Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([O:23][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:52]([O:56][C:57]([N:59]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:60]1[N:68]=[C:67]2[C:63]([N:64]=[CH:65][N:66]2O)=[C:62]([O:70][CH3:71])[N:61]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:75]([O:74][C:72]([N:59]([C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:58])[C:60]1[N:68]=[C:67]2[C:63]([N:64]=[CH:65][N:66]2[O:22][CH2:21][C@H:20]([O:23][CH2:24][P:25]([O:26][CH2:27][CH3:28])([O:29][CH2:30][CH3:31])=[O:32])[CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:62]([O:70][CH3:71])[N:61]=1)=[O:73])([CH3:78])([CH3:77])[CH3:76]
Reactant: CCOP(=O)(CO[C@@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CO[C@@H](COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a stirred mixture of diethyl (S)-[1-(t-butyldiphenylsilyloxymethyl)-2-hydroxyethoxy]methylphosphonate (540 mg, 1.12 mmol), triphenylphosphine (440 mg, 1.68 mmol) and 2-[bis-(t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine (prepared as described in EF-A-319228) (428 mg, 1.12 mmol) in dry THF (20 ml), cooled in ice and under a nitrogen atmosphere, was added dropwise diethyl azodicarboxylate (0.27 ml, 1.68 mmol). Within five minutes complete dissolution had occurred and the ice bath was removed. After 1 hour, the solution was evaporated to dryness and the residue obtained chromatographed on silica gel (initial eluant hexane: ethyl acetate 2:1, then hexane:ethyl acetate in the proportions 1:1, 1:2, 1:3) to yield (S)-2-[bis-(t-butoxycarbonyl)amino]-9-[3-(t-butyldiphenylsilyloxy)-2-(diethoxyphosphorylmethoxy)propoxy]-6-methoxypurine as a colourless glass (310 mg, 32%). 1H NMR: δH [(CD3)2SO] 0.96 (9H, s, t-Bu), 1.18, 1.19 (2×3H, 2×t, J= 7 Hz, (OCH2CH3)2), 1.37 (18H, br.s, 2×t-Bu), 3.7-4.15 (12H, m, CHCH2, (OCH2CH3)2, OCH2P, OCH3), 4.45-4.70 (2H, m, NOCH2), 7.25-7.75 (10H, m, 2×Ph), 8.75 (1H, s, H-8). m/z: (FAB+ve ion, thioglycerol/HCl) 844 (MH+, 4%), 644 (100%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[N:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=[O:33])[CH:26]=[C:27]([Cl:29])[CH:28]=1>C1COCC1.C1CCCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[C:31]([CH:32]([OH:33])[CH:1]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:34][CH:35]=[CH:36][N:37]=2)[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: O=Cc1cccnc1-c1cc(Cl)cc(Cl)c1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OC(c1cccnc1-c1cc(Cl)cc(Cl)c1)C(c1cccnc1)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,3′-methylenedipyridine (340 mg, 1.99 mmol) in THF (20 mL) at −78° C. was treated with lithium diisopropylamide (2.65 mL of a 1.5 M solution of the mono-THF complex in cyclohexane, 3.98 mmol) dropwise. After stirring at −78° C. for 30 min, 2-(3,5-dichlorophenyl)nicotinaldehyde (500 mg as a solution in 6 mL THF, 1.99 mmol) was added dropwise via syringe. The reaction mixture was stirred for 1 h at −78° C., warmed to 0° C. over 5 min, then quenched with the addition of 100 mL H2O. The mixture was extracted with EtOAc (3×60 mL) and organic extracts were pooled, dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (40 g SiO2, 0-10% MeOH/CH2Cl2 gradient elution) to provide racemic 1-[2-(3,5-dichlorophenyl)pyridin-3-yl]-2,2-dipyridin-3-ylethanol. Resolution was performed by HPLC using a chiral stationary phase (ChiralPak AD, 5 cm×50 cm, 20μ, 40-100% i-PrOH/hexanes gradient elution modified with 1 mL/L diethylamine, 80 mL/min) and provided the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[NH:21][CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:30]([O:37]CCC=O)[C:31]1C=CC=C[CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[N:21]([CH2:32][CH2:31][CH2:30][OH:37])[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1
Reactant: O=CCCOCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1CCCO
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane (3.4 mL) was added 3-(benzyloxy)propanal (160 mg, 0.98 mmol) at room temperature. After 10 min of stirring, NaBH(OAc)3 (140 mg, 0.65 mmol) was added in one portion and the reaction mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was taken-up in a mixture of 50/50 CH3CN—H2O containing 0.05% TFA. The mixture was concentrated to dryness and the residue was dissolved in CDCl3 (5 mL) and briefly exposed to daylight. The purple solution was stirred open to the atmosphere at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was treated with Pd—C (10 mg) in MeOH (2 mL) under 1 atm of H2 for 2 h. The catalyst was filtered through Celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC 30% ethyl acetate/hexanes to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-(3-hydroxypropyl)-1H-indol-5-yl)cyclopropanecarboxamide (18 mg, 8% from 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropane-carboxamide). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=7.8 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 6.94 (dd, J=7.9, 1.7 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 6.85 (d, J=11.7 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.10 (s, 1H), 5.94 (s, 2H), 4.25-4.21 (m, 2H), 3.70 (dd, J=5.7, 5.7 Hz, 2H), 1.93-1.86 (m, 2H), 1.61 (dd, J=6.8, 3.7 Hz, 2H), 1.35 (s, 9H), 1.04 (dd, J=6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 453.0.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:27][CH2:26][CH2:25][S:24]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:7]2([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)[S:27][CH2:26][CH2:25][S:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCC2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2(C3CCCCC3)SCCS2)c1

