Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[C:18]3[CH2:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.C(O)(C)C>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[C:18]3[CH2:25][CH2:26][CH2:27][C:28]([F:30])([F:29])[F:31])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cncc(CCCC(F)(F)F)c3c2)CC1
Agent: Cl
Solvent: CC(C)O
Product: FC(F)(F)CCCc1cncc2ccc(OC3CCNCC3)cc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
42 mg of compound 89 were dissolved in 5M hydrochloric acid in isopropanol. The solution was stirred at room temperature for 2 hrs and another 2 hrs at 40° C., evaporated to dryness and taken up in water and lyophilized three times to give 32 mg of the desired product as the hydrochloride salt. LCMS Method #1, retention time 0.98 min, detected mass 338.16 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.[NH2:11][CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][CH:12]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Reactant: Cn1cc(Br)cc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)cc1C(=O)NC(CNC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (610 mg, 3.0 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (748 mg, 2.99 mmol) [prepared according to the procedure of Preparation 2] and PyBrop (1.71 g, 3.67 mmol) in Chloroform (15 mL). DIEA (1.8 mL, 10.3 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (Hex/EtOAc) affording the title compound (335 mg, 26%): LC-MS (ES) m/z=438 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH2:27][C:28]4[CH:29]=NC=[CH:32][C:33]=4[Cl:34])=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].[CH2:36]([N+:40](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:34][C:33]1[CH:32]=[N:40][CH:36]=[CH:29][C:28]=1[CH2:27][NH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)=[CH:25][N:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3cnccc3Cl)nc2)c2cccnc21
Agent: [F-]
Solvent: C1CCOC1
Product: Clc1cnccc1CNc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-pyridin-3-ylmethyl)-amine (602, 0.08 g, 0.16 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (P-0183, 4.0 mg, 7%). MS (ESI) [M+H+]+=350.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C@H:8]1[CH2:13][N:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:11]([CH3:26])[CH2:10][N:9]1[C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].[CH3:36][NH:37][CH3:38].CCOC(C)=O>C(Cl)Cl>[CH3:7][C@H:8]1[CH2:13][N:12]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23](=[O:24])[N:37]([CH3:38])[CH3:36])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@H:11]([CH3:26])[CH2:10][N:9]1[C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C(=O)N(C)C)cc1
Yield: 7.7 %

Procedure:
Oxalyl chloride (0.08 ml, 0.88 mmol) was added to a solution of (R)-[(2S,5R)-2-methyl-5-methyl-4-(4-carboxyphenylsulphonyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (320 mg, 0.73 mmol) (Example 4) in DCM (25 ml). The resultant mixture was stirred at ambient temperature for 4 hours, evaporated to dryness, the residue treated with 40% aqueous dimethylamine (0.82 ml, 7.3 mmol) and the resultant mixture was stirred at ambient temperature overnight. The mixture was treated with EtOAc (25 ml), washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc in DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (26 mg, 0.056 mmol). Mp: 86-87° C.; NMR: 0.95 (d, 3H), 1.25 (dd, 3H), 1.65 (s, 3H), 2.95 (s, 3H), 3.1 (s, 3H), 3.25 (dd, 1H), 3.5 (dd, 1H), 4.2 (m, 2H), 4.5 (s, 1H), 4.8 (s, 1H), 7.5 (d, 2H), 7.85 (d, 2H); m/z: 464.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:13]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])[N:14]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=3)=[C:13]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])[N:14]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(C(F)(F)F)cc3)[nH]2)cc1
Yield: 63.7 %

Procedure:
2-(4-Nitrophenyl)-5-(4-trifluoromethylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.42 g) obtained in Example 49 was hydrogenated in methanol using palladium. The catalyst was filtered off and the residue was concentrated to give 2-(4-aminophenyl)-5-(4-trifluoromethylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (0.25 g), melting point 175-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:32]1[O:34][C@H:33]1[CH2:35][OH:36].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][C@@H:33]([OH:34])[CH2:35][OH:36])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Oc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: OC[C@H]1CO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H](O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
To a solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-ol (30 mg, 0.07 mmol) in EtOH (1.0 mL) was added (S)-(−)-glycidol (5 mg, 0.07 mmol, 1.0 equiv) and triethylamine (0.34 mg, 0.0035 mmol, 0.05 equiv) under nitrogen. The reaction mixture was stirred at 80° C. for 15 h and then was cooled to rt. The solvent was removed in vacuo. The crude material was purified by preparative HPLC to give (2S)-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propane-1,2-diol as a white solid (14.8 mg, 40%). 1H-NMR (CD3OD) δ 8.45 (s, 1H), 8.32 (d, J=8.9 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.46 (dd, J=2.7, 9.0 Hz, 1H), 7.40 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.25 (dd, J=2.3, 9.0 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.05 (td, 1H), 5.22 (s, 2H), 4.20 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.72 (m, 2H), LCMS RT=3.36 min, [M+H]+=526.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Nc1cccc(CCCCO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the 4-(3-aminophenyl)butan-1-ol [Hua Hsueh Hsueh Pao 1964, 30, 166-75. CAN 61:47615] (3.66 g) in dry DMF (30 ml) was treated with imidazole (1.66 g) and tert-butyldimethylsilyl chloride (3.5 g). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue partitioned between sat. NH4Cl(aq) and ethyl acetate. The aqueous phase was extracted with EtOAc and the combined organic phase washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, Petroleum ether-EtOAc 9:1) to give the title compound. LCMS RT=3.89 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].Cl[CH2:15][CH2:16]Cl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:15]1[CH2:16][O:12][C:11]2[C:2](=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:13])[CH2:6][CH2:5][CH2:4]3)[O:1]1
Reactant: O=C1CCCc2c1ccc(O)c2O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCCc2c1ccc1c2OCCO1

