left heating at reflux for a further seven hours, with stirring. The mixture is then diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. Recrystallization is carried out from a mixture of isopropanol and diisopropyl ether. 31.2 g of product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]COCC[Si](C)(C)C)=[CH:8][N:7]=1.Cl.CCOCC>CO>[CH3:21][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[N:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: CN(C)CC#Cc1ccc(OCOCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN(C)CC#Cc1ccc(O)cn1

Procedure:
Compound 57B (40 mg, 0.131 mmol) in MeOH (3 ml) was treated with 2 N hydrogen chloride in ether (0.1 ml, 0.200 mmol) for 1 h and the mixture was concentrated to provide the title compound 57C. LCMS (APCI) m/e 177 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[CH3:23][N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(OCC)(=O)C.C(O)C>[CH3:22][C:21]1[S:20][CH:19]=[C:9]2[C:10](=[O:18])[NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][CH2:29][CH:25]4[CH2:26][CH2:27][CH2:28][N:24]4[CH3:23])[CH2:33][CH2:34]3)=[O:6])[C:8]=12
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Reactant: CN1CCCC1CCCC1CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCC3CCCN3C)CC1)c1ccccc1NC2=O
Yield: 18 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[3-(1-methyl-pyrrolidin-2-yl)propyl]piperidine in a yield of 18% of theory. Colourless crystals, m.p. 145°-146° C. (from ethyl acetate/ethanol). RF =0.5 (TLC investigation as in Example 114).