Procedure:
Compound 11 was prepared from Compound 7 using the same procedure as described above for Compound 9. Yield 16.8 g (89.6%) as an oil. Rf=0.43 (hexane:ethyl acetate 92:8); IR (neat) 2930, 1198, 1062, 698 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.33 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.33–3.09 (m, 4H), 2.17–2.09 (m, 1H), 1.92–1.88 (m, 2H), 1.73–1.58 (m, 3H), 1.27–0.97 (m, 5H). 13C NMR δ 160.20, 148.17, 107.00, 98.59, 80.97, 55.60, 50.71, 39.07, 31.18, 26.91, 26.35; MS: (ESI, Pos.) m/z 347 ([M+23]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:28]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[C:21](=[N:29]O)[C:20]=5[CH:19]=[CH:18][CH:17]=4)[NH:13][C:12]=3[CH:31]=2)[CH2:4][CH2:3]1>[Ni].C(O)C.O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:28]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[CH:21]([NH2:29])[C:20]=5[CH:19]=[CH:18][CH:17]=4)[NH:13][C:12]=3[CH:31]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3nc(-c4cccc5c4-c4ccccc4C5=NO)[nH]c3c2)CC1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3nc(-c4cccc5c4-c4ccccc4C5N)[nH]c3c2)CC1
Yield: 89.7 %

Procedure:
The procedure used in Example 6 is followed, but starting from 1.5 g of 4-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 229 mg of Raney nickel in 35 ml of ethanol and 35 ml of tetrahydrofuran for 48 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, concentration to dryness under reduced pressure and purification by formation of a paste in diisopropyl ether, in this way we obtained 1.3 g of 4-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9(R,S)-ylamine, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=1.[N:20]1([C:26]2[N:27]=[C:28]([CH2:33][C:34]([O-])=[O:35])[NH:29][C:30](=[O:32])[CH:31]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[Na+]>CN(C)C=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:34](=[O:35])[CH2:33][C:28]2[NH:29][C:30](=[O:32])[CH:31]=[C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:27]=2)=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=1
Reactant: COCCOc1cc(F)ccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COCCOc1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.9 %

Procedure:
3 ml of pyridine, 500 mg of N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride and 590 mg of 4-fluoro-2-(2-methoxyethoxy)phenylamine are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 155 mg of N-[4-fluoro-2-(2-methoxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH3:7][N:8]([CH3:17])[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([OH:16])=[CH:11][N:10]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH3:17][N:8]([CH3:7])[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][N:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(N(C)C)ncc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(N(C)C)ncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Potassium hydroxide (85%, 2.64 g, 40 mmol) was powdered and added to 20 ml of DMSO at room temperature. 2-Dimethylamino-4-methyl-5-hydroxypyrimidine (1.53 g, 10 mmol) was added and the reaction mixture stirred for 5 minutes at room temperature. Benzylbromide (1.2 ml, 10 mmol) was added and the reaction mixture after stirring for a half hour at room temperature was poured into 50 ml of water. The reaction mixture was extracted four times with 50 ml hexane portions. The combined hexane extracts were dried over Na2SO4, filtered, and evaporated. Recrystallization of the formed solid from hexane yielded 1.8 g (75% yield) of the title compound as pale yellow crystals, m.p. 73° to 74° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19](O)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:12]=[CH:13][C:14]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)cc1
Solvent: CN(C)c1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
Into a 50 mL round-bottomed equipped with a reflux condenser and N2 inlet septum was place a stir bar, 1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (93 mg, 0.32 mmol), dimethylaniline (0.3 mL) and POCl3 (10 mL). The reaction mixture was stirred at room temperature under N2 for 5 minutes and brought to reflux for 6 hrs. After cooling down to room temperature, the reaction mixture was poured into ice and extracted with CH2Cl2 quickly. The crude product was then purified by flash chromatography (EtOAc: Hex=1:1), 24 mg of product was obtained (27% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.29 (s, 3H), 8.19 (d, 2H), 8.53 (d, 2H), 8.89 (s, 1H), 9.08 (s, 1H). LCMS calculated C12H9ClN4O2S 308.01, observed 309.1 (MH+).
Reaction SMILES: [N+](C1C=C(C=C([N+]([O-])=O)C=1)C([O:9][C@@H:10]([C@@:12]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:14][O:13]1)[CH3:11])=O)([O-])=O.Cl>CO.[OH-].[Na+]>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C@:12]1([C@H:10]([OH:9])[CH3:11])[CH2:14][O:13]1
Reactant: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
[(1R)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate (50 g) was dissolved in methanol (2 lit.), to which 1N-sodium hydroxide (255 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and neutralized by an addition of 1 N-hydrochloric acid (127 ml) thereto. The resultant was concentrated under reduced pressure, to which ethyl acetate (1 lit.) and water (200 ml) were added. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride (200 ml), dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate/hexane=1/3) to give (1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (25 g) as a pale yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:25]=1.[CH3:26][O:27][C:28]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:29]=1[CH2:30][N:31]([C:44]1[S:48][N:47]=[CH:46][N:45]=1)[S:32]([C:35]1[CH:40]=[C:39]([F:41])[C:38](F)=[CH:37][C:36]=1[F:43])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:29]=1[CH2:30][N:31]([C:44]1[S:48][N:47]=[CH:46][N:45]=1)[S:32]([C:35]1[C:36]([F:43])=[CH:37][C:38]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][N:8]=[C:7]([N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]=3[CH:25]=2)=[C:39]([F:41])[CH:40]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(O)cc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of di-tert-butyl (5-hydroxy-1,2-benzoxazol-3-yl)imidodicarbonate (0.40 g, 1.1 mmol) in dimethyl sulfoxide (5 mL) was added N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.50 g, 1.1 mmol) and potassium carbonate (0.19 g, 1.4 mmol). The reaction was stirred at ambient temperature for 18 h, diluted with ethyl acetate (10 mL), washed with water (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (5-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}-1,2-benzoxazol-3-yl)imidodicarbonate as a colorless solid in 87% yield (1.09 g): 1H NMR (300 MHz, CDCl3) δ8.17 (s, 1H), 7.66-7.59 (m, 2H), 7.30-7.26 (m, 2H), 7.18-7.16 (m, 1H), 6.45-6.40 (m, 1H), 6.35 (d, J=8.1 Hz, 1H), 6.37 (s, 1H), 2.60 (s, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 1.56 (s, 9H), 1.40 (s, 9H); MS (ES+) m/z 775.8 (M+1).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]12[CH2:36][CH2:35][CH2:34][C:32]3[C:33]1=[C:28]([CH:29]=[CH:30][CH:31]=3)[NH:27][C:26]2=[O:37]>CN(C=O)C>[CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][CH2:23][CH2:24][C:25]12[CH2:36][CH2:35][CH2:34][C:32]4[C:33]1=[C:28]([CH:29]=[CH:30][CH:31]=4)[NH:27][C:26]2=[O:37])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2c([nH]c4ccccc24)C1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A 168 mg (0.98 mmol) portion of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 269 mg (1.96 mmol) of potassium carbonate were added to 3 ml of DMF solution containing 150 mg (0.49 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one and stirred overnight at room temperature. The reaction solution was extracted with chloroform and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the residue was recrystallized from acetone to obtain 98 mg of the title compound (48% in yield). An oily material obtained by concentrating the mother liquid was purified by a silica gel column chromatography (30 cc; elution by chloroform-methanol=15:1) to obtain 73 mg of the title compound (38% in yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2[CH2:15][CH2:16][CH2:17][CH2:18][C:10]1=2.C(O)(=O)C>C(Cl)(Cl)Cl>[OH:8][C:4]1[N:3]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[CH2:15][CH2:16][CH2:17][CH2:18][C:10]=3[C:9]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cccc(O)n1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)n1

