Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(S[CH:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][CH:10]2O)=CC=1.[CH:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24](C(OO)=O)[CH:23]=1.[O-:33][S:34]([O-:37])(=S)=O.[Na+].[Na+].S(Cl)(C)(=O)=O.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:28][C:26]1[CH:27]=[CH:22][C:23]([S:34]([C:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][CH:10]=2)(=[O:37])=[O:33])=[CH:24][CH:25]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1COc2c(F)ccc(F)c2C1Sc1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
4-(4-Chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-ol (23.2, 71 mmole) was dissolved in 200 ml DCM and MCPBA (77%, 31.7 g, 142 mmole) was added. The reaction was stirred at room temperature for 3 hours. 10 g Na2S2O3 in 50 ml water was added to quench the reaction. The organic layer washed with 1N NaOH solution (2×100 ml), brine (100 ml), dried over Na2SO4 and concentrated. The residue was dissolved in 200 ml DCM, mesyl chloride (16.1 g, 142 mmole) and triethylamine (14.3 g, 142 mmole) were added. The reaction was stirred at room temperature for one hour. The reaction solution washed with brine (100 ml), dried over Na2SO4 and concentrated. The residue was recrystallized from EtOAc/Hexane solution to give rise to 8.4 g pure product. The residue from mother liquor was purified by column chromatography (EtOAc/hexane from 0/100 to 25/75 in 55 minute, 7.1 g). Total yield: 15.5 g, 64%. 1H NMR (CDCl3 400 MHz δ 7.84 (dd, J=8.8 and 2.2 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.30 (t, J=4.4 Hz, 1H), 7.00 (m, 1H), 6.54 (m, 1H), 4.99 (d, J=4.4 Hz, 2H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:36][CH3:37])[N:30]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:37][O:36][CH2:35][C:31]1[N:30]=[C:29]([CH2:28][N:11]([CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: COCc1cccc(CBr)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCc1cccc(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)n1

Procedure:
Using General Procedure A: Reaction of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl)-isoindole-1,3-dione, 2-bromomethyl-6-methoxymethyl-pyridine (Gillespie, R. J. et al. PCT Int. Appl. (2002), WO 2002055083), and DIPEA in CH3CN gave 2-{4-[(6-methoxymethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a yellow oil. Deprotection with H2NNH2.H2O following General Procedure E gave the free base. Conversion to the HBr salt using General Procedure D gave COMPOUND 356 as a white solid. 1H NMR (D2O) δ 1.52-1.70 (m, 4H), 1.75-1.89 (m, 1H), 1.98-2.10 (m, 1H), 2.16-2.22 (m, 1H), 2.39-2.43 (m, 1H), 2.59-2.68 (m, 1H), 2.84-3.02 (m, 5H), 3.53 (s, 3H), 4.28 (d, 1H, J=15.9 Hz), 4.36 (d, 1H, J=15.9 Hz), 4.49 (dd, 1H, J=5.7, 10.5 Hz), 4.88 (s, 2H), 7.80 (dd, 1H, J=5.7, 7.8 Hz), 7.91 (d, 1H, J=7.8 Hz), 8.08 (d, 1H, J=7.8 Hz), 8.26 (d, 1H, J=8.1 Hz), 8.47 (dd, 1H, J=7.8, 8.1 Hz), 8.57 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 20.42 (2 carbons), 24.93, 25.01, 27.62, 39.53, 51.42, 53.24, 59.28, 60.01, 70.38, 125.20, 125.72, 126.27, 140.04, 140.29, 146.84, 146.93, 151.24, 153.50, 153.82; ES-MS m/z 355 (M+H). Anal. Calcd. for C21H30N4.3.4HBr.1.2H2O: C, 38.73; H, 5.54; N, 8.60; Br, 41.72. Found: C, 39.06; H, 5.54; N, 8.44; Br, 41.42.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3]1.C1COCC1.[BH4-].[Na+]>CO.O.[Co](Cl)Cl>[NH2:13][CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:3][C:2]2=[O:1]
Reactant: N#Cc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Prepared from INT-87. To a stirring solution of 4-oxo-2-phenyl-3,4-dihydroquinazoline-6-carbonitrile INT-87 (540 mg, 2.18 mmol) in MeOH (30 mL) and THF (10 mL) was added cobalt(II) chloride hydrate (646 mg, 4.37 mmol) and sodium borohydride (826 mg, 21.8 mmol) portionwise. After stirring at room temperature for 30 min the reaction mixture was quenched with 1 M HCl (5 mL) and filtered through a celite plug, washing with THF (50 mL). The mixture was diluted with EA (100 mL) and washed with NaHCO3 (120 mL) and brine (20 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford 306 mg (56%) of 6-(aminomethyl)-2-phenylquinazolin-4(3H)-one INT-88 as a white powder. LCMS-ESI (m/z) calculated for C15H13N3O: 251; found 250 [M−H]−, tR=0.80 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:18]1[CH:22]=[C:21]([CH2:23][OH:24])[N:20]=[CH:19]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:18]1[CH:22]=[C:21]([CH2:23][O:24][C:32](=[O:33])[NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=[CH:19]1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(Cl)cc2[nH]c1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Yield: 32.7 %

