Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])[CH3:13]>C(=O)([O-])O.[Na+].O.O1CCCC1>[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:19])(=[O:14])[CH3:13]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)O)ccc1C
Yield: 52.4 %

Procedure:
3-Amino-4-methylbenzoic acid (1.5 g) is dissolved in a solution of sodium hydrogen carbonate (1.68 g) in water (25 ml), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (2.86 g) in tetrahydrofuran (8 ml) with vigorously stirring, and the mixture is stirred at room temperature for 3 hours. Tetrahydrofuran is distilled off at a low temperature under reduced pressure, and the residue is washed with diethyl ether and acidified with hydrochloric acid, and the resulting oily substance is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure, and the precipitated crystals are separated by filtration to give the title compound (1.93 g).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1.[CH3:19][NH:20]/[C:21](/[C:28]([F:31])([F:30])[F:29])=[CH:22]\[C:23](OCC)=[O:24].C(NC(C)C)(C)C>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23](=[O:24])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[N:20]([CH3:19])[C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C(\NC)C(F)(F)F
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2ccc(Cl)cc2)C(=O)C=C1C(F)(F)F
Temperature: -62.5 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To 200 ml of toluene, 6.7 g (35 mmol) of 4-chlorophenylacetyl chloride and 14.0 g (71 mmol) of ethyl 3-methylamino-4,4,4-trifluorocrotonate were added, followed by stirring for 8 hours under heating and refluxing. After completion of the reaction, the reaction solution was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography. This crotonic acid ester was dissolved in 20 ml of THF and dropwise added to a LDA-THF solution [prepared from 54 ml (86 mmol) of a 1.6N-n-butyllithium-hexane solution, 11.3 g (112 mmol) of diisopropylamine and 200 ml of THF] under cooling to −65 to −60° C., followed by stirring at room temperature for 2 hours. After completion of the reaction, excess THF was distilled off, and a 10% citric acid aqueous solution was added thereto. Precipitated crude crystals were washed with ethyl acetate to obtain 3.6 g (yield: 34%) of the desired product. 1H-NMR (300 MHz, DMSO-d6) δ value: 3.39(3H,s), 5.82(1H,s), 7.14(2H,d), 7.40(2H,d)ppm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N>C(Cl)(Cl)Cl.CO>[C:25]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN1CCC[C@H]2Cc3nc(N)ncc3C[C@@H]21
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCN1CCC[C@H]2Cc3nc(NC(C)=O)ncc3C[C@@H]21

Procedure:
A solution was prepared containing 0.75 g of trans-(±)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline in 20 ml. of pyridine and 0.34 g. of acetic anhydride was added thereto in dropwise fashion. The reaction mixture was heated to reflux temperature under a nitrogen blanket overnight. TLC at this point in time indicated that starting material was still present; therefore, about 1.5 ml. more acetic anhydride were added and the reaction mixture again heated to reflux temperature under a nitrogen blanket. TLC, using a 9:1 chloroform/methanol solvent system containing ammonia, indicated that the reaction had gone largely toward completion but that some starting material was still present. The reaction mixture was therefore concentrated in vacuo and the resulting residue triturated in hot ethyl acetate. On cooling, crystals formed which were isolated by filtration. Thirty-four hundredths grams of trans-(±)-2-acetylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were obtained; molecular ion at 288; nmr and infrared spectra were in comformance with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([S:11][CH3:12])[NH:8]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[N:3]=1.[CH3:30]I>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([S:11][CH3:12])[N:8]2[CH3:30])=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[N:3]=1
Reactant: CI
Reactant: CSc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2[nH]1
Product: CSc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2n1C
Yield: 97 %

Procedure:
This compound was synthesized from 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-8-methylthio-9H-purine using methyl iodide, yielding the title compound in 97% yield.
Reaction SMILES: C(=O)([O-])OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1.C(Br)C=C.[CH2:32]([C@@H:34]1[N:43]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:54])[CH:41]=2)[N:36]([CH2:55][CH2:56][CH3:57])[C:35]1=[O:58])[CH3:33]>>[CH2:55]([N:36]1[C:37]2[C:42](=[CH:41][C:40]([F:54])=[CH:39][CH:38]=2)[N:43]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[C@@H:34]([CH2:32][CH3:33])[C:35]1=[O:58])[CH:56]=[CH2:57]
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Agent: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Solvent: C=CCBr
Product: C=CCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with allyl bromide according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1-allyl-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−20° (c=0.005 G/ML, DMSO); MS (ESI) m/z 391 ([M+H]+); MS (ESI) m/z 389 ([M−H]−); Anal. Calcd for C19H19FN2O4S: C, 58.45; H, 4.91; N, 7.17. Found: C, 54.53; H, 4.50; N, 6.22.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NCCCCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.27 g (6.72 mmol) of [4-(3-nitro-benzoylamino)-butyl]-carbamic acid-tert-butyl ester is mixed with 9 ml of trifluoroacetic acid and stirred for 3 hours at room temperature. The batch is carefully added to 2N NaOH solution and then extracted from ethyl acetate. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. The crude product that is obtained is recrystallized from ethanol/diisopropyl ether. 519 mg (2.19 mmol, corresponding to 33% of theory) of the product is obtained.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[I-:18].[Na+].O1CCCC1>CC(C)=O.CCOCC>[I:18][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)CCC/C=C\CI
Reaction time: 0.03 h

Procedure:
To a solution of 31.4 g of cis-7-bromo-5-heptenoic acid, methyl ester in 260 ml of acetone, containing a trace of sodium carbonate was added a solution of 24.7 g of sodium iodide in 260 ml of acetone. A precipitate formed immediately. After 2 minutes, the solution was diluted with 850 ml of ether and filtered. A trace of sodium carbonate was added to the filtrate which was then stripped, redissolved in ether, refiltered, sodium carbonate added and the filtrate stripped, giving 37.9 g of light sensitive product. This product was stored in the cold as a 1M solution in either ether or tetrahydrofuran containing a trace of sodium carbonate and protected from the light. NMR: 5.95-5.2 ppm (2H, m, olefins), 3.85 ppm (2H, d, 7 Hz, ICH2), 3.65 ppm (3H, s, OMe), 2.45-2.0 ppm (4H, m, CH2 --CH2), 1.8 ppm (2H, q, 7 Hz, CH2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-(4-fluoro-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=377.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12]1([CH3:14])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1

Procedure:
D-ribose 1 of a starting material was reacted with acetone according to the method disclosed in J.Biol.Chem., 102,187-201 (1933) to form a compound 3. Physical data for the compound 3 were found to be in accord with those in literature.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:19][CH:20]1[CH2:29][C:28]2[C:27]([NH2:30])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1)(C(C)(C)C)(C)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:30][C:27]1[C:28]2[CH2:29][CH:20]([OH:19])[CH2:21][CH2:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2c1CC(O)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Benzylchloroformate (6.96 g, 40.8 mmol) was added dropwise to a solution of Example 18B (10.3 g, 37.1 mmol,) and diisopropylethylamine (7.20 g, 55.7 mmol) in 120 mL CH2Cl2 at 0° C. The mixture was stirred for 18 hours gradually warming to ambient temperature after which the volatiles were evaporated under reduced pressure. The residue was purified on silica gel eluting with 25% EtOAc/hexanes which yielded the benzyl carbamate as a light brown oil (15.2 g, 36.9 mmol). This product was taken up in 100 mL THF followed by addition of 1.79 g (111 mmol) of triethylamine trihydrofluoride. After 24 hours, the mixture was concentrated under reduced pressure and the residue partitioned between EtOAc and 1N aq. HCl. The separated organic layer was washed with 1N aq. HCl, brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated with Et2O, and the solid was collected by vacuum filtration and dried under vacuum at 50° C. resulting 8.82 g (80%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 7.45-7.30 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.0 Hz, 1H), 5.12 (s, 2H), 4.77 (d, J=3.7 Hz, 1H), 3.87 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.43 (m, 1H), 1.84 (m, 1H), 1.58 (m, 1H); MS (ESI+) m/z 298 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:9]3[CH2:15][NH:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>CO.[OH-].[Na+]>[CH3:27][N:14]1[CH2:13][CH2:12][C:10]2[N:11]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:9]=2[CH2:15]1
Reactant: Cc1ccc(-c2nc(N3CCCC3)nc3c2CNCC3)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(N3CCCC3)nc3c2CN(C)CC3)cc1
Yield: 89.2 %

Procedure:
To a solution of 2-pyrrolidin-1-yl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.034 g, 0.12 mmol) in MeOH (2 mL) was added formaldehyde (37% in water; 0.10 mL) and NaBH(OAc)3 (0.030 g, 0.14 mmol). After the reaction was judged complete, the mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. The resulting residue was purified by FCC (2 M NH3 in MeOH/CH2Cl2) to give 0.033 g (91%) of the title compound. HPLC: Rt=8.2 min. MS (ESI): mass calcd. for C19H24N4, 308.4; m/z found, 309.5 [M+H]+. 1H NMR (CDCl3): 7.44 (d, J=8.1, 2H), 7.24 (d, J=7.9, 2H), 3.61-3.58 (m, 4H), 3.42 (5, 2H), 2.92 (dd, J=6.1, 6.0, 2H), 2.74 (dd, J=6.1, 6.0, 2H), 2.40 (5, 3H), 2.39 (5, 3H), 1.97-1.94 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccc(C)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Cc1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 58 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.44 (s, 3H), 7.29-7.38 (m, 2 H), 7.42 (t, J=7.6 Hz, 1H), 7.64-7.81 (m, 2H), 8.17 (ddd, J=9.4, 2.8, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3.[CH3:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([NH:36][CH2:37][CH2:38][NH2:39])[CH:27]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:39][CH2:38][CH2:37][NH:36][C:28]2[CH:27]=[C:26]([CH3:25])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Reactant: Cc1cc(NCCN)nc2ccccc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn4c3c2OCC42CCCC2)nc2ccccc12
Yield: 3.9 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]-quinoline-3,1′-cyclopentane]-6-carboxylic acid (13 mg, 0.04 mmol) and N1-(4-methylquinolin-2-yl)ethane-1,2-diamine (10 mg, 0.05 mmol) and 11 μL triethylamine in DMSO (0.3 mL) was stirred at 90° C. for 72 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in CH2Cl2 and purified by preparative TLC to yield 8-amino-9-fluoro-10-(2-(4-methylquinolin-2-ylamino)ethylamino)-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxylic acid (0.8 mg, 4%) as a yellow solid. MS (EP) m/z: 518 (M++1). (Calcd. for C28H28FN5O4, 517.21).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])[CH3:2].[Cl-].O=S(Cl)Cl.Cl.[NH2:25][OH:26]>C(Cl)(Cl)Cl.ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[OH:26][NH:25][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18]
Reactant: NO
Reactant: CCOC(=O)CCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCCCCCC(=O)NO
Temperature: 25 °C
Yield: 82 %