Procedure:
5,6-Dihydroxy-1-tetralone (6 g) was heated at 125° C. with 1,2-dichloroethane (7 ml) and K2CO3 (14 g) in DMSO (70 ml) under N2 for 45 min. The reaction was quenched with ice water then extracted with Et2O. The aqueous layer was removed, then EtOAc added to the remaining organics. This solution was dried (MgSO4), filtered and evaporated to give the desired product.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[K].[C:21]([O:24][CH2:25][C:26]([OH:28])=[S:27])(=[O:23])[NH2:22]>O1CCOCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-]>[C:21]([O:24][CH2:25][C:26]([S:27][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])=[O:28])(=[O:23])[NH2:22]
Reactant: NC(=O)OCC(O)=S
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [K]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1SC(=O)COC(N)=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the potassium salt of carbamoyloxythioacetic acid (2.1 g) was added. Zinc bromide (2.7 g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40° C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The solid residue was taken-up with CH2Cl2. Upon addition of hexanes and cooling a white solid was precipitated, and collected by filtration to give 3.26 g of the title product (90% yield).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[Br:14][O-].[Na+].Br[O-].BrBr.OS(O)(=O)=O>[OH-].[Na+]>[Br:14][C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12]
Reactant: C#CCCCCCCCCC(=O)O
Reactant: [O-]Br
Agent: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCCCCCCCC#CBr
Reaction time: 4 h

Procedure:
To a solution of 36.45 g (200 mmol) of 10-undecynoic acid in 200 ml 1N NaOH at 0° C. was added a solution of alkaline sodium hypobromite dropwise over 30 minutes, maintaining the temperature below 5° C. (the hypobromite solution was prepared by the dropwise addition of 35.16 g (220 mmol) of bromine to 55 ml of 20N NaOH at 0°-5° C.). The mixture was stirred four hours at 0°-5° C., and was then acidified to pH 1 with 9M H2SO4. The solution was extracted with three 150 ml portions of ether. The combined extracts were dried (Na2SO4) and evaporated yielding 50.159 (96% crude) of a pale yellow solid. This was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>FC(F)(F)S(O)(=O)=O>[NH:18]1[CH2:19][CH2:20][CH:15]([CH:13]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH2:7][N:8]3[CH:12]=[CH:11][N:10]=[C:9]23)[CH2:16][CH2:17]1
Reactant: OC(c1nccn1Cc1ccccc1)C1CCNCC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)Cn1ccnc1C2C1CCNCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of α-[1-(phenylmethyl)-1H-imidazol-2-yl]-4-piperidinemethanol (5.4 g) in trifluoromethanesulfonic acid (25 ml) was stirred overnight at 100° C. The reaction mixture was cooled, poured out onto ice, then alkalized with NaOH and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent :CH2Cl2/(CH3OH/NH3) 95/5, upgrading to 90/10). The pure fractions were collected and the solvent was evaporated, yielding 2.5 g (50%) of 5,10-dihydro-10-(4-piperidinyl)-imidazo[1,2-b]isoquinoline (intermediate 10).
Reaction SMILES: [O:1]1[CH2:18][C@@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@H]3CO3)c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(CNC[C@@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
To a solution of (R)-(−)-4-(2,3-Epoxypropoxy)-carbazole (7 g, 0.029 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (8.7 mL, 0.058 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was concentrated to half its volume, and cooled to room temperature to give a colorless solid. The solid was filtered, re-dissolved in EtOAc (60 mL) by refluxing, concentrated to 40 mL and the colorless precipitate formed on cooling to room temperature, was filtered and dried. Recrystallization of the residue obtained from the filtrate was repeated until maximum amount of the solid was recovered. The combined solid was triturated with diethylether by stirring for 6 hours, followed by filtration to afford 5.5 g (46% yield) of the desired compound as a colorless solid with m.p: 152-153° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.86-2.92 (m, 1H), 2.99-3.02 (m, 1H), 3.74-3.86 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.44 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.41 (m, 4H), 8.09 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.99%
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([O:11]S(C(F)(F)F)(=O)=O)=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32): (500 mg, 0.938 mmol) in THF (5 mL) was added TBAF (1.0 M in THF, 4 mL) slowly. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed by a mixture of H2O (20 mL) and HOAc (200 ul), extracted by EtOAc, the organic phase was washed by sat. NaHCO3, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75A (380 mg). LCMS-ESI+: calc'd for C16H20BrNO4S: 402.0 (M+H+); Found: 401.9 (M+H+).
Reaction SMILES: N.C([O:5][C@H:6]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[NH:22])[C:16]2=[O:24])[O:8][C@@H:7]1[CH2:25][O:26]C(=O)C)(=O)C.[ClH:30]>C(O)(=O)C>[ClH:30].[OH:11][C@@H:10]1[C@H:6]([OH:5])[C@@H:7]([CH2:25][OH:26])[O:8][C@H:9]1[N:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[NH:22])[NH2:23])[C:16]1=[O:24]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccnc(C(=N)N)c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: N=C(N)c1nccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 5.0 mL of 25% aqueous solution of ammonia was added 0.10 g of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[3-[amino(imino)methyl]-2oxo-1(2H)-pyrazinyl]tetrahydro-3-furanyl acetate at an ice-cooled temperature, and the mixture thus formed was stirred at the same temperature as above for 2 hours. After adding 4.9 mL of acetic acid to the reaction mixture, the solvent was removed under reduced pressure. Further, the same reaction as above was repeated by using 20 mg of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[3-[amino(imino)methyl]-2-oxo1(2H)-pyrazinyl]tetrahydro-3-furanyl acetate, and the reaction mixture thus obtained was united with the reaction mixture obtained above. The united mixture was purified by reversed phase silica gel column chromatography [eluent: water]. To the solid product thus obtained was added 5.0 mL of 1 mol/L hydrochloric acid, and the solvent was removed under reduced pressure. Further, 5.0 mL of 1 mol/L hydrochloric acid was added and the solvent was removed under reduced pressure. Ethanol was added to the residue thus obtained, and the solid product was collected by filtration to obtain 30 mg of 4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboximidamide hydrochloride as a light yellow-colored solid product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:73]([NH2:79])[C@@H:74]1[O:78][CH2:77][CH2:76][CH2:75]1>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:79][CH2:73][C@H:74]4[CH2:75][CH2:76][CH2:77][O:78]4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: NC[C@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(NC[C@H]1CCCO1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Yield: 71.8 %

