Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl.O>[N:11]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: OCc1ccc(CN2CCOCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(CN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to −78° C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at −78° C. The reaction mixture was stirred for 15 min at −78° C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at −78° C. and the mixture was stirred at −78° C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]1)=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].C1(C)C=CC=CC=1>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[N+:16]([NH:15][C:14](=[NH:19])[NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]1)=[O:21])[NH2:8])([O-:18])=[O:17]
Reactant: CCOC(=O)CC1CCN(C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCN(C(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1-((S)-Nα -t-butoxycarbonyl-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)piperidine (1.2 g) in dichloromethane (25 ml) cooled to 0° to 5° C. is slowly added trifluoroacetic acid (2.8 g) and the reaction mixture is allowed to warm to room temperature and is then stirred for 6 hours. Toluene (30 ml) is then added and the mixture is concentrated by evaporation and then co-evaporated with further toluene portions (2×30 ml) and the eventual residue is triturated with ether, collected by filtration, washed with ether and dried to constant weight in vacuo to give 1-((S)-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)-piperidine trifluoroacetate as a white solid, Rf (BuOH/CH3COOH/H2O 3:2:1)=0.50.
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[Na+].[Cl:6][C:7]1[CH:8]=[C:9](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]CO)[C:20](=[O:28])[C@@H:19]2[CH3:29])=[O:17])[CH:10]=[CH:11][C:12]=1[F:13].[Br-].[K+].Cl[O-].[Na+]>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:1]([OH:2])=[O:4])[C:20](=[O:28])[C@@H:19]2[CH3:29])=[O:17])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: C[C@H]1C(=O)N(CCCO)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reactant: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Yield: 4 %

Procedure:
Saturated aqueous sodium hydrogencarbonate solution (15 ml) was added to a solution of (S)-4-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-1-(3-hydroxy-propyl)-3-methyl-piperazin-2-one (PCT Int. Appl. WO 2009010429 A2; 5.70 g, 16.1 mmol), potassium bromide (191 mg, 1.61 mmol), and 2,2,6,6-tetramethylpiperidin-1-oxyl (25 mg, 0.16 mmol) in dichloromethane (300 mL). Sodium hypochlorite solution (10% in water, 9.6 ml, 16 mmol) was added portionwise at 0° C., and the course of the oxidation was monitored by thin layer chromatography. After all starting material had reacted, the reaction mixture was washed with sodium hydrogencarbonate, and the aqueous layer was extracted twice with dichloromethane. The organic phases were pooled, dried over magnesium sulfate, filtered, and evaporated, thus affording 3-{(S)-4-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-propionaldehyde (5.15 g, 91%). The aqueous layer was acidified to pH 3 with 1 M aq. hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated to afford the title compound (254 mg, 4%). Colorless gum, MS: 367.3 (M−H, Cl)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][NH:30]3)=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].N1C=CC=CC=1>ClCCl>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][N:30]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1Cl
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Chlorobenzenesulphonyl chloride (71 mg, 0.3 mmol, 1.1 equiv.) was added to a mixture of crude 2-chloro-4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester (100 mg, 0.3 mmol, 1 equiv.) and pyridine (0.2 mL, 2.4 mmol, 8 equiv.) in dichloromethane (2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). The fractions were combined to afford crude 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, 101 mg. This material was taken onto the next step without further purification. LC @215 nm; Rt 2.52: 84%, m/z (ES+): 505 (M+H+.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][CH:34]([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: CC(O)CN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (204 mg, 0.458 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (R)-(+1-amino-2-propanol (72.0 μmL, 0.914 mmol), WSCI.HCl (130 mg, 0.678 mmol) and 4-dimethylaminopyridine (115 mg, 0.941 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (191 mg, yield 83%) as a white solid.
Reaction SMILES: [CH3:1][Li].[Br-].[Li+].[CH3:5][N:6]1[C@@H:22]2[CH2:23][C:11]3[CH:12]=[CH:13][C:14]([O:26][CH3:27])=[C:15]4[O:16][C@H:17]5[C:18]([O:24][CH3:25])=[CH:19][CH:20]=[C:21]2[C@:9]5([C:10]=34)[CH2:8][CH2:7]1.[NH4+].[Cl-]>CCOCC.C1C=CC=CC=1.[Cu](I)I>[CH3:27][O:26][C:14]1[CH:13]=[CH:12][C:11]2[CH2:23][C@H:22]3[N:6]([CH3:5])[CH2:7][CH2:8][C@@:9]4([C:10]=2[C:15]=1[OH:16])[C:21]3=[CH:20][C@@H:19]([CH3:1])[C:18]([O:24][CH3:25])=[CH:17]4
Reactant: [Li]C
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: I[Cu]I
Agent: [Br-]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(O)c42)C3=C[C@H]1C
Yield: 74 %