Procedure:
In a single-neck flask equipped with reflux condenser, under stirring and argon flux, the 12-ethoxy-12-oxododecanoic acid (13; 1.5 g, 5.8 mmol) is solved in chloroform (20 mL). Thionyle chloride is dropped (SOCl2; 0.64 mL, 8.8 mmol) and the reaction is carried on under reflux for 3 h. The mixture is cooled down to room temperature and the solvent is eliminated under high vacuum. The obtained product is solved in dichloromethane (20 mL) and is added, at room temperature and under stirring, with a solution of hydroxylamine hydrochloride (0.61 g, 8.8 mmol) in pyridine (10 mL) leaving to react for 12 h under the same conditions. All the solvent are eliminated under high vacuum and the remaining product is solubilised in ethyl acetate (50 mL), washed with distilled water (3×20 mL). The organic phase is anhydrified with anhydrous sodium sulphate and filtered under vacuum. The solvent is evaporated and dried under high vacuum to give 1.3 g (Yield=82%) of product as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.C1COCC1.Br[CH2:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[CH:33][N:34]2S(C1C=CC(C)=CC=1)(=O)=O>[NH4+].[Cl-]>[NH:34]1[C:35]2[C:31](=[C:30]([CH2:29][N:18]3[CH2:17][CH2:16][CH2:15][C:14]4([CH2:21][CH2:22][N:11]([C:2]5[CH:3]=[N:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=5)[CH2:12][CH2:13]4)[C:19]3=[O:20])[CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CBr)cccc32)cc1
Reactant: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc3[nH]ccc23)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
To a solution of 9-quinoxalin-2-yl-2,9-diaza-spiro[5.5]undecan-1-one (100 mg, 0.34 mmol) in THF (5 ml) sodium hydride 95% (18 mg, 0.74 mmol) was added and the mixture was stirred for 10 min at rt. Then 4-bromomethyl-1-(toluene-4-sulfonyl)-1H-indole (147 mg, 0.4 mmol) was added and the reaction mixture was heated at 50° C. over 18 h. Saturated aqueous NH4Cl solution (50 ml) was added and the reaction mixture was extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (EtOAc/hexane 4:6) to yield 80 mg (55%) of the title compound. [1H NMR (DMSO, 600 MHz) δ 11.14 (br.s, 1H), 8.84 (s, 1H), 7.81 (d, 1H, J=8.28 Hz), 7.63-7.52 (m, 2H), 7.44-7.34 (m, 2H), 7.34-7.25 (m, 2H), 7.03 (t, 1H), 6.82 (d, 1H, J=7.06 Hz), 6.43 (br.s., 1H), 4.76 (s, 2H), 4.35-4.25 (m, 2H), 3.48-3.38 (2H, m), 3.13 (t, 2H), 2.21-2.04 (m, 2H), 1.91-1.80 (m, 2H), 1.77-1.65 (m, 2H), 1.62-1.52 (m, 2H), LCMS RtE=2.70 min, [M+H]+=426.4].
Reaction SMILES: C([O:3][P:4]([N:9]([S:16]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]2[N:34]=[C:33]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:26]=2)[CH:24]=1)(=[O:18])=[O:17])[P:10](=[O:15])([OH:14])[O:11]CC)([O:6]CC)=[O:5])C.I[Si](C)(C)C>C(Cl)Cl>[C:43]1([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:32]=2[C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[N:34][C:25]([C:23]2[CH:24]=[C:19]([S:16]([N:9]([P:4]([OH:5])([OH:6])=[O:3])[P:10](=[O:11])([OH:15])[OH:14])(=[O:18])=[O:17])[CH:20]=[N:21][CH:22]=2)=[N:26]3)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCOP(=O)(O)N(P(=O)(OCC)OCC)S(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=P(O)(O)N(P(=O)(O)O)S(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a suspension of ethyl hydrogen diethoxyphosphoryl((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidate (9) (0.040 g, 0.056 mmol) in DCM (5 mL) was added iodotrimethylsilane (0.067 g, 0.34 mmol) dropwise, under a nitrogen atmosphere at 0° C. The mixture was stirred for 2 h at 0° C. and the solvent was removed under reduced pressure. The residue was cooled to 0° C. and treated with a mixture of acetone (10 mL) and H2O (0.20 mL). After stirring at 0° C. for 1 h, the mixture was stirred at room temperature overnight. The resulting suspension was filtered and the solid was washed with acetone (20 mL), dried and purified by preparative HPLC to afford ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)(phosphono)phosphoramidic acid (10) (0.025 g, 0.040 mmol, 71% yield) as a white solid. Preparative HPLC Conditions: Column: KROMASIL® C-4 (250×21.2) mm, 5 μm, Mobile Phase A: 10 mM ammonium acetate in water, Mobile Phase B: acetonitrile, Gradient: 20 to 40% B over 7 min, 100% B for 12.5 min., Flow Rate: 17 mL/min., Retention time: 9 min.; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 4.78 (d, J=3.76 Hz, 2H), 6.96 (br. s., 1H), 7.23 (dd, J=6.53, 5.27 Hz, 1H), 7.31 (dd, J=7.03, 1.25 Hz, 1H), 7.41 (d, J=7.78 Hz, 1H), 7.51-7.61 (m, 5H), 7.73 (td, J=7.65, 1.76 Hz, 1H), 7.80-7.88 (m, 1H), 7.96 (dd, J=8.41, 1.13 Hz, 1H), 8.23 (d, J=4.27 Hz, 1H), 9.11 (d, J=2.01 Hz, 1H) 9.17 (t, J=2.01 Hz, 1H), 9.67 (d, J=2.01 Hz, 1H); 31P (162.0 MHz, DMSO-d6) δ (ppm) −8.820, −8.917, −15.535, −15.629; LCMS Method I: retention time 1.56 min, [M−1]=627. HPLC Method H: Purity 95.0%, retention time 5.27 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([C:25]([O:27]CC)=[O:26])[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:19]=2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32])#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([C:25]([OH:27])=[O:26])[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[CH:19]=2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32])#[N:2]
Reactant: CCOC(=O)c1cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cc(C(=O)O)cc(C(=O)O)c2)c1F
Temperature: 60 °C

Procedure:
To 5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylic acid, diethyl ester (0.97 g, 2.0 mmol) in tetrahydrofuran/water (20 mL, 1/1) was added lithium hydroxide (0.42 g, 10 mmol). After heating at 60° C. for 90 minutes, the material was partitioned between ethyl acetate and 2 N HCl. The organic layer was separated, dried (MgSO4), and the solvent removed in vacuo to give 5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]benzene-1,3-dicarboxylic acid; NMR (DMSO) 8.25 (s,1), 7.85 (s,2), 7.4-7.7 (m,3), 7.3 (m,3), 2.4 (s,3) ppm.