Procedure:
To a suspension of the compound of Example 36 (100 mg, 288 μmol) in ethyl acetate (5 ml) were added phenyl isocyanate (68.6 mg, 576 μmol) and successively triethylamine (58.3 mg, 576 μmol), and the mixture was refluxed for 24 hours. After cooling, the precipitated crystals were collected by filtration, washed with ethyl acetate and water in sequence, and then dried under reduced pressure, thereby obtaining 44.0 mg of title compound as colorless powder. Yield 33%.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:14][CH:13]2[O:15][CH:9]([CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:12]2)[CH2:8]1.[CH3:27][C:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:11]2[CH2:10][CH:9]3[O:15][CH:13]([CH2:14][N:7]([CH2:6][CH2:5][NH:4][S:33]([C:32]4[C:28]([CH3:27])=[N:29][O:30][C:31]=4[CH3:37])(=[O:35])=[O:34])[CH2:8]3)[CH2:12]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1ccc(OCCN2CC3CN(CCN)CC(C2)O3)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1S(=O)(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile tri hydrochloride salt (1 g, 2.35 mmol; Prep F) and 3,5-dimethylisoxazole-4-sulfonyl chloride (0.597 g, 3 mmol) were dissolved in DCM (25 mL). Triethylamine (1.95 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen amosphere. The reaction mixture was concentrated and then redissolved in DCM (25 mL) and transferred to a phase separator. The DCM layer was washed with water (30 mL) and the layers were separated. The retained water was extracted with DCM (25 mL) and the layers were separated. The combined DCM fractions were concentrated under reduced pressure. Purification was performed by precipitation from a mixture of DCM, EtOAc and IPA to give a solid material (0.2 g, 17%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25](C)=[CH:24][CH:23]=2)(=O)=O)=[N:17][N:16]=[N:15]1)(OC(C)(C)C)=O.C1C=CC(S)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]1([S:19][C:18]2[N:14]([CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[N:15]=[N:16][N:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)c2nnnn2C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Sc2nnnn2C[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 135.4 %

Procedure:
The mixture of 2 (6.0 g, 14.7 mmol), phenylthiol (6.5 g, 58.8 mmol) and K2CO3 (4.5 g, 41.1 mmol) in CH3CN (74 ml) was stirred for 2 days at room temperature. The reaction mixture was filtered through a pad of Celite and then concentrated in vacuo. The crude was purified by silica gel column with (Hexane:EtOAc=1:1) as an eluant to give 3 (5.2 g, 97%) as an colorless oil. [α]D −29.2 (c 1.34, CHCl3). 1H NMR (400 MHz, CD3OD, −20° C., rotamers 1:1): δ 1.30 & 1.42 (s, 9H), 1.73 & 2.01 (m, 4H) 3.40 & 3.45 (m, 13.2 Hz, 2H), 4.23 & 4.25 (m, 1H), 4.38 & 4.58 (m, 2H), 7.42 & 7.46 (m, 3H) 7.56 & 7.60 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 21.2, 23.6, 28.5, 46.5, 49.7, 50.4, 56.7, 60.5, 80.7, 128.1, 129.9, 133.1, 153.5, 154.9; IR (film): 2975, 1693, 1391, 1167, 688 cm−1; MS:(ESI) [M+1]+361.2
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([Cl:11])=[CH:5][N:4]=1.I([O-])(=O)(=O)=[O:13].[Na+].C(Cl)Cl.CO.C(O)(=O)C.[OH2:27]>>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([Cl:11])=[CH:5][N:4]=1)(=[O:13])=[O:27]
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNc1nc(SC)ncc1Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nc(S(C)(=O)=O)ncc1Cl

Procedure:
Prepared from 2-methylsulphenyl-4-methylamino-5-chloro-pyrimidine by reacting with sodium periodate in glacial acetic acid/water, Rf value: 0.50 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.284 mol), 4-fluoro phenylboronic acid (120 g, 0.853 mol), Cu(OAc)2 (113 g, 0.568 mol) and pyridine (88 g, 1.137 mol) in DCM (500 mL) was stirred at RT for 4 h open to air. The reaction mixture was filtered and the solids were washed with water. The filtrate was extracted with DCM (2×250 mL). The combined organics were dried over Na2SO4 and concentrated to afford ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. The product was carried forward without further purification. (77 g, 95% yield).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CS(Cl)(=O)=O.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH3:34])=[CH:25][CH:24]=2)[N:17]=1>N1C=CC=CC=1>[NH2:22][C:20]1[N:21]=[C:16]([NH:15][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[N:17]=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH3:34])=[CH:25][CH:24]=2)[N:19]=1
Reactant: O=C(O)c1cccnc1
Reactant: COc1ccc(-c2nc(N)nc(N)n2)c2ccccc12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(N)nc(NC(=O)c3cccnc3)n2)c2ccccc12
Reaction time: 3 h

Procedure:
Nicotinic acid (2.98 grams) was dissolved in 40 ml of pyridine, 1.39 grams of methanesulfonyl chloride was added thereto, and the mixture was heated to reflux for thirty minutes. Then 2.7 grams of 2,4-diamino-6-(1-methoxy-4-naphthyl)-s-triazine was added thereto, the mixture was heated to reflux for four hours, and the refluxing was continued for three hours more after addition of 0.35 gram of methane sulfonyl chloride. After the reaction was completed, pyridine was evaporated therefrom, water was added to the residue, the crystals separated out were collected by filtration, well washed with water, added to 130 ml of methyl alcohol, the mixture was heated to reflux for twenty minutes, and the crystals were collected by filtration when the solution was still hot. The crystals were then suspended in 50 ml of methyl alcohol, the suspension was heated to reflux for three hours, and dioxane was added to the suspension to afford 2-amino-4-nicotinoylamino-6-(1-methoxy-4-naphthyl)-s-triazine, beige needles, melting point 208° to 209° C. The yield was 1.84 grams.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C=O)C>[N:3]1([C:9]2[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1-n1ccnc1
Temperature: 100 °C
Yield: 73 %

