Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]#[CH:11])[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].I[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:14]=1.C(NC(C)C)(C)C>COC(C)(C)C.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1([CH2:9][C:10]#[C:11][C:13]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[N:14]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reactant: C#CCC1(N)CCN(C)C1=O
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CCC2(N)CCN(C)C2=O)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 80.3 %

Procedure:
To a stirred solution of 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may be prepared as described in Description 3) (2.3 g, 15.11 mmol) in tert-butyl methyl ether (50 mL) was added 2-iodo-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (which may be prepared as described in Description 12) (6.05 g, 16.62 mmol). diisopropylamine (6.35 mL, 45.34 mmol) was then added, followed by copper iodide (57.56 mg, 0.300 mmol) and bis(triphenylphosphine)palladium (II) dichloride (106.07 mg, 0.1500 mmol). The reaction was then stirred at room temperature for 5 days. The reaction mixture was transferred to a separating funnel and the flask washed with an additional quantity of tert-butyl methyl ether (15 ml). The organic solution was washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over magnesium sulphate, filtered, and then the magnesium sulphate washed with dichloromethane (30 ml). The filtrate was concentrated at reduced pressure to give a yellow foam. The product was purified by silica gel chromatography eluting with ethyl acetate followed by an increasing percentage of a solution of 10% 0.880 ammonia in methanol, to give the title compound (D14b) as a yellow foam (4.71 g). This racemate was consistent by NMR and mass spectroscopy with the R isomer prepared in Description 14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7](=[S:22])[NH:9][CH3:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cc(Br)ccc1F
Solvent: Cc1ccccc1
Product: CNC(=S)c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
A mixture of 5-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson's reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 3.5 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purified by flash column chromatography (0-20% ethyl acetate/heptanes) to give the title compound (494 mg, 92%) as a yellow oil that solidified upon standing. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.20 (dd, J=6.93, 2.63 Hz, 1H), 8.06 (br.s., 1H), 7.47 (ddd, J=8.73, 4.44, 2.63 Hz, 1H), 6.95 (dd, J=11.12, 8.78 Hz, 1H), 3.32 (dd, J=4.88, 0.78 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].O.[NH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([S:27][C:28]#[N:29])[CH:24]=[CH:23][C:21]=2[N:22]=1>O1CCCC1>[S:27]([C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([NH:17][C:1](=[O:9])[O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[S:19][C:20]=2[CH:26]=1)[C:28]#[N:29]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#CSc1ccc2nc(N)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen carbonate and 9.4 cm3 of water are added, at 20° C., to a solution of 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of tetrahydrofuran. The resulting mixture is subsequently stirred at 20° C. for 20 h and then extracted with 2×150 cm3 of ethyl acetate. The organic phases are combined and then washed with 3×50 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and the product is spin-filter-dried and dried under vacuum at 20° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[Br:22][C:23]1[C:24]([N:2]2[CH2:3][CH:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=3)[CH2:5]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Reactant: Fc1ncccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccnc1N1CC(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
To a solution of 2-azetidin-3-yl-quinoline hydrochloride (1.70 g, 7.75 mmol) in DMF (30 mL) at room temperature was added Cs2CO3 (5.2 g, 16 mmol) and 3-bromo-2-fluoro-pyridine (1.5 g, 9.0 mmol). The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.50 g, 4.4 mmol, 58% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(O[K])(C)(C)C.CC(O)(C)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCOCC2

