Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.C(N(C(C)C)CC)(C)C.[Na]>C(Cl)Cl.CS(C)=O>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1
Reactant: NCC1CCN(c2nccc(/C=C3\NC(=O)NC3=O)n2)CC1
Reactant: O=Cc1ccc2ccccc2n1
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2ccnc(N3CCC(CNCc4ccc5ccccc5n4)CC3)n2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
A 2 dram round bottomed vial was charged with (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (17 mg, 0.056 mmol), quinoline-2-carbaldehyde (8.84 mg, 0.056 mmol, 1 equiv.), diisopropylethylamine (0.1 mL, 0.573 mmol, 10 equiv.), and DMSO (1 mL). The reaction mixture was shaken for 1 h at room temperature then treated with sodium triacetoxyhydroborate (23.83 mg, 0.112 mmol, 2 equiv.) and DCM (0.5 mL). The reaction mixture was shaken overnight. The sample was then filtered through a 0.45 micron syringe filter. The DMSO solution was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the desired product (3.2 mg, 24.9 mg theoretical, 12.8%). LC-MS m/z 444 (M+1).
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:2]([C:7]([N:9](C(C2C(C3C=CC=CC=3)=CC=CC=2)=O)[C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].C(O)(=O)C>CO.O1CCCC1>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(N(C(=O)c2ccccc2-c2ccccc2)C(=O)c2ccccc2-c2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a chilled (0° C.) mixture of 6.0 g of methyl 6-[[bis(2-biphenylcarbonyl)]amino]pyridine-3-carboxylate in 40 ml of methanol and 30 ml of tetrahydrofuran is added slowly 18 ml of 2N NaOH. The mixture is stirred at room temperature overnight and brought to pH 5 with glacial acetic acid. The mixture is concentrated, acidified to pH 2-3 with 1N HCl and extracted with 250 ml of ethyl acetate. The extract is washed with 50 ml of brine, dried (Na2SO4) and the solvent removed under vacuum. The residual white solid is triturated with 15 ml of ethyl acetate to give 3.35 g of white crystals, m.p. 215°-217° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1>CN(C=O)C.CCOCC.Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:5]([CH3:23])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]3[CH2:20][N:19]([CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[C:18](=[O:21])[N:17]3[CH3:22])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:32])=[CH:26][CH:27]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc3ccccc3c2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 99 mg of 2-bromomethyl naphthalene is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 51 mg (51%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.82-7.79 (m, 3H), 7.67 (s, 1H), 7.50-7.44 (m, 2H), 7.35 (d, 1H, J=8.4 Hz), 7.14 (d, 2H, J=8.6 Hz), 6.93 (t, 2H, J=8.4 Hz), 6.87-6.83 (m, 2H), 6.71 (d, 2H, J=8.6 Hz), 5.11 (bs, 1H), 4.53 (s, 2H), 3.95-3.90 (m, 2H), 3.85-3.70 (m, 1H), 3.46 (t, 1H, L=8.7 Hz), 3.23, 3.09 (ABq, 2H, J=14.0 Hz), 3.07 (t, 1H, J=8.7 Hz), 2.89 (s, 3H), 2.26-2.18 (m, 1H), 1.96-1.87 (m, 1H), 1.36 (s, 3H). HRMS (ES+) m/z exact mass calcd for C33H34N2O5F (m+1) 557.2452, found 557.2439.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:27]=[C:12]2[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:27]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccncc1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Product: COc1ccccc1CNc1cccn2nc(Nc3ccncc3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 4-aminopyridine (36.47 mg, 0.3875 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as a off-white foam (4.14 mg, 3.5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.04 (s, 1H), 8.32 (m, 2H), 8.01 (d, J=6.7 Hz, 1H), 7.68 (m, 2H), 7.24 (m, 2H), 7.03 (d, J=8.2 Hz, 1H), 6.87 (t, J=14.9, 7.6 Hz, 1H), 6.80 (t, J=14.3, 7.6 Hz, 1H), 6.40-6.31 (m, 2H), 4.47 (d, J=5.8 Hz, 2H), 3.87 (s, 3H). MS=347 (MH)+.