Procedure:
A mixture of 2-amino-6-hydroxypyridine (2.2 g), 3,4,5,6-tetrahydrophthalic anhydride (3.0 g) and acetic acid (40 ml) is heated to reflux for about 18 hours. The reaction is then cooled and stripped. The concentrate is taken up in CHCl3 (100 ml), washed with water, dried and stripped to yield N-(6-hydroxy-2-pyridyl)-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3.[C:20]([C@:22]1([OH:29])[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28])#[CH:21]>>[OH:29][C@@:22]1([C:20]#[C:21][C:2]2[CH:19]=[CH:18][C:5]3[CH:6]4[CH2:17][CH:8]([C:9]5[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=5[C:4]=3[CH:3]=2)[CH2:7]4)[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2c(s1)C1CC(C1)c1ccc(Br)cc1-2
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2CC3C2)C1=O
Yield: 59 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as an off-white solid (14.4 mg, 59%).
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncccc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 154.2 %

Procedure:
A mixture of 3-fluoro-2-nitropyridine (1.07 g, 6.75 mmol), aniline (1.8 mL, 20.2 mmol) and Et3N (2.8 mL, 20.2 mmol) in DMF (10 mL) was stirred at 100° C. for 16 h under a nitrogen atmosphere. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% MeOH in DCM) to afford the title compound as a red oil (2.24 g, quantitative). LCMS (Method C): RT 3.03 min [M+H]+ 216.2.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O1CCOCC1>[CH3:8][C:9]([O:16][C:15](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:6])([CH3:14])[CH3:10]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 118 %

Procedure:
98% H2SO4 (7 mL; 0.13 mol) was dripped over 20 min into dioxane (70 mL), maintaining the temperature of the solution below 20° C. After addition of L-phenylalanine (commercial product) (16.5 g; 0.10 mol), the solution was stirred over 12 h at 132 kPa under an isobutene (commercial product) atmosphere (consumed isobutene 45 g; 0.80 mol). The solution was dropped into a mixture of ice (200 g) and 10 N NaOH (30 mL, 0.30 mol) and extracted with Et2O (1 L). After washing with H2O (150 mL), the organic phase was dried over Na2SO4 and evaporated in vacuo. The residue was distilled to give L-phenylalanine 1,1-dimethylethyl ester (13 g; 0.059 mol). Yield 59%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH3:7])[N:4]([CH3:8])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14](Cl)=[O:15]>>[CH3:23][O:22][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([O:10][CH3:9])[C:19]=1[O:20][CH3:21])[C:14]([NH:1][CH:2]1[CH2:6][N:5]([CH3:7])[N:4]([CH3:8])[CH2:3]1)=[O:15]
Reactant: CN1CC(N)CN1C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)NC2CN(C)N(C)C2)cc(OC)c1OC

Procedure:
The title compound was prepared as described in Example 3 of U.S. Pat. No. 4,207,327 from 4-amino-1,2-dimethylpyrazolidine and 3,4,5-trimethoxybenzoyl chloride, m.p. 163°-166° C.