Procedure:
To a solution of 6-bromo-1-indanone (1.033 g, 4.89 mmol) in anhydrous THF (100 mL) under N2 atmosphere at room temperature was added a solution of tBuOK in tBuOH (1 M, 10.3 mL, 10.3 mmol) within 30 min (the color turned to deep black upon a drop of tBuOK solution was added), followed by 1-bromo-2-(2-bromoethoxy)ethane (1.134 g, 0.62 mL, 4.89 mmol). The reaction was quenched with saturated aqueous NH4Cl, and extracted with ether two times. The combined organic phases were washed with H2O, brine, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black tar. It was purified by flash chromatography on silica gel yield 300 mg of the desired product. MS ESI+ve m/z 281 (M+H)30.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([CH:12]([OH:14])[CH3:13])[CH2:9][C@H:8]1[CH2:15][OH:16])=[O:6])[CH:2]=[CH2:3].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[C:12]([CH:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([C:15]([OH:19])=[O:16])[CH2:9]1)(=[O:14])[CH3:13]
Reactant: C=CCOC(=O)N1CC(C(C)O)C[C@H]1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-4-(1-hydroxyethyl)-2-hydroxymethylpyrrolidine (30 g) in acetone (300 ml) was added dropwise Jones' Reagent (2.67N, 245 ml) at 0° C. After stirring for 3 hours, to the reaction mixture was added dropwise 2-propanol (500 ml), and the mixture was stirred at 0° C. for 1 hour. The precipitate was filtered off and the filtrate was evaporated to give a residual oil, which was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave (2S)-4-acetyl-1-allyloxycarbonylpyrrolidine-2-carboxylic acid (26.56 g).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].C([Mg]Br)C.Br[CH2:17][C:18]#[C:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:17][C:18]#[C:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C#CCCCCCCC(=O)O
Reactant: CCCCCCC#CCC#CCBr
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCC#CCC#CCC#CCCCCCCC(=O)O
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of non-8-ynoic acid (nD25 1.4529, m.p. 20°-2°; 30.8 g, 0.2 mol) in tetrahydrofuran (100 ml) was added a 1.45 M solution (275 ml) of ethylmagnesium bromide in tetrahydrofuran during 30 minutes at 0°. The resulting mixture was stirred for 21/2 hours, after which cuprous cyanide (720 mg, 4 mmol) was added and stirring was continued for 10 minutes. A solution of 1-bromododeca-2,5-diyne (Struyk et al., loc.cit., b.p. 78°-80°/0.001 mm Hg, nD25 1.5055; 36.2 g, 0.15 mol) in tetrahydrofuran (75 ml) was then added during 10 minutes, and the stirred mixture heated to boiling and boiled under reflux for 15 hours: at the end of the first 4 hours another portion of cuprous cyanide (360 mg) was added. After refluxing was completed the bulk of the solvent present was distilled off under reduced pressure and to the cooled residue were added ether (100 ml) and aqueous 2N sulphuric acid. The mixture was thoroughly shaken, the ether layer which formed on standing was separated off and the aqueous layer extracted with ether; the combined ether layers were washed with saturated aqueous ammonium chloride solution, then with water, dried with anhydrous sodium sulphate and evaporated. The residue was dissolved in a small quantity of light petroleum and the solution chromatographed on a column (30 cm length and 2.2 cm diameter) of silica gel using as eluant mixtures of light petroleum and ether commencing with a proportion by volume of 95:5 and proceeding with increasing proportions of ether, with a final proportion of 40:60. The eluted fractions found to contain acid were combined and evaporated: the residue was crystallised from a mixture of light petroleum and ether (85:15 by volume) at -5° to give heneicosa-8,11,14-triynoic acid (22.7 g, 48%), m.p. 57°-8°; infrared absorption peaks at 1690 (--COOH) and 1309 cm-1 (--CH2C≡C--). The acid was converted by reaction with an ether solution of diazomethane to its methyl ester which was submitted to GLC and shown to be of 99.5% purity; mass spectrum parent peak m/e=328.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[Si:15]([O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1

