Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
1-tert-Butoxycarbonyl-piperazine (5.6 g) was dissolved in dry DCM (100 ml) followed by the addition of cyclobutanone (2.10 g). The reaction mixture was stirred at rt for 30 min. Sodium triacetoxyborohydride (6.37 g) was added portion-wise over 15 min. The mixture was then stirred at rt overnight to give a black solution. The reaction mixture was washed with 1N NaOH (70 ml) and the DCM layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give the subtitled compound as an oil (6.1 g) 1H NMR δ [DMSO-d6]: 1.39 (6H, s), 1.68-1.87 (4H, m), 1.9-2.01 (2H, m), 2.15-2.2 (3H, m), 2.5 (1H, m), 2.6-2.78 (1H, m), 3.18-3.3 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.80 g, 3.5 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.66 g, 3.5 mmol). The resulting free base was recrystallized from methanol to yield a white crystalline solid. Yield 0.63 g (43%). mp 155°-160° C. FDMS m/e=417 (M+ of free base). α[D]589 =+4.30 (c=0.98, methanol/dimethylsulfoxide).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[C-:10]#[N:11].[K+]>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]#[N:11])=[N:6][CH:7]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(Br)cn1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a stirred solution of 5-bromo-2-(bromomethyl)pyridine (0.70 g, 2.12 mmole), in EtOH (50 mL) at 60° C. was added KCN (0.21 g, 3.18 mmole) in H2O (3 mL). After 1.5 h, the reaction contents were cooled to RT and concentrated under vacuum. The aqueous residue was dissolved in EtOAc and washed with H20, and dried over Na2SO4. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (0.38 g, 65%) as light yellow solid: LC-MS (ES) m/e 277 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C@@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br-].[K+].Cl[O-].[Na+].[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)[O:24][C@@:11]([CH:42]=[O:43])([CH2:12][O:13]2)[C@@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a solution of (1S,2R,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol 28j (0.22 g, 0.36 mmol) in dichloromethane (20 mL) was added saturated aqueous sodium bicarbonate (0.3 g, 3.6 mmol) at room temperature. To the mixture was added potassium bromide (25.7 mg, 0.22 mmol), 2,2,6,6-tetramethylpiperidinooxy (5.6 mg, 0.04 mmol) and sodium hypochlorite (0.8 mL, 0.94 mmol, 3.14% available chlorine) in turn at 0° C. The resulting mixture was stirred at 0° C. for 10 min and adjusted with saturated aqueous ammonium chloride till pH becomes 7. The resulting mixture was extracted with dichloromethane (15 mL×2). The combined organic layers were washed with water (10 mL×2) and saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28k as a white solid (221 mg, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1)[CH2:2][CH3:3].[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: CCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(O)c(N)c1
Yield: 93.2 %

Procedure:
A mixture of 6.65 g of 4-propyl-2-nitrophenol, 55 ml of ethyl acetate and 1.0 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for two hours. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 5.17 g of 2-amino-4-propylphenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:24])[C@@H:15]([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:24])[C@@H:15]([NH:23][C:40](=[O:42])[CH3:41])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H]1CO[C@@H](CCC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Dissolve 5-(R)-(2-(S)-amino-1-(S)-hydroxy-3-phenylpropyl)-2-(S)-(2-cyclohexylethyl)-morpholine-4-carboxylic acid tert-butyl ester (140 mg, 0.31 mmol) in dry tetrahydrofuran (3 mL). Add triethylamine (0.05 mL, 0.35 mmol) followed by acetic anhydride (0.03 mL, 0.35 mmol) and stir at room temperature for 1 hour. Dilute with dichloromethane, wash with 0.1 N hydrochloric acid/saturated aqueous sodium chloride (30 mL), dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 40:60 to 60:40 ethyl acetate:dichloromethane) acetate/dichloromethane to give the title compound (83 mg, 54%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cnccc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1C(=O)Nc1ccncc1C(N)=O

Procedure:
In a similar manner to Example 68 a) reaction of 2-propoxybenzoyl chloride (0.79 g), 4-aminonicotinamide (0.55 g) and triethylamine (0.40 g) in acetonitrile (12 ml) afforded a crude product which was recrystallized from ethanol-ether to afford 4-(2-propoxybenzamido)nicotinamide, 0.53 g, m.p. 164-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22]([CH:24]=[O:25])=O>Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22]1[C:24](=[O:25])[N:3]2[C:4]3[C:9]([NH:10][CH:11]=[C:2]2[N:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: Nc1cnc2ccccc2n1
Reactant: COc1ccc(F)c(C(=O)C=O)c1
Agent: Cl
Solvent: O
Product: COc1ccc(F)c(-c2nc3c[nH]c4ccccc4n-3c2=O)c1
Temperature: 25 °C