Procedure:
To a suspension of NaH 60% (0.09 g, 3.97 mmol) in DMF (20 mL) at 0° C. was added in one portion 1H-imidazole (2.5 mol eq, 0.61 g). After 10 min 2-chloro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.61 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction was cooled at room temperature, water was added and the aqueous solution was extracted with EtOAc (3×25 mL). The recombined organic phases were dried over sodium sulfate and evaporated to dryness to give the 2-imidazol-1-yl-4-(trifluoromethyl)benzonitrile as pale yellow oil (0.63 g, 73% Yield) used for the reduction without further purification.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[C:22]([CH3:31])[N:23]3[C:28]=2[C:27]([Cl:29])=[CH:26][C:25]([Cl:30])=[CH:24]3)[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[Cl:30][C:25]1[CH:26]=[C:27]([Cl:29])[C:28]2[N:23]([C:22]([CH3:31])=[CH:21][C:20]=2[CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:11]2=[O:32])[CH:24]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 0.041 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (2 mg, 0.082 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product. LCMS (ESMS): m/z 460.17 (M+H+).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:44]([NH:46][C@H:47]([C:53]([OH:55])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:45])[C@@H:41]([CH3:43])[OH:42].C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:44]([NH:46][C@H:47]([C:53]([OH:55])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:45])[C@@H:41]([CH3:43])[OH:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a solution of N-hydroxysuccinimide ester of 3-hexadecanoyloxyoctadecanoic acid (1.5 g) in tetrahydrofuran (100 ml) were added a solution of N-(L-threonyl)-L-glutamic acid (0.79 g) and triethylamine (0.88 ml) in water (220 ml). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was purified by silica gel column chromatography. Elution with chloroform-methanol (20:1) afforded powder of N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamic acid (1.0 g).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][C:6]2=[O:11])[CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCCC[CH2:13]1.BrCCCCBr.[NH4+].[Cl-].Cl>C1COCC1.C1(C)C=CC=CC=1>[C:12]([C:6]1([OH:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[CH2:1][CH2:2][CH2:3][CH2:4]2)#[CH:13]
Reactant: O=C1CCCCC12CCCC2
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: BrCCCCBr
Product: C#CC1(O)CCCCC12CCCC2
Temperature: 20 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
At 5° C., a solution of lithium acetylide ethylene diamine complex (200 g, 2.17 mol) in THF (1 l) was treated dropwise with a solution of spiro[4.5]decan-6-one (196 g, 1.29 mol, prepared from cyclohexanone and 1,4-dibromobutane in the presence of potassium tert.-butylate in toluene) in THF (0.8 l). The resulting mixture was stirred for 3 h at 20° C., poured into a saturated aqueous solution of NH4Cl, acidified with conc. HCl and extracted three time with MTBE (500 ml). The aqueous phase was extracted twice with MTBE (150 ml) and the combined organic phases were washed twice with water (500 ml), once with a saturated aqueous solution of NaCl, dried (MgSO4), and concentrated. Short-path Vigreux-distillation (0.08 mbar, bath temperature: 140° C., head temp.: 100-105° C.) of the crude product (257 g) gave 6-ethynylspiro[4.5]decan-6-ol (180.8 g, 79%).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.[CH3:28][C:29]1[CH2:33][S:32][C:31](=[S:34])[N:30]=1.Cl.C(OC(C)C)(C)C>O.C(=O)(O)[O-].[Na+].CO>[C:25]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:34][C:31]1[S:32][CH:33]=[C:29]([CH3:28])[N:30]=1)[CH:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]1[S:18][C:19](=[O:22])[S:20][CH:21]=1)[C:9]2=[O:24])([OH:27])=[O:26]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: CC1=NC(=S)SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)OC(C)C
Product: Cc1csc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)n1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
3-Acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (7.7 g.) is dissolved in distilled water (100 cc.) and sodium bicarbonate (1.64 g.). A solution of 4-methyl-2-thioxo-1,3-thiazoline (2.76 g.) in distilled water (75 cc.) and sodium bicarbonate (1.64 g.) is added and the resulting solution is heated to 60° C. for 6 hours. After cooling, it is acidified to pH 5.5 by adding 4 N hydrochloric acid and then extracted with ethyl acetate (100 cc.), which is discarded. The acidification is continued to pH 2 in the presence of ethyl acetate (300 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.). The organic extracts are washed twice with water (200 cc.), dried over magnesium sulphate, treated with decolourising charcoal and then filtered and concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is dissolved in methanol (30 cc.) and this solution is then added to isopropyl ether (200 cc.). A product precipitates and is isolated by filtration to give 2-carboxy-3-[(4-methyl-1,3-thiazol-2-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[C:14]([CH:23]=[CH2:24])=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:26])([CH3:25])[C:9]2=[O:27])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:23]([C:14]1[C:13]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[O:11][C:12]=2[CH:17]=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=1)[CH3:24]
Reactant: C=Cc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Yield: 104 %

Procedure:
To a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 156, 200 mg) in ethanol (20 mL) was added 10% palladium-carbon (water content: ca. 50%, 200 mg), and the mixture was stirred under atmospheric pressure of hydrogen at room temperature for 20 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; chloroform→chloroform/ethyl acetate=10/1) to give N-[5-ethyl-4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (209 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([NH:11][C:12]1[N:21]=[C:20]2[C:15]([C:16]([N:35]3CCCC3)=[N:17][C:18]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[N:19]2)=[N:14][C:13]=1Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:4]([NH:11][C:12]1[N:21]=[C:20]2[C:15]([C:16]([N:35]3[CH2:42][CH2:43][CH2:44][CH2:45]3)=[N:17][C:18]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[N:19]2)=[N:14][C:13]=1[O:2][CH3:1])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCCC3)c3nc(Cl)c(NCc4ccccc4)nc3n2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Product: COc1nc2c(N3CCCC3)nc(N3CCNCC3)nc2nc1NCc1ccccc1
Reaction time: 0.1 h

Procedure:
100 mg (1.76 mmol) sodium methoxide and 300 mg (0.571 mmol) tert.butyl 4-(7-benzylamino-6-chloro-4-pyrrolidin-1-yl-pteridin-2-yl)-piperazine-1- carboxylate are suspended in 5 ml of tetrahydrofuran, then placed in the microwave for 0.1 hours at 120° C. Then the reaction mixture is concentrated by evaporation, the residue is combined with methanol and suction filtered. The mother liquor is concentrated by evaporation, then extracted with water and dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography. Corresponding fractions are concentrated by evaporation and crystallised from diethyl ether.