Procedure:
To a methanol (28 mL) solution of 1-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}piperidine (2.80 g, 9.18 mmol) was added palladium hydroxide on carbon (20 weight %, 280 mg. 0.40 mmol) and stirred under an atmospheric pressure of hydrogen for 16 hours. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated in vacuo to afford the title compound. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 3.77-3.70 (m, 1H), 3.09-3.02 (m, 2H), 2.61 (ddd, J=12.5, 9.5, 3.0 Hz, 2H), 1.82-1.72 (m, 2H), 1.42 (dtd, J=13.0, 9.0, 3.7 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H); LC-MS: m/z 216.2 (M+H).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]1[C:22]2[C:17](=[C:18]([OH:24])[C:19]([OH:23])=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1>>[ClH:9].[NH2:11][CH2:12][C:13]1[C:22]2[C:17](=[C:18]([O:24][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]([O:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Agent: Cl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(OC(=O)c1ccccc1)c2OC(=O)c1ccccc1

Procedure:
Following the procedures described in Example 5, replacing trimethylacetyl chloride with benzoyl chloride and 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride with the compound of Example 15, the title compound was prepared. m.p. 173°-182° C.; 1H NMR (CD3OD) δ: 2.88 (t, 1H), 3.05 (dd, 1H), 3.65-3.8 (m, 2H), 4.0-4.1 (br s, 1H+CH3OH), 6.35 (d, 1H), 7.05-7.35 (m, 10H), 7.35-7.55 (m, 3H), 7.9-8.0 (m, 4H), 8.5-8.65 (br s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:21]=[O:22]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]cc(C=O)c2c1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To stirred dimethylformamide is added dropwise phosphorus oxychloride. The mixture is stirred for 10 min and a solution of 5-methoxyindole in dimethylformamide is added dropwise. The mixture is heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide in water. The mixture is heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice and filtered. The filter cake is recrystallised (methanol) to give the product as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl-].[Li+]>CS(C)=O.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([OH:17])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 23.3 %

Procedure:
Cyanoester 2 (0.76 g, 3.91 mmol), water (0.14 mL, 7.82 mmol) and lithium chloride (0.66 g, 15.6 mmol) were heated to 150° C. in DMSO (40 mmL) for 22 hours. The mixture was allowed to cool, diluted with water (150 mL), and extracted with ether (3×50 mL). The combined ether fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 95:5) to give the cyanide 3 (0.21 g, 44%) as a 60:40 mixture of diastereoisomers; Rf(heptane-ethyl acetate, 9:1) 0.44; νmax(film)/cm−1 2238 (CN); Major diastereoisomer: δH (400 MHz; CDCl3) 2.97 (1H, m), 2.87 (2H, m), 2.32–2.18 (2H, m), 2.10–1.96 (3H, m), 1.92–1.78 (2H, m), 1.48–1.38 (1H, m); Minor diastereoisomer: δH (400 MHz; CDCl3) 3.13 (1H, m), 2.87 (2H, m), 2.32–2.18 (2H, m), 2.10–1.96 (3H, m), 1.92–1.78 (2H, m), 1.48–1.38 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)[N:5]=[CH:6][C:7]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Yield: 22.3 %

Procedure:
6,7-Difluoroquinoxalin-2(1H)-one (Intermediate 152, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 5% toluene/ethyl acetate gave 500 mg (23%) of the product as a colorless solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)(=O)=O.O.[I-:23].[Li+]>CN(C)C=O>[I:23][C:7]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: [I-]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1OS(=O)(=O)C(F)(F)F)CCC2
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2c(c1I)CCC2
Temperature: 150 °C
Reaction time: 7 h
Yield: 77.8 %

Procedure:
To a solution of 5-methyl-7-nitroindan-4-yl trifluoromethanesulfonate (3.02 g) in N,N-dimethylformamide (10 mL) was added lithium iodide mono hydrate (6.10 g). The mixture was stirred under an argon atmosphere at 150° C. for 7 hours. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 1 mol/L aqueous solution of sodium hydroxide, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.19 g).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:12]=3[N:3]12.[Br-].[CH2:27]([CH:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:37]=[C:36](OS(C(F)(F)F)(=O)=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:27]([CH:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:37]=[C:36]([C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:4]4=[N:5][NH:6][C:7](=[O:8])[CH:2]([CH3:1])[N:3]4[C:12]=3[CH:13]=2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (prepared from the corresponding bromide (Preparation #1, Step D) following similar procedure as describe in Example #109, Step B, 0.103 g, 0.3 mmol), tert-butyl 6-benzyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.253 g, 0.6 mmol), Pd(dppf)Cl2—CH2Cl2 complex (0.073 g, 0.09 mmol) and K2CO3 (0.124 g, 0.9 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was heated at 90° C. for 10 h. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by PTLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 6-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.147 g, 99%). LC/MS (Table 1, Method 2) Rt=1.308 min; MS m/z: 489 [M+H]+.
Reaction SMILES: C1C=CC(C[NH:8][CH:9]([C:22]([OH:24])=[O:23])[CH:10]([NH:14]CC2C=CC=CC=2)[C:11]([OH:13])=[O:12])=CC=1.O>C(O)(=O)C.Cl.[Pd]>[CH:9]([NH2:8])([C:22]([OH:24])=[O:23])[CH:10]([NH2:14])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: NC(C(=O)O)C(N)C(=O)O

Procedure:
Meso-2,3-bis(benzylamino)succinic acid (9.5 g, 0.029 mol) was dissolved in a mixture of glacial acetic acid (50 ml) and concentrated hydrochloric acid (50 ml). Hydrogenolysis was effected at ambient temperature with 10% palladium on charcoal (1.0 g) as catalyst. The reaction was run until NMR showed that unreacted starting material was no longer present. Water (100 ml) was added and the catalyst was removed by filtration. The filtrate was concentrated (rotavapor) and the residue was dissolved in dilute aqueous sodium hydroxide. pH was adjusted to approximately 5 upon addition of glacial acetic acid. Crystals were filtered off and washed.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:11])[C@@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:10][C:6]1([CH3:9])[O:5][C@H:4]([C:3]([Cl:11])=[N:2][O:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:8][O:7]1
Reactant: CC1(C)OC[C@@H](C(Cl)=NO)O1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A solution of (S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (9.88 g, 55.01 mmol) in THF (200 mL) at 0° C. was added methanesulfonyl chloride (4.703 ml, 60.51 mmol), followed by N,N-diisopropylethylamine (10.54 ml, 60.51 mmol) and the reaction was stirred for 1 hour at ambient temperature, filtered and concentrated in vacuo. The residue was purified over silica gel (25 to 100% ethyl acetate in hexanes) to afford (S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (12.28 g, 47.65 mmol, 86.63% yield) as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18](=O)[CH3:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>ClCCCl>[F:1][C:2]1[C:3]([NH:17][C:18](=[S:30])[CH3:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: ClCCCl
Product: CC(=S)Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 100 °C
Yield: 3.2 %

Procedure:
N-(5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl)acetamide (50 mg, 0.42 mmol) was stirred in a Biotage Initiator® microwave vessel with 1,2-dichloroethane (3 mL) and Lawesson's reagent (170 mg, 0.42 mmol). The vessel was heated in a Biotage Initiator® microwave to 100° C. for 5 minutes then cooled room temperature, filtered, and diluted with CH2Cl2. The reaction mixture was then washed brine, and the layers were separated. The organic extract was dried onto silica and purified by flash chromatography. The product-containing fractions were then evaporated to dryness and purified again by reverse-phase HPLC to give 4 mg of N-(5-fluoro-2-(4-fluorobenzyl-oxy)pyrimidin-4-yl)ethanethioamide (4%) as a yellow glass: 1H NMR (CDCl3) δ 9.34 (b, 1H), 8.29 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.06 (m, 2H), 5.33 (s, 2H), 3.13 (s, 3H); HPLC-MS (ESI): m/z 294 (ES−).