Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]3=[C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]4)[CH:24]=[CH:25][N:21]3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=CN=4)=C(Cl)C=2)=NC=N3)CC1.FC(F)(F)C(O)=O>CO>[NH2:33][CH:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:23]2[CH:24]=[CH:25][N:21]3[C:22]=2[C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)=[C:2]([Cl:1])[CH:3]=2)=[N:18][CH:19]=[N:20]3)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccncc5)c(Cl)c4)c23)CC1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccncc5)c(Cl)c4)c23)CC1

Procedure:
Compound 21C (31 mg) was prepared from 21B by a route analogous to that used for the preparation of 1G as a white solid. Analytical HPLC retention time=1.480 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=464+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][S:24][C:25]1[N:30]=[C:29]([NH:31][S:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:28]=[C:27]([O:41][CH3:42])[N:26]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:38]1[CH2:37][CH2:36][N:35]([S:32]([NH:31][C:29]2[CH:28]=[C:27]([O:41][CH3:42])[N:26]=[C:25]([S:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=3[F:15])[N:30]=2)(=[O:34])=[O:33])[CH2:40][CH2:39]1)(=[O:3])[CH3:2]
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCN(C(C)=O)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.78 mL) was added to a mixture of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the title product of Example 36, 0.84 g) and N,N-diisopropylethylamine (1 mL) in DCM (5 mL). The reaction mixture was stirred at room temperature for 30 min and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc which was washed with aqueous citric acid, H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with EtOAc to give the title compound as a white solid. Yield: 78 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.[BH4-].[Na+]>FC(F)(F)C(O)=O>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]3)[CH2:16][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc2c(c1)CC(=O)NC2=O
Reactant: COC1CCC(OC)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(N3CCCC3)ccc2C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
To a solution of 6-Amino-4H-isoquinoline-1,3-dione (17.6 mg, 0.1 mmol) in trifluoroacetic acid (250 μL) is added 2,5-dimethoxytetrahydrofuran (15 μL, 0.11 mmol). The reaction mixture is shaken for 5 minutes at ambient temperature, followed by addition of sodium borohydride (9 mg, 0.22 mmol). After shaking at ambient temperature for 15 minutes, gas evolution had ceased and the reaction mixture is quenched with saturated bicarbonate solution. Upon quenching, a precipitate formed. The precipitate is filtered off, rinsed with water, and dried to yield 19.5 mg of 6-Pyrrolidin-1-yl-4H-isoquinoline-1,3-dione.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4].[CH:10](O)=[O:11].CNC1(NC)C=CN=CC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[CH:10]([O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4])=[O:11]
Reactant: C#CCOC(=O)C(C)O
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC1(NC)C=CN=CC1
Solvent: ClCCCl
Product: C#CCOC(=O)C(C)OC=O
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
19.96 g (156 mmol) of the obtained 2-propynyl 2-hydroxypropionate, 7.17 g (156 mmol) of formic acid, and 15.23 g (125 mmol) of 4,4-dimethylaminopyridine (nucleating agent) were dissolved in 100 g of 1,2-dichloroethane (solvent), and a mixed solution of 35.35 g (171 mmol) of N,N′-dicyclohexylcarbodiimide (dehydrating agent) and 50 g of 1,2-dichloroethane was added thereto at 10° C., taking 30 minutes. These were reacted at room temperature for 4 hours, and the absence of the starting materials was confirmed through gas chromatography. Subsequently, the reaction liquid was filtered to remove N,N′-dicyclohexylurea, and the filtrate was concentrated. The concentrate was purified through silica gel column chromatography, and from the fraction taken with hexane/ethyl acetate=4/1, 20.78 g (yield 85%) of 2-propynyl 2-(formyloxy)propionate was obtained.