Reaction SMILES: CN=C=O.[CH3:5][CH:6]([N:8]=[C:9]=[O:10])[CH3:7].CP1CC=CC1.CN1[C:22](=O)[N:21](C)[C:20](=[O:25])[P:19]1[CH3:26]>>[CH3:26][P:19]1[C:20](=[O:25])[N:21]([CH3:22])[C:9](=[O:10])[N:8]1[CH:6]([CH3:7])[CH3:5]
Reactant: CC(C)N=C=O
Reactant: Cn1c(=O)n(C)p(C)c1=O
Agent: CN=C=O
Agent: CP1CC=CC1
Product: CC(C)n1c(=O)n(C)c(=O)p1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 0.41 g (7.2 mmol) of methyl isocyanate and 6.13 g (72 mmol) of 2-propyl isocyanate was added, at room temperature, over the course of 1 h, 0.7 g (7 mmol) of 1-methyl-2,5-dihydro-1H-phosphole. No exothermicity was observed. The initially colourless liquid mixture gradually changed colour to pale yellow. Stirring at room temperature for 48 hours was followed by analysis by means of 1H and 31P NMR and GC-MS. As well as unconverted 1-methyl-2,5-dihydro-1H-phosphole and small amounts of the P-oxide thereof, essentially 2 singlets in the 31P NMR spectrum at 30.8 ppm (1,2,4-trimethyl-1,4,2-diazaphospholidine-3,5-dione; cf. Ex. 1) and 15.6 ppm (compound 3) were found. The integration ratio was 1:2.2. This ratio was determined by gas chromatography to be 1:3.5. The arrangement of the N-bonded exocyclic substituents was confirmed by means of 2D NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[CH:10]=[O:11]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Br)cc1C=O
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
p-Bromoanisole (15 g., 0.08 mole) in 350 ml. of methylene chloride was cooled to 0° C. Titanium tetrachloride (30 g., 17.4 ml., 0.16 mole) was added dropwise. After 10 minutes 1,1-dichloromethyl methyl ether (12.7 g., 0.088 mole) was added dropwise and the reaction stirred for 90 minutes at 0°-10° C., then quenched into excess saturated sodium bicarbonate and methylene chloride. The organic layer was separated and combined with a further methylene chloride extract of the aqueous phase. The combined organic layers were back washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield 5-bromo-2-methoxybenzaldehyde (16.4 g., m.p. 107°-110° C.).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.S(=O)(=O)(O)[O-].[Na+]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
To a solution of (S)-4-benzyl-3-(2-(4-bromo-2-fluorophenyl)acetyl)oxazolidin-2-one (3.6 g, 9.2 mmol) in THF (40 mL) was added a solution of methyl iodide (1 M solution in toluene, 9.6 mL, 9.6 mmol). The mixture was cooled to −78° C. and a solution of sodium bis(trimethylsilyl)amide (1 M in THF, 9.6 mL, 9.6 mmol) was added dropwise. The resultant dark red mixture was stirred for 15 min at ca. −78° C. and allowed to warm up to room temperature. After 3.5 h the reaction mixture was diluted with saturated aqueous sodium bisulfate (ca. 20 mL), and extracted with ethyl acetate (1×50 mL). The extract was washed with brine (2×50 mL), dried over sodium sulfate, and evaporated under vacuum. Flash chromatography of the residue afforded the desired product (1.7 g, 45%) as light yellow solid: ESI MS m/z 407 [C19H17BrFNO3+H]+
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].Cl.C(N(CC)CC)C.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N:15]1([CH:3]=[CH:4][C:5]#[N:6])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CC=CO
Reactant: C1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC=CN1CCCCC1
Temperature: 25 °C
Yield: 79 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 75%) is added to a suspension of 41.3 g (0.3 mol) of triethylamine hydrochloride and 21.3 g (0.25 mol) of piperidine in 200 ml of ethanol and maintained for 24 h at 25° C. After working up as in Example 56, 26.9 g of 3-piperidinoacrylonitrile is obtained (79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[OH-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21

Procedure:
A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide, and 1.0 mol (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was heated at reflux for 2 hr. The mixture was poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give off-white crystals, mp 122°-124° C.