Procedure:
A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), 1-hydroxybenzotriazole (14 mg, 0.1 mmol), and (R)-(−)-tetrahydrofurfurylamine (10 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. overnight, diluted with CH2Cl2 (5 mL), and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow oil. Et2O (5 mL) was added to dissolve the oil, and concentration afforded the title compound as an off-white solid (32 mg, 72% yield). LC/MS (ESI) retention time: 1.75 min, m/z 637 (MH+); 1H NMR (400 MHz, CDCl) 8 1.31-1.44 (m, 3 H) 1.48-1.57 (m, 1 H) 1.58-1.69 (m, 2 H) 1.72-1.80 (m, 2 H) 1.87-1.96 (m, 3 H) 1.98-2.11 (m, 4 H)2.25-2.36 (m, 1 H) 2.42 (s, 3 H) 2.62-2.78 (m, 1 H) 2.78-2.89 (m, 1 H) 3.39 (ddd, J=12.53, 6.20 Hz, 1 H) 3.66 (s, 4 H) 3.74-3.85 (m, 2 H) 3.86-3.95 (m, 1 H) 4.40 (s, 1 H) 5.07 (s, 1 H) 6.60 (t, J=5.29 Hz, 1 H) 6.82 (s, 1 H) 7.34- 7.50 (m, 4 H) 7.52-7.59 (m, 1 H) 7.86 (d, J=8.56 Hz, 1 H) 7.97 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([C:27]1[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]=3[N:17]=2)[C:10]1=[O:26].O.[OH-].[Li+]>O1CCCC1.O>[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[CH2:22][CH2:21][CH2:20][NH:19][C:18]=4[N:17]=3)[C:10]2=[O:26])[C:3]([OH:35])=[O:2])=[CH:32][CH:31]=1
Reactant: COC(=O)C(CCCCN1CC[C@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc(OC)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(CCCCN2CC[C@H](CCc3ccc4c(n3)NCCC4)C2=O)C(=O)O)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 2-3b (55 mg) in tetrahydrofuran (3 mL) was added lithium hydroxide monohydrate (20 mg) in water (3 mL) and the mixture was stirred for 16 h. The reaction mixture was then concentrated at reduced pressure and resulting oil was purified by flash column chromatography (silica gel, 30:3:3 to 50:5:5% ethanol/ammonium hydroxide/water in ethyl acetate) to give 2-4b.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].N1C=NC=N1>CO>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)CCN
Agent: c1nc[nH]n1
Solvent: CO
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 60 °C
Yield: 94.9 %

Procedure:
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (1000 g), N,N-dimethylethylenediamine (795 g), and 1H-1,2,4-triazole (207 g) in methanol (2.0 l) was heated under reflux under nitrogen for 10 hr and was left to stand at room temperature over night. The reaction mixture was warmed to 60±2° C. and methanol (4.0 l) was added for 35 min. After stirring under reflux for additional one hr the reaction mixture was cooled to room temperature. The precipitate was collected by filtration and washed with methanol (2.0 l) to obtain the titled compound (1109 g).