Procedure:
To a solution of lithium dimethyl cuprate in ether (500 ml), prepared from copper iodide (23.81 g, 125 mmol) and methyl lithium (250 mmol, 136 ml of a 1.8 M solution in ether containing lithium bromide), stirred in an ice-salt bath under an argon atmosphere was added rapidly in a thin stream a solution of thebaine (1, 31.14 g, 100 mmol) in benzene (500 ml). The resulting suspension was stirred for 1 hr. in the cold, then poured into saturated NH4Cl solution (600 ml) and the mixture stirred for 15 min. The organic layer was separated, and the aqueous phase adjusted to pH 13-14 by use of 50% NaOH. The aqueous phase was then extracted with two portions of chloroform, the combined organic phases washed with dilute NH4OH and dried. Evaporation gave a foam which crystallized from chloroform with the addition of hexane to give 33.20 g (74%) of 2 as the mono-chloroform solvate, mp. 97°-100°. Recrystallization from the same solvent pair gave analytically pure 2.CHCl3, mp. 98°-101.5°. IR (CDCl3): 3500 cm-1 (OH). NMR (CDCl3):δ7.30, s (1), CHCl3 ; 6.65, m(2), H1 and H2; 6.13 s(1), H5α; 5.47, d(1), H8, J7,8 =3 Hz; 3.86, s(3), 3--OCH3 ; 3.63, s(3), 6--OCH3 ; 2.33, s(3), 17--NCH3 ; 1.17, d(3), 7--CH3, J7H,7CH3 =7 Hz; exchangeable, 4--OH at ~6.20.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.CCCCCC.[Li]CCCC.[CH3:28][C:29](N(C)C)=[O:30]>CCOCC.C1COCC1>[C:29]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1)(=[O:30])[CH3:28]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.59 g, 5.26 mmol) in a mixture of ether, hexane and THF (2:1:1, 105 mL) was added n-BuLi (3.29 mL, 5.26 mmol, 1.6 M in hexane solution) dropwise at −78° C. during 5-10 min. To the resulting dark brown solution was dropped anhydrous DMA (0.74 mL, 7.89 mmol) at the same temperature. The reaction mixture was stirred for 30 min and then quenched with water (8 mL) and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. After purification by column chromatography on silica gel (hexane/EtOAc 98:2) 0.78 g (56%) of the title compound as an oil were obtained. 1H NMR (CDCl3) δ 7.95 (d, 1H, J=7.5 Hz, H-3), 7.88 (t, 1H, J=7.6 Hz, H-4), 7.73 (t, 1H, J=7.6 Hz, H-5), 4.93 (s, 2H, CH2), 2.75 (s, 3H, CH3), 1.03 (s, 9H, (CH3)3C), 0.20 (s, 6H, (Me)2Si); 13C NMR (CDCl3) δ 200.8 (CO), 161.4 (C-6), 153.0 (C-2), 139.4 (C-4), 124.0 (C-5), 118.0 (C-3), 66.4 (CH2), 26.3 ((CH3)3C), 18.8 ((CH3)3C), -4.96 ((Me)2Si).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)=[CH:4][N:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:16]([OH:18])[CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
To a solution of 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (2.500 g, 8.3 mmol) in 100 ml MeOH was slowly added NaBH4(1.566 g, 41.4 mmol) at 0° C. The solution was allowed to warm to rt. After 20 h, the saturated NH4Cl was added, the mixture was concentrated in vacuo and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via silica gel column chromatography (9:1 CH2Cl2/MeOH) afforded to 1-[5-(2,4-diamino-pyrimidine-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanol (1.613 g, 60%) as white foam; [MH]+=301.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:19][O:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 39.2 %

Procedure:
A solution of 15 g of 2-chloro-3-nitropyridine, 11.7 g of 5-amino-2-methoxypyridine and 26.1 g of potassium carbonate in 150 mL dimethylformamide was stirred at room temperature for 4 hours and 25 minutes and further stirred at 70° C. for 3 hours and 10 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The organic layer was washed 3 times with a saturated aqueous ammonium chloride solution and once with brine, and dried over sodium sulfate. The residue was purified crudely by short-column chromatography. From and the resulting black brown oil was extracted with diethyl ether to give 9.10 g of the title compound as reddish brown crystals (39% y.). (2) N2-(6-Methoxy-3-pyrdyl)-2,3-pyridinediamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:14])[C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:10](=[O:14])[C:11](=[O:12])[S:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccc2c(c1)SC(=O)C2=O
Temperature: 25 °C
Yield: 47.4 %

Procedure:
To a solution of 3-methoxythiophenol (3.75 g, 26.7 mmol) in ether (20 mL) was added oxalyl chloride (3.7 mL, 43 mmol) dropwise. The mixture was heated at reflux for 1.5 h, cooled to rt, and concentrated in vacuo. The resulting yellow oil was dissolved in dichloromethane (50 mL), cooled to 0° C., and was treated with aluminum chloride (4.30 g, 32.0 mmol) in portions. The mixture was heated at reflux for 30 min, cooled to rt, and poured onto ice water with stirring. The organic layer was separated and successively washed with saturated, aqueous sodum bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (4/1 ethyl acetate/hexane) which provided 2.46 g (47%) of 6-methoxy-1-benzothiophene-2,3-dione as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][O:21][CH3:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH:39]1([NH2:43])[CH2:42][CH2:41][CH2:40]1>O1CCCC1.Cl>[CH:39]1([NH:43][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:19][C:18]([CH2:20][O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCC1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)O)c2)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of the title compound of Step D (238 mg, 0.67 mmol) in tetrahydrofuran (7 ml) at 0° C. under nitrogen was added isobutylchloroformate (0.13 mL, 1 mmol) and N-methylmorpholine (0.15 ml, 1.3 mmol). After stirring for about 30 minutes at 0° C., cyclobutylamine (0.11 ml, 1.3 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (2×50 ml), brine (50 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (170 mg) as a viscous oil. MS (APCl+) Calc: 409.1, found: 409.7 (M+1)
Reaction SMILES: C(=N[NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][C:27]1([CH3:35])[CH2:32][NH:31][C:30](=[O:33])[CH2:29][C:28]1=O.[OH-].[Na+].Cl>C(O)(=O)C.O.CO>[CH3:26][C:27]1([CH3:35])[C:28]2[NH:15][C:16]3[C:25](=[CH:24][CH:23]=[C:22]4[CH:21]=[N:20][CH:19]=[CH:18][C:17]4=3)[C:29]=2[C:30](=[O:33])[NH:31][CH2:32]1
Reactant: CC1(C)CNC(=O)CC1=O
Reactant: c1ccc(C(=NNc2cccc3cnccc23)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC1(C)CNC(=O)c2c1[nH]c1c2ccc2cnccc21
Yield: 56.5 %

Procedure:
A mixture of N-benzhydrylidene-N′-isoquinolin-5-yl-hydrazine (154 mg, 0.48 mmol) and 5,5-dimethylpiperidine-2,4-dione (98 mg, 0.69 mmol), dissolved in acetic acid (2 mL) and water (8 drops), was submitted to microwaves for 40 minutes at 150° C. The mixture was treated with concentrated NaOH to pH 9 and was extracted three times with ethyl acetate. Purification by flash chromatography of the concentrated residue, with dichloromethane/methanol/acetic acid/water 30/2/0.5/0.2→30/4/1/0.5 as eluant, afforded a solid product, which was dissolved in methanol and treated with 1.25M HCl in methanol to pH 1. The solvent was removed under vacuum and the residue was treated with diethylether. The resulting solid was filtered, washed with diethylether, and dried under vacuum, affording 72 mg of the title compound as hydrochloric salt (28%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[CH2:19]([C@@H:26]1[CH2:31][C@@H:30]([N:32]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([C@@H:26]1[CH2:31][C@@H:30]([N:32]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:36])([F:37])[F:35])[CH2:29][CH2:28][N:27]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 16 h

Procedure:
67 μl (0.468 mmol) of benzyl chloroformate and 72 μl (0.515 mol) of triethylamine are added to a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 4 ml methylene chloride at 0°, and the mixture is left to stir at this temperature for 16 hours. Then a further 34 μl (0.234 mmol) of benzyl chloroformate and 36 μl (0.257 mmol) of triethylamine are added and stirred at room temperature for 3 hours. This is followed by dilution with methylene chloride, and the organic phase is washed with brine, dried over magnesium sulfate and evaporated to dryness. The oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.61, FD-MS: M+ =561.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1.C(Cl)Cl.CO>C(O)C>[NH2:23][CH2:22][C@H:4]1[C@H:5]2[N:6]([C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10]2)[C:2](=[O:1])[O:3]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Temperature: 78 °C

Procedure:
Compound 2-(((3S,3aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)isoindolin-1,3-dione (3.71 g, 8.263 mmol) prepared as above in (d) was partly dissolved in 50 ml of ethanol. 60 ml of methylamine alcohol solution was added and the mixture was allowed to react under reflux at 78° C. for 3 h. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, the solvent was evaporated, and the remainder was directly subjected to the next step of reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C@H:18]2[O:24][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.[K].[OH:40]OS([O-])=O.[K+]>CO.O>[CH3:13][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:12])=[O:40])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:14]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C@H:18]2[O:24][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1
Reactant: O=S([O-])OO
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCSC)cc5C)ccc(F)c43)ccc21
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CO
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCS(C)=O)cc5C)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(2-(methylthio)ethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (230 mg) in methanol (4 mL) and water (2 mL) is added potassium peroxomonoslufate (Oxone®) (490 mg). The mixture is stirred for 1 hour at room temperature and then partitioned between dichloromethane and water. The organic phase is dried (MgSO4) and concentrated to give the crude product, which is directly in the next step. Yield: 220 mg; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=553 [M+H]+.