Reaction SMILES: [OH:1]C1C=CC2[C@H]3CC[C@H]4[C@H]([C@@H]3CCC=2C=1)CCC4.[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:35]2[C@H:27]3[CH2:28][CH2:29][C@H:30]4[C@H:34]([C@@H:26]3[CH2:25][CH2:24][C:23]=2[CH:22]=1)[CH2:33][CH2:32][CH2:31]4>>[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:35]2[C@H:27]3[CH2:28][CH2:29][C@H:30]4[C@H:34]([C@@H:26]3[CH2:25][CH2:24][C:23]=2[CH:22]=1)[CH2:33][CH2:32][C:31]4=[O:1]
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]3CCC[C@H]3CC[C@H]21
Reactant: Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC[C@H]3CC[C@H]21
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@H]3CC[C@H]21

Procedure:
The 7α-substituted gon-4-en-3-one thus obtained can be aromatized to the 3-hydroxygona-1,3,5(10)-triene [Yuan, S.-S. et al, Steroids 39, 279 (1982)] which then can be methylated to the 3-methoxy derivative. Conversion to a 3-methoxygona-1,3,5(10)-triene can also be achieved directly [Brito, M. et al, Synth. Commun. 26, 623 (1996)]. When R6 is (17α-H,17β-OR7), the 17-hydroxy group is deprotected and oxidized to produce a 3-methoxygona-1,3,5(10)-trien-17-one derivative [for oxidation reactions, see: Hudlicky, M., Oxidations in Organic Chemistry, ACS Monograph 186, Washington, D.C., 1990]. When R6 is (17α-C≡CH,17β-OR7), the 17-hydroxy group is again deprotected and the 17α-ethynyl-17β-hydroxy derivative is converted to the 17-ketone e.g. by reaction with silver carbonate on celite [Rao, P. N. et al, Steroids 59, 621 (1994)] or other methods known in the art. In both cases, conversion to the 17-ketone can also be accomplished prior to aromatization. The 3-methoxygona-1,3,5(10)-trien-17-one derivative thus obtained can be brominated directly, for instance by reaction with copper(II) bromide in benzene/methanol [Segaloff, A. et al, Steroids 22, 99 (1973)]. The 3-methoxygona-1,3,5(10)-trien-17-one derivative can also be converted to the enol acetate and then treated with bromine [Johnson, W. S. et al, J. Am. Chem. Soc. 79, 2005 (1957)], or to the enol silyl ether followed by reaction with e.g. N-bromosuccinimide [Heathcock, C. H. et al, J. Amer. Chem. Soc. 104, 6081 (1982)]. Dehydrobromination of the 16α-bromoketone, e.g. by reaction with LiBr/Li2CO3/DMF [Bull, J. R. et al, J. Chem. Soc., Perkin Trans. I, 241 (1990)], usually results in a mixture of (14β)-3-methoxygona-1,3,5(10),15-tetraen-17-one and 3-methoxygona-1,3,5(10),14-tetraen-7-one derivatives. They can be separated whereafter the latter is reduced to the corresponding (17β)-3-methoxygona-1,3,5(10),14-tetraen-17-ol derivative by use of sodium borohydride, lithium aluminium hydride or other reducing agents.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][C@H:28]3[C:32](=[O:33])[CH2:31][O:30][CH2:29]3)[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:43][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:27][CH:28]3[C:32]([OH:33])([CH3:43])[CH2:31][O:30][CH2:29]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O[C@@H]3COCC3=O)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC3COCC3(C)O)CC2)c2ncnn12
Reaction time: 3 h

Procedure:
3′-Fluoro-4′-{[5-oxo-4-(trans-4-{[(3R)-4-oxotetrahydrofuran-3-yl]oxy}cyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.18 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.95 mL) was added at room temperature. The reaction mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.077 g, 42%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:26]([N:28]([CH2:39][CH3:40])[C:29]([S:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[NH2:38])=[S:30])[CH3:27]>CN(C)C=O.ClCCl>[CH2:39]([N:28]([CH2:26][CH3:27])[C:29]([S:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[NH:38][C:10]([C:3]1[N:4]=[C:5]([S:8][CH3:9])[N:6]=[CH:7][C:2]=1[Br:1])=[O:12])=[S:30])[CH3:40]
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Reactant: CCN(CC)C(=S)Sc1cnccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1nc(SC)ncc1Br
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A catalytic amount of N,N-dimethylformamide (2 drops) was added to a stirred suspension of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (2.07 g, 8.33 mmol) and a 2 M solution of oxalyl chloride (21 mL, 0.042 mol) in dichloromethane under nitrogen at r.t. Vigorous effervescence was observed. After 30 min everything had dissolved and the solvent was then evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL) and placed under nitrogen. Triethylamine (2.32 mL, 16.66 mmol) was added to this stirred solution at r.t. followed by 4-aminopyridin-3-yl diethylcarbamodithioate (2.01 g, 8.33 mmol). Everything quickly dissolved with a noticeable exotherm. After 3 h at r.t. tlc showed a new major product. The reaction was diluted with dichloromethane (20 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (40 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexane 15:85 to 60:40) to yield 4-(5-bromo-2-(methylthio)pyrimidine-6-carboxamido)pyridin-3-yl diethylcarbamodithioate (1.99 g, 51%) as a pale yellow amorphous solid. 1H NMR: δ (CDCl3, 400 MHz) 1.30 (t, J=7 Hz, 3 H), 1.51 (t, J=7 Hz, 3 H), 2.60 (s, 3 H), 3.93-4.08 (m, 4 H), 8.57-8.62 (m, 2 H), 8.69 (d, J=6 Hz, 1 H), 8.85 (s, 1 H), 10.67 (s, 1 H).