Procedure:
A solution of 2-aminoquinoxaline (100 mg) and 2-fluoro-5-methoxyphenylglyoxal monohydrate (150 mg) in 5% HCl (6 mL) was heated to 60°-65° C. for 8 h. After cooling the mixture to room temperature the precipitate which had formed during the reaction was collected via suction filtration and washed with 5% HCl (1×) followed by H2O (3×). The product was then washed with methylene chloride and dried. The above procedure provided 2-(2-fluoro-5-methoxyphenyl)-imidazo-[1,2-a]quinoxalin-1(5H)-one (Compound 30) as a brick-red solid, mp 318°-320° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:27][C:28]([CH3:34])=[C:29]([C:31](Cl)=[O:32])[N:30]=1.O>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:29]5[N:30]=[C:26]([CH3:25])[O:27][C:28]=5[CH3:34])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) in N,N-dimethylacetamide (4.0 mL) was added 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (127 mg, 0.79 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (198 mg, 72%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21](=O)[O:22]C(C)(C)C)[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[C:30](C(O)=O)=[N:31][CH:32]=[CH:33][N:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21]([C:30]4[C:29]([NH2:28])=[N:34][CH:33]=[CH:32][N:31]=4)=[O:22])[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reactant: Nc1nccnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1nccnc1N)c1nnc2ccc(Nc3cccc(Cl)c3)nn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.4 %

Procedure:
(Steps 1-v & 1-yl) tert-Butyl (R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethylcarbamate (110 mg, 0.28 mmol) was dissolved in 5 mL TFA/CH2Cl2 (1:1) and left standing for 20 min. The solvent was removed under reduced pressure and CH2Cl2 was added and removed 4 times to remove residual TFA. The resulting amine was dissolved in DMF and 3-aminopyrazine-2-carboxylic acid (200 mg, 1.4 mmol), HBTU (0.50 g, 1.3 mmol) and DIEA (1 mL, 5.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, then poured into ethyl acetate/0.1 M NaOH. The organic layer was dried over sodium sulfate and concentrated to yield an oil. This oil was purified by reversed-phase HPLC. Fractions containing pure product were concentrated to give N—((R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-3-aminopyrazine-2-carboxamide as a yellow solid (60 mg, 0.13 mmol, 48% yield): 1H NMR (500 MHz, DMSO-d6) 10.43 (s, 1H), 9.19 (d, J=8.1 Hz, 1H), 8.22-8.20 (m, 2H), 7.89 (t, J=2.0 Hz, 1H), 7.75-7.73 (m, 2H), 7.33 (m, 2H), 7.07 (dd, J=1.3, 7.9 Hz, 1H), 5.76-5.71 (m, 1H), 1.75 (d, J=6.9 Hz, 3H); MH+410.2.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[SiH:9]([CH3:11])[CH3:10])[CH:2]=[CH2:3].C([Li])CCC.CN([CH:20]=[O:21])C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:4]1[S:5][C:6]([CH:20]=[O:21])=[CH:7][C:8]=1[SiH:9]([CH3:11])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCc1sccc1[SiH](C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1sc(C=O)cc1[SiH](C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of 2-allyldimethylsilylthiophene (1 Scheme 28, 10.6 g, 58.5 mmol) in dry THF (300 mL) at −78° C. was added n-butyllithium (23.4 mL, 2.5 M solution in hexanes, 58.5 mmol) over a period of 10 min. After 30 min stirring at −78° C., anhydrous DMF (6.8 mL, 87.8 mmol) was added dropwise. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (4 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (150 mL) and brine (20 mL), and the organic layer was dried (Na2SO4) and concentrated to afford a colorless oil (12.1 g, 98%); 1H NMR (300 M CDCl3) δ 0.32 (s, 6 H), 1.76 (dd, J=8.10, 1.20 Hz, 2 H), 4.85 (m, 1 H), 4.89 (s, 1 H), 5.72 (m, 1 H), 7.30 (d, J=3.60 1 H), 7.77 (dd, J=3.60, 1.50 Hz, 1 H), 9.90 (s, 1 H); 13C NMR (75 MHz, CDCl3) −2.4 (2C), 24.0, 114.9, 133.3, 135.4, 137,0, 148.7, 150.7, 182.7; HRMS (EI) calcd for C10 H14OSSi 210.0533, found 210.0531.
Reaction SMILES: C(Cl)Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:11]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=2)[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:30][N:8]3[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]3)[CH:27]=2)[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Yield: 47 %