Reaction SMILES: [F-:1].[Cs+].[O:3]([C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])([F:14])[F:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:18]1[C:25]([F:26])=[N:24][C:22](F)=[N:21][C:19]=1[F:20]>>[F:20][C:19]1[N:18]=[C:25]([F:26])[N:24]=[C:22]([C:11]([F:16])([C:12]([F:13])([F:14])[F:15])[C:10]([F:1])([F:17])[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:21]=1
Reactant: FC(Oc1ccccc1)=C(F)C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Reactant: [F-]
Agent: [Cs+]
Product: Fc1nc(F)nc(C(F)(C(F)(F)F)C(F)(F)Oc2ccccc2)n1
Reaction time: 16 h
Yield: 83.5 %

Procedure:
One g (0.1 mole) of CsF and 22 g (0.1 mole) of 1-phenoxy perfluoropropene and 10 g (0.1 mole) of cyanuric fluoride are placed into a Parr bomb. The bomb is sealed and stirred at 100°-130° C. for 16 hours. After cooling, the solids are filtered off and 30 g of oil are obtained. This is distilled to produce the product compound as an oil with a boiling point of 195° C. in a yield of 39 percent.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH2:14][OH:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:25][C:26](OC(C)=O)=[O:27]>C(Cl)Cl.O>[OH:15][CH2:14][C:9]1[CH2:10][N:11]([C:26](=[O:27])[CH3:25])[CH2:12][CH2:13][C:8]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCC1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N1CCC(c2ccccc2)=C(CO)C1
Yield: 77.6 %

Procedure:
To a solution of (4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methanol hydrochloride (110 mg, 0.49 mmol) in DCM (2 mL) was added DIPEA (0.17 mL, 0.98 mmol) and Ac2O (0.05 g, 0.49 mmol), 15 min later, it was diluted with water and extracted with DCM. Organic layers were combined, dried and concentrated, the resulting crude oil was purified by column (EtOAc followed by DCM/MeOH=9:1) to give 1-(5-(hydroxymethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (88 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.Cl.Cl.[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].COC(OC)OC>ClCCCl.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([CH:21]4[CH2:23][CH2:22]4)[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2cc(CN3CCN(C4CC4)CC3)sc2n1
Yield: 61.5 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (254 mg), 1-cyclopropyl-piperazine di-HCl (264 mg), sodium triacetoxyborohydride (619 mg) and trimethylorthoformate (968 μL), was stirred in anhydrous 1,2-dichloroethane (25 mL) for 12 hours at room temperature, then diluted with dichloromethane (50 mL), and washed with 50% sodium bicarbonate solution. The organic phase was dried (MgSO4) and the solvents removed in vacuo to give a residue which was purified using flash silica chromatography to yield the title compound (217 mg) as a buff solid.
Reaction SMILES: [CH2:1]([CH:4]1[C@@:9]([CH2:20][F:21])([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[F:19])[N:8]=[C:7]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]([CH3:38])([CH3:37])[S:5]1(=[O:40])=[O:39])[CH:2]=[CH2:3].C(=O)(O)[O-:42].[Na+].O=O.[BH4-].[Na+]>C(Cl)Cl.CO>[C:25]([O:24][C:23]([N:22]([C:7]1[C:6]([CH3:38])([CH3:37])[S:5](=[O:39])(=[O:40])[CH:4]([CH2:1][CH2:2][CH2:3][OH:42])[C@@:9]([CH2:20][F:21])([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[F:19])[N:8]=1)[C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C([O-])O
Reactant: C=CCC1[C@@](CF)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: O=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(CCCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl N-[(3S)-2-allyl-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (1.95 g, 3.33 mmol) in DCM (60 mL) and MeOH (20 mL) was added sodium bicarbonate (0.56 g, 6.65 mmol). The reaction mixture was cooled to −78° C. and ozonolized for about 15 min or until analysis showed no starting material present. A stream of oxygen was passed through the solution for 5 min, and then solid sodium borohydride (252 mg, 6.65 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach RT and stirred for 1 h. The reaction was quenched with satd. aqueous NH4Cl, diluted with water to dissolve solids, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-2-(3-hydroxypropyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate which was taken to next step without further purification. LC/MS (ESI+) m/z=614 (M+Na).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:15]1([C:21]2[O:22][C:23]3[C:33]([N:34]=2)=[CH:32][C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=2[CH:24]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl:35][CH2:36][CH2:37][CH2:38][S:39][C:40]1[N:41]([CH3:56])[C:42]([C:45]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:46]=2[CH:47]=[CH:48][C:49]([CH3:55])=[N:50]3)=[N:43][N:44]=1>>[ClH:35].[ClH:35].[CH3:56][N:41]1[C:42]([C:45]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:46]=2[CH:47]=[CH:48][C:49]([CH3:55])=[N:50]3)=[N:43][N:44]=[C:40]1[S:39][CH2:38][CH2:37][CH2:36][N:29]1[CH2:28][CH2:27][C:26]2[CH:32]=[C:33]3[N:34]=[C:21]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[O:22][C:23]3=[CH:24][C:25]=2[CH2:31][CH2:30]1
Reactant: c1c2c(cc3oc(N4CCCCC4)nc13)CCNCC2
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(N7CCCCC7)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(1-piperidinyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine bis(trifluoroacetate) (0.130 mmol) and 5-(5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl)-2-methylquinoline and was obtained as a white slightly hygroscopic solid (6.2 μmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:21]([CH3:23])=[CH2:22])[C:16]([O:18]CC)=O.C(N(CCCC)CCCC)CCC.Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:18])[C:15](=[C:21]([CH3:22])[CH3:23])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Ethyl N-(4-methylphenyl)carbamate (2.87 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (3.90 g, 30 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 8 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-methylphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.07 g, yield 46.1%).