Reaction SMILES: C1(S)C=CC=CC=1.[CH2:8]([NH2:11])[CH2:9][NH2:10].[CH3:12][CH2:13][CH:14]([CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C@@H:30]1[C:61](=[O:62])[NH:60][C@@H:59]([C@H:63]([OH:65])[CH3:64])[C:57](=[O:58])[N:56]2[C@@H:52]([CH2:53][C@@H:54]([OH:66])[CH2:55]2)[C:50](=[O:51])[NH:49][C@@H:48]([C@H:67]([OH:77])[C@@H:68]([OH:76])[C:69]2[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=2)[C:46](=[O:47])[NH:45][C@@H:44]([C@H:78]([OH:83])[CH2:79][C:80]([NH2:82])=O)[C:42](=[O:43])[N:41]2[C@@H:37]([C@@H:38]([OH:84])[CH2:39][CH2:40]2)[C:35](=[O:36])[NH:34][C@H:33](O)[C@H:32]([OH:86])[CH2:31]1)=[O:28])[CH3:18])[CH3:15]>>[CH3:12][CH2:13][CH:14]([CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C@@H:30]1[C:61](=[O:62])[NH:60][C@@H:59]([C@H:63]([OH:65])[CH3:64])[C:57](=[O:58])[N:56]2[C@@H:52]([CH2:53][C@@H:54]([OH:66])[CH2:55]2)[C:50](=[O:51])[NH:49][C@@H:48]([C@H:67]([OH:77])[C@@H:68]([OH:76])[C:69]2[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=2)[C:46](=[O:47])[NH:45][C@@H:44]([C@H:78]([OH:83])[CH2:79][CH2:80][NH2:82])[C:42](=[O:43])[N:41]2[C@@H:37]([C@@H:38]([OH:84])[CH2:39][CH2:40]2)[C:35](=[O:36])[NH:34][C@H:33]([NH:10][CH2:9][CH2:8][NH2:11])[C@H:32]([OH:86])[CH2:31]1)=[O:28])[CH3:18])[CH3:15]
Reactant: NCCN
Reactant: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: Sc1ccccc1
Product: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CCN)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
According to WO96/24613 and US5552521, the primary amide group in Pneumocandin B0 is reduced to amine group (47% of yield), and then the resulting product reacts with thiophenol and ethylenediamine in turn to obtain caspofungin.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:21])([CH3:20])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: CC(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.3 mL, 6.6 mmol) was added to a solution of 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 1.0 g, 3.3 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=O)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl.[CH:32]12[O:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2.C([O-])(=O)C.[Na+].Cl.C([O-])([O-])=O.[K+].[K+]>O.ClCCCl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:34]5[CH2:33][CH:32]6[O:39][CH:36]([CH2:37][CH2:38]6)[CH2:35]5)[C:20]([C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: C1CC2CNCC1O2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CC4CCC(C3)O4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaHB(O2CCH3)3 (30 mg) is added to a mixture of {(S)-6-[(R)-4-formyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (20 mg), 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (14 mg), sodium acetate (4 mg), and 1,2-dichloroethane (1 mL) at room temperature. The mixture is stirred at room temperature overnight. 1 M aqueous HCl solution is added, the resulting mixture is stirred for 10 min, and then water is added. The mixture is basified with aqueous K2CO3 solution and extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated to give the title compound. LC (method 4): tR=1.15 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]#[CH:66])=[CH:61][CH:60]=1.C(N(CC)CC)C>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu]I>[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]#[C:66][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:20])([F:21])[F:22])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:61][CH:60]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3C#Cc3ccc(OC)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 1 Step B (374 mg, 0.991 mmol) and pyridine (0.241 mL, 2.97 mmol) in DCM (5 mL) was added trifluoromethanesulfonic anhydride (0.251 mL, 1.487 mmol). The cooling bath was immediately removed, and the reaction mixture was allowed to stir at ambient temperature. After 45 min, the reaction mixture was poured into water and extracted with DCM. The layers were separated and the organic phase was concentrated in vacuo, yielding material that was sufficiently pure for use in the next step: LCMS m/z 510.0 [M+H]+. To a flask containing the unpurified triflate were added copper (I) iodide (56.1 mg, 0.294 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (68.9 mg, 0.098 mmol), tetrabutylammonium iodide (1.088 g, 2.94 mmol), and 4-methoxyphenylacetylene (195 mg, 1.47 mmol). The flask with flushed with nitrogen, and acetonitrile (5 mL) was added. The mixture was degassed with nitrogen, triethylamine (1.00 mL, 7.17 mmol) was added, and the resulting mixture was stirred at ambient temperature. After 20 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 492.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J=8.0 Hz, 1H), 8.14 (s, 1H), 7.99 (t, J=8.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.65-7.63 (m, 2H), 7.47-7.39 (m, 2H), 7.33 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH3:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12].[C:15]([O-:20])(=[O:19])[C:16]([CH3:18])=[CH2:17]>>[CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[C:10]([O:9][CH3:8])(=[O:14])[C:11]([CH3:13])=[CH2:12].[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)[O-]
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCC
Product: C=C(C)C(=O)O

Procedure:
The procedure of Example 1 was repeated, a mixture of monomers containing 250 g of ethylacrylate, 225 g of methylmethacrylate, 25 g of methacrylate acid was employed.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C@@H:16]1[C@@H:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:19][C:17]1([C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=1[O:55][CH2:56][CH3:57])O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:8]([O:15][C@@H:16]1[C@@H:22]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:19][C@H:17]1[C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=1[O:55][CH2:56][CH3:57])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOc1ccc(C)cc1C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(C)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Boron trifluoride-diethyl ether complex (0.6 ml) and triethylsilane (1.7 ml) were added dropwise to a solution of 2,3,4,6-tetra-O-benzyl-1-C-(2-ethoxy-5-methylphenyl)-D-glucopyranose (3.5 g) at −50° C. and the mixture was stirred for two hours. Saturated aqueous solution of potassium carbonate was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(2-ethoxy-5-methylphenyl)-D-glucitol (3.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([NH:37][C:38]2[N:43]=[C:42](Cl)[N:41]=[C:40](Cl)[N:39]=2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([NH:37][C:38]2[N:43]=[C:42]([N:11]3[CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]3)[N:41]=[C:40]([N:11]3[CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]3)[N:39]=2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(=O)Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 95 %

Procedure:
(3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidine (4) (1.68 g, 5.33 mmol) was suspended in DMF (20 mL), sonicated for 2 minutes and added to the crude reaction mixture containing N-[2-benzyloxy-4-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (400). The mixture was heated to 80° C. for 8 h. LC-MS indicated complete reaction at this point. The mixture was concentrated to a volume of 50 mL and poured into ice-water. A white solid precipitated immediately and was collected by filtration under reduced pressure followed by drying under high vacuum for 16 h to give the desired product (401) as a white powder (2.32 g, 2.4 mmol, 95% total yield for two steps). LC-MS (ESI): (exact mass: 961.54) m/e=962.7 [M+1]+ (100%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:21]([O:23]C)=[O:22].[I-].[Li+].N1C=CC=CC=1>O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A mixture of methyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (4.32 g), anhydrous lithium iodide (10.8 g) and dry pyridine (43 ml) was stirred at 120° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (900 ml). Insoluble materials were removed by filtration. The aqueous layer was adjusted to pH 5 with conc. hydrochloride acid to give crystals, which were filtered off, suspended in a mixture of chloroform and methanol, stirred and filtered to give crystals, which were dried to give crystalline 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid (2.8 g).