Procedure:
DCM (33 L) and N-methylpiperazine (21.45 L, 193.4 mol) were stirred at 25° C. and the solution from step 8 added over a minimum of 30 mins such that temperature 20-30° C. After stirring the solution for a further 30 mins water (55 L) was added and the organic phase was washed with water (2×55 L). The product was extracted into 0.8M HCl (66 L) and the layers separated. The aqueous phase was washed with DCM (55 L) and then basified with 2M NaOH to pH 10-11 and the product was extracted into EtOAc (2×55 L). The combined organic phase were filtered to remove solids and the evaporated followed by azeotroping with toluene and drying to constant weight to give the title compound, 6.63 kg (47% yield, 98% pure by hplc).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C:14]([O:16][NH:17][C:18]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[NH:19])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1(C)C=CC=CC=1>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:18]3[N:19]=[C:14]([C:13]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:11]([C:1]56[CH2:10][CH:5]7[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]7)[CH2:2]5)[CH2:8]6)[CH:12]=4)[O:16][N:17]=3)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: COc1ccc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 104.4 %

Procedure:
The suspension of the product of Step C (0.16 g; 0.36 mmol) and 1 M TBAF in THF (0.3 ml; 0.3 mmol) in anhydrous toluene was refluxed for 1 h under reduced pressure, cool to room temperature and evaporated to dryness under reduced pressure. The residue was diluted to 15 ml with EtOAc, washed with water, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by crystallization from hexane/EtOAc to give the title compound (0.16 g; 100%) as colourless solid. 1H-NMR (CDCl3) 1.79 (s, 6H); 2.0-2.16 (m, 9H); 3.92 (s, 3H); 6.66 (s, 1H); 6.98 (d, 1H, J=8.6 Hz); 7.26 (m, 1H); 7.48 (d, 1H, J=8.5 Hz); 7.9-8.11 (m, 2H); 8.29 (broad s, 1H); 8.51 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:10][CH:9]1[C:33](O)=[O:34])=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].O>C1COCC1>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[C:27]1([S:24]([N:19]2[C:20]3[C:16](=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH:9]([CH2:33][OH:34])[CH2:10]4)[CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18]2)(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCNC(CO)C3)cccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1M BH3 in THF (0.2 mL, 0.2 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-2-carboxylic acid (0.010 g, 0.020 mmol, Intermediate 51) in THF (0.5 mL) and the mixture was stirred for 2 days at room temperature. TFA (1 mL) and water (0.5 mL) were added and the mixture was stirred overnight. The mixture was evaporated and dissolved in MeOH, filtered and purified by reversed phase preparative HPLC using ACE Prep UV C8 150×30 mm, flow 38 mL/min, gradient time 8.5 min using the eluent system: water/0.1% TFA and CH3CN (31-62% MeCN), fractions collected based on UV-signal (254 nm). The purest fractions were pooled and the acetonitrile was evaporated. Yield: 2.7 mg (22%). Colorless oil. MS (electronspray; [M+H]+) m/z 386.4.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1([OH:59])[CH2:56][S:57][CH3:58])[CH3:2].C[OH:61]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1([OH:59])[CH2:56][S:57]([CH3:58])=[O:61])[CH3:2]
Reactant: CO
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(O)CSC)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(O)CS(C)=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 0.050 g (0.059 mmole) of 17-ethyl-1,14,16-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-16-(methylthiomethyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10-trione in 5 mL of methanol was cooled to 0° C. in an ice bath. Then 2 mL of a 0.5M solution of NaIO4 was added and the mixture was stirred at room temperature for 1 h. The solution was partitioned between ether and water and the ether layer was washed with KHCO3 and brine, then dried over MgSO4 and concentrated. The residue was purified by flash chromatography (2×20 cm silica gel) using 20% acetone-hexane to afford 0.022 g (44%) of the title compound as a white solid; MASS SPECTRUM (FAB) m/e 876 (M+Li).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[NH:13][C:12](=[O:20])[N:11]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:10]2=[O:26].FC(F)(F)C(O)=O>ClCCl.C(OCC)C>[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[NH:13][C:12](=[O:20])[N:11]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[C:10]2=[O:26]
Reactant: COc1ccc(CNc2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])c(OC)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[6-(2,4-dimethoxy-benzylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (725 mg, 1.56 mmol) in dichloromethane (4 ml) is added trifluoroacetic acid (0.5 ml) and the mixture is stirred at room temperature for 30 minutes. Then the solvent is removed by rotavapor evaporation to give an orange solid which is suspended in diethyl ether, filtered and the residue washed 3 times with diethyl ether and two times with ethyl acetate to give the title product as a pure orange solid, m.p. 326-335° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11]1([C:17]2[O:18][CH2:19][CH:20]([OH:29])[CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:29][CH:20]2[CH2:19][O:18][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:22][CH:21]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCCl
Product: O=C(Nc1ccc(Cl)cc1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 57.1 %

Procedure:
4-Chlorophenyl isocyanate (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.2 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 7 hours 30 minutes and then concentrated to dryness under reduced pressure (2.7 kPa). After two successive recrystallizations in acetonitrile, (4RS, 5RS)-5-(4-chlorophenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 200° C., is obtained.