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][CH2:20][CH2:21][S:22][CH:23]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.[S-][C:30]#[N:31].[K+].P(=O)(O)(O)O>O.C(C(C)=O)C(C)C.N1C=CC=CC=1>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][N+:31]1[CH:30]=[CH:26][CH:8]=[CH:7][CH:6]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][CH2:20][CH2:21][S:22][CH:23]=1)[C:10]2=[O:25])([O-:28])=[O:27]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Reactant: N#C[S-]
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [Na]
Solvent: CC(=O)CC(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(CC1=CSCCS1)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CSC12
Temperature: 60 °C
Yield: 35.2 %

Procedure:
Water (47 cc.) and pyridine (16.1 cc.) are added to the sodium salt of 3-acetoxymethyl-2-carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-8-oxo-5-thia-1-aza- bicyclo[4,2,0]oct-2-ene (45.2 g.) and potassium thiocyanate (194 g.). After stirring, a homogeneous syrupy mixture is obtained, the pH of which is adjusted to 6.5 by addition of concentrated phosphoric acid. The mixture is heated at 60° C. for 5 hours. After cooling, the reaction mixture is diluted with distilled water (1 liter) and is washed three times with chloroform (total 800 cc.). The last traces of chloroform in the aqueous phase are removed by distillation under reduced pressure (20 mm.Hg) and the resulting solution is then treated with decolourizing charcoal, filtered through "Supercel" and cooled by means of an ice-water bath. The solution is then acidified to pH 2 by addition of 4 N hydrochloric acid whilst keeping the temperature below 5° C.; a product precipitates. The mixture is stirred for one hour whilst continuing to cool it with a mixture of ice and water, and is then washed twice by decantation with ice-water (1 liter). The precipitate is filtered off and is washed three times with ice-water (total 2 liters). The solid obtained is suspended in water (120 cc.) and a 25% solution of "Amberlite LA 2" in methyl isobutyl ketone (120 cc.) is added. The mixture is stirred until the solid has dissolved completely, and then the organic phase is decanted and discarded. The aqueous phase is extracted twice with a 25% solution of "Amberlite LA 2" in methyl isobutyl ketone (total 240 cc.), then with ethyl acetate (300 cc.) and finally three times with diethyl ether (total 300 cc.). The water is evaporated under reduced pressure (20 mm.Hg) at 40° C. An oil is obtained which is triturated in acetone (800 cc.). The resulting solid is filtered off, washed three times with acetone (total 300 cc.) and then dried under reduced pressure (0.5 mm.Hg). 2-Carboxylato-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-8-oxo-3- (1-pyridinio-methyl)-5-thia-1-aza-bicyclo[4,2,0]- oct-2-ene (8.3 g.) is thus obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](OCN1C2C(Cl)=NC(CCCC)=NC=2C(I)=C1C)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c2c(n1)c(I)c(C)n2COCc1ccccc1
Reactant: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Product: CCCCc1nc(N)c2c(n1)c(I)c(C)n2COCc1ccccc1

Procedure:
Prepared similarly to Intermediate 6 from 5-((benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine