Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C=O.P([O-])(OCC)([O:13][CH2:14]C)=O.C1(C)C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:13][CH2:14][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CCOP(=O)([O-])OCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOP([O-])OCC
Agent: C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC

Procedure:
To a reaction vessel containing inert atmosphere, e.g., nitrogen, was added diethyl phosphite, paraformaldehyde, triethylamine and toluene, the mixture was heated for 4-8 hours until TLC showing no diethyl phosphate remaining. After cooling to below 0° C., to the mixture was added a solution of p-toluenesulfonyl chloride toluene and triethylamine, after completion of the reaction, diethyl p-toluenesulfonyloxymethylphosphonate (C) was obtained;
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:46])([CH3:45])[NH:37][S:38]([CH2:41][CH2:42][CH2:43][Cl:44])(=O)=[O:39]>>[CH3:35][Si:36]([CH3:46])([CH3:45])[N:37]=[S:38]([Cl:1])([CH2:41][CH2:42][CH2:43][Cl:44])=[O:39]
Reactant: C[Si](C)(C)NS(=O)(=O)CCCCl
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)CCCCl

Procedure:
The reactants used in the foregoing general procedure were hexachloroethane (0.0902 mol, 21.79 g), triphenylphosphine (0.0911 mol, 24.14 g), triethylamine (0.0902 mol, 12.8 mL), N-trimethylsilyl sulfonamide (3e) (0.0902 mol, 20.66 g). The identity of the reaction product was confirmed by the presence of signals at the following shifts in the 1H NMR spectrum: 90 MHz (CHCl3): 0.05 (s, 9H), 2.12 (m, 2H, SCH2CH2), 3.38 (t, 2H, SCH2), 3.45 (t, 2H, ClCH2).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].N[C@H:8]([C@H:11]([C@H:13]([C@@H:15](CN)[OH:16])[OH:14])[OH:12])[CH:9]=[O:10].C(Cl)(=[O:22])C=C>N1C=CC=CC=1>[O:16]=[CH:15][C@@H:13]([C@H:11]([C@H:8]([C@@H:9]([CH2:1][OH:4])[OH:10])[OH:22])[OH:12])[OH:14]
Reactant: NC[C@@H](O)[C@H](O)[C@H](O)[C@@H](N)C=O
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)Cl
Agent: [K+]
Solvent: c1ccncc1
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Using a similar procedure as outlined in Example 4 and shown in FIG. 2 (with either pyridine or potassium carbonate as base), 2,6-diamino-2,6-dideoxy-D-galactose is reacted with acryloyl chloride to yield N,N-(2,6-deoxy-D-galactose)-2,6-acrylamide, galactose-derived N-((5-acrylamido-3,4,6-trihydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([C:15]#[N:16])=[CH:6]2.[CH3:17][N:18]([CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>COCCO>[CH3:17][N:18]([CH3:26])[C:19]1[CH:20]=[C:21]([NH:25][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][C:7]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2cc(C#N)cnc2cc1OC
Reactant: CN(C)c1cccc(N)c1
Solvent: COCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(N(C)C)c3)c2cc1OC
Yield: 19 %

Procedure:
A 1.25 gram (5 mmole) portion of 4-chloro, 6,7-dimethoxy-quinoline-3-carbonitrile and a 1.05 gram (5 mmole) portion of N,N-dimethyl-1,3-phenylenediamine in 1 ml of 2-methoxyethanol were refluxed for 2 hours in an oil bath at 154 deg. Cooling gave a solid which was recrystallized from water to give 0.4 grams (19%) of 4-(3-Dimethylamino-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile which melted at 246-249° C.: mass spectrum (electrospray m/e): (M+H)=349.2., (M+2H)+2=174.9.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][C@H:59]1[C:63](=[O:67])[N:64]([CH3:66])[CH3:65]>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][CH2:57][N:58]4[CH2:62][CH2:61][CH2:60][C@H:59]4[C:63](=[O:67])[N:64]([CH3:65])[CH3:66])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN(C)C(=O)[C@@H]1CCCN1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCC[C@H]1C(=O)N(C)C
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
Diethyl azodicarboxylate (0.18 ml, 1.14 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (111 mg, 0.35 mmol), (prepared as described for the material in Example 2), triphenylphosphine (312 mg, 1.19 mmol) and (S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl) pyrrolidine (84 mg, 0.42 mmol) in methylene chloride (10 ml) cooled at 0° C. under nitrogen. The mixture was stirred for 15 minutes at 0° C., the mixture was allowed to warm to ambient temperature and was then stirred for 22 hours. Further (S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidine (10 mg, 0.05 mmol), triphenylphosphine (355 mg, 0.13 mmol) and diethyl azodicarboxylate (20 μl, 0.13 mmol) were added and the mixture was stirred for a further 2 hours. The mixture was partitioned between water and methylene chloride and the aqueous phase was adjusted to pH with 2M hydrochloric acid. The aqueous layer was separated, adjusted to pH9 with sodium hydrogen carbonate and was extracted with methylene chloride. The combined organic extracts were washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (85/15 followed by 75/25 and 60/40). The purified product was dissolved in methylene chloride (5 ml) and methanol (1 ml), 3.9M ethereal hydrogen chloride (0.5 ml) was added and the mixture was diluted with ether. The resulting precipitate was collected by filtration, washed with ether, and dried under vacuum to give (S)-4-(4-chloro-2-fluoroanilino)-7-(3-(2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (86 mg, 32%).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15](=[S:19])([NH2:18])[CH2:16][CH3:17].C(=O)([O-])O.[Na+]>C(O)C>[CH2:16]([C:15]1[S:19][CH:2]=[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:18]=1)[CH3:17]
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1nc(Cc2ccc([N+](=O)[O-])cc2)cs1
Yield: 95.1 %

Procedure:
A mixture of 1-bromo-3-(4-nitrophenyl)-2-propanone (0.50 g), propanethioamide (0.17 g) and ethanol (10 mL) was heated under reflux for 2 hrs. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-4-(4-nitrobenzyl)-1,3-thiazole as a colorless oil (0.45 g, yield 96%) from a fraction eluted with hexane-ethyl acetate (9:1-4:1, v/v).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:31][OH:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]([C:22]2[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=2)=[O:21])=[NH:18])=[CH:8][CH:7]=1.CO.O.[C:36]1(C)[CH:41]=CC(S(O)(=O)=O)=C[CH:37]=1>CC(C)=O>[CH3:37][C:36]1([CH3:41])[O:2][CH:3]([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]([C:22]3[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=3)=[O:21])=[NH:18])=[CH:10][CH:11]=2)[CH2:31][O:32]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N=C(NCCCCc1ccc(OCC(O)CO)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC1(C)OCC(COc2ccc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)cc2)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 185.6 %

Procedure:
Compound 33 (150 mg, 0.3 mmol) was suspended in dry acetone (50 mL) then methanol was added until a clear solution was formed (approx. 15 mL). p-Toluenesulfonic acid monohydrate (25 mg) was added along with molecular sieves (5 A) and the reaction mixture was stirred for 48 h at room temperature. After this time, the reaction mixture was filtered, silica gel (20 mL) was added and the solvent was removed under reduced pressure. This silica gel with the reaction mixture adsorbed was added to the top of a silica gel flash chromatography column. Compound 37 (120 mg, 81%) was isolated by flash chromatography (silica gel, 10:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (s, 3H), 1.34 (s, 3H), 1.52 (br s, 4H), 2.56 (br s, 2H), 3.13 (br s, 2H), 3.71 (m, 1H), 3.92 (m, 2H), 4.08 (m, 1H), 4.45 (m, 1H), 6.64 (br s, 2H), 6.82 (m, 2H), 7.12 (m, 2H). APCI MS m/z=492 [C22H30ClN22H30ClN7O4+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]=[O:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.CN(C1CCCCC1)C1CCCCC1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]=[O:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1cc(Cl)cc2c(Br)n[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(Br)c2cc(Cl)cc(C=O)c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-chloro-1H-indazole-7-carbaldehyde (1.4 g, 5.4 mmol) and N-methyldicyclohexylamine (1.6 mL, 7.28 mmol) were suspended in tetrahydrofuran (6 mL), cooled to 0° C., and treated with (2-(chloromethoxy)ethyl)trimethylsilane (2.0 mL, 6.74 mmol). The ice bath was removed and stirring continued for 4 h. The reaction was poured into ethyl acetate, washed with water (3×), 1M potassium bisulfate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 1.45 g (69%) as a faint yellow oil. 1H-NMR (CDCl3, 500 MHz) δ 10.28 (s, 1H), 7.97 (d, J=1.83 Hz, 1H), 7.87 (d, J=2.14 Hz, 1H), 6.0(s, 2H), 3.48-3.51 (m, 2H), 0.80-0.83 (m, 2H), 0.10 (s, 9H).
Reaction SMILES: [CH2:1](Cl)[CH:2]([CH3:4])[CH3:3].[F:6][C:7]([F:16])([F:15])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].C(N(CC)CC)C.CC(C)=[O:26]>>[F:6][C:7]([F:15])([F:16])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:1](=[O:26])[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(C)CCl
Reactant: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
34.5 g of isobutyl chloride were added over 15 minutes to a mixture of 46.7 g of o-trifluoromethylaniline, 32.6 g of triethylamine and 470 ml of acetone and the mixture was held at 15° C for 30 minutes and then returned to room temperature. The mixture stood for 12 hours and was filtered and the filtrate was evaporated to dryness. The residue was taken up in 700 ml of ethyl acetate and the solution was washed with 10% potassium carbonate solution and then with water until the wash water pH was 6, then with N hydrochloric acid and finally with water until the wash water pH was 6. The solution was dried over magnesium sulfate, was treated with activated carbon and was evaporated to obtain 68 g of raw product which was washed with hexane to obtain 60 g of N-(2-trifluoromethylphenyl)-2-methyl-propanamide melting at 114° C which was used as is for the next step.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:3][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
Heat 101.6 g (0.65 mol) of methyl 4-fluorobenzoate, 66.65 g (0.98 mol) of imidazole, and 182.0 g (1.31 mol) of potassium carbonate in dimethylsulfoxide at ca. 120° C. for about 3 hr. Cool the solution to room temperature and pour into 500 mL of cold water. Filter to obtain crystals of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1)([O-:3])=[O:2].I[CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[H-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([O:10][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Temperature: 110 °C
Yield: 95 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-nitro-5-hydroxypyridine (2.00 g, 14.3 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (6.06 g, 21.5 mmol), sodium hydride (800 mg, 20.2 mmol) and DMF (30 mL). The reaction mixture was heated at 110° C. for 24 h. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 251a in 95% yield (4.00 g) as a yellow oil: 1H NMR (500 MHz, CDCl3) d 8.27 (d, 1H, J=9.0 Hz), 8.14 (d, 1H, J=3.0 Hz), 7.26 (dd, 1H, J=9.0, 3.0 Hz), 5.04 (m, 1H), 4.39 (m, 2H), 4.06 (m, 2H), 1.44 (s, 9H); MS (ESI+) m/z 196.1 (M-Boc+H).
Reaction SMILES: ClC1C(C(C2C=C3C(C=CC(C4C=CC=CC=4)=N3)=CC=2)N2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=NC=CN=1.[NH2:36][NH2:37].C(Cl)Cl.CC[OH:43]>>[C:17]([NH:36][NH2:37])(=[O:18])[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]([OH:19])=[O:43]
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: NN
Reactant: CCO
Solvent: ClCCl
Product: NNC(=O)c1ccccc1C(=O)O

Procedure:
A solution of 2-[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-isoindole-1,3-dione (1.536 g, 3.22 mmol) and anhydrous hydrazine (335 μL, 342 mg, 10.7 mmol) in EtOH (2 mL)/CH2Cl2 (12 mL) is stirred at rt overnight. The white precipitate formed (phthalic hydrazide) is filtered off and washed with CH2Cl2. The combined filtrate and washings are concentrated in vacuo, the residue is suspended in CDCl3 and filtered (0.45 μM pore size), and the filtrate is concentrated in vacuo to obtain the title compound as yellow foam, which is used for the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 2.4 (brs, 2H), 5.79 (s, 1H), 7.43-7.55 (m, 3H), 7.61 (dd, J=1.8, 8.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 8.10-8.15 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H). MS (ES+): m/z 347.0/349.0 (30/10) [MH+], 330.0/332.0 (18/6) [MH+-NH3]. HPLC: tR=2.1 min (MicromassZQ, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](=O)(OC1C=CC([N+]([O-])=O)=CC=1)[O:29]C1C=CC([N+]([O-])=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:28]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(CNCCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of the product from Example 17C (10.27 g, 27.1 mmol), bis (4-nitrophenyl) carbonate (8.24 g, 27.1 mmol), in toluene (100 mL) was heated at 110° C. for 16 hours, cooled to 25° C., treated with 1M sodium bicarbonate, and extracted with ethyl acetate. The organic phase layer was concentrated and the residue was purified by flash chromatography on silica gel eluting with 60% ethyl acetate in hexane to give the title compound as a white solid (9.44 g, 64% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:19])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)cc(O)c2ccc(F)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cc(OC)c2ccc(F)cc21
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 7-fluoro-4-hydroxy-1-(2-propen-1-yl)-2(1H)-quinolinone (see Example 130(c) for a preparation) (1.0 g, 4.56 mmol) in DMF (50 ml) at 0° C. was added sodium hydride (0.20 g, 5.0 mmol, 60% in paraffin). To the resulting solution was added methyl iodide (0.3 ml, 4.8 mmol) and stirring continued at 0° C. for 1 h, then at ambient for 18 h. The mixture was evaporated and the residues separated between dichloromethane and water. The organics were isolated, dried and concentrated. Chromatography over silica (50 g SPE, eluting with dichloromethane) provided the title compound (0.386 g, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)[N:4]=1.[C:21]([O:24][CH2:25][CH2:26][N+:27]#[C-:28])(=O)[CH3:22].C1CCN2C(=NCCC2)CC1.C1C[O:43]CC1>>[CH2:21]([O:24][C:25]([C:26]1[N:27]=[CH:28][O:16][C:14]=1[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1)=[O:43])[CH3:22]
Reactant: C1CCOC1
Reactant: COc1cc(OC)nc(Sc2ccccc2C(=O)O)n1
Reactant: [C-]#[N+]CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ncoc1-c1ccccc1Sc1nc(OC)cc(OC)n1
Temperature: 45 °C
Reaction time: 0.83 h

Procedure:
2 g (4,6-dimethoxypyrimidine-2-ylthio)benzoic acid was dissolved in THF, and the solution was added while stirring with 1.22 g N,N'-carbonyldiimidazole at room temperature. The mixture was then stirred for 50 min. at 40-50° C. The solution reacted was fed dropwise while stirring into THF solution of 1.55 g isocyanoethyl acetate at -5° C., immediately after dropping of 2 g DBU at -15° C., and the resulting solution was stirred for two nights at room temperature. After completing the reaction, the solution reacted was poured into ice water, stirred for 30 min. and then extracted with a mixed-solvent consisting of ether and ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate, and then, the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective substance in an amount of 1.36 g.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.[NH3:14]>CC(O)C>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12
Reactant: O=[N+]([O-])c1cnc2sccc2c1Cl
Reactant: N
Solvent: CC(C)O
Product: Nc1c([N+](=O)[O-])cnc2sccc12
Yield: 87 %

Procedure:
To a stirred suspension of 3.35 g of 4-chloro-5-nitrothieno[2,3-b]pyridine 7 in 160 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 45°-50° C. during 4 hours. After removal of the solvent, the residue is suspended in water. The solid is washed with water and cold ether, affording 2.65 g (87%) of Compound 8 as crystals. Recrystallization from methanol-ether gives a pure sample melting at 227°-228.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: CCNC(=O)c1cc(/C=C/c2c(-c3ccc(F)cc3)noc2C)n[nH]1
Yield: 33 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using ethylamine instead of morpholine, to the title compound (8.9 mg, 33%) which was obtained as an off white solid. MS: m/e=341.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2]>CO.C(O)(=O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:18])=[O:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
3-[6-(3-Fluoro-benzenesulfonyl)-naphthalen-1-yl]-acrylic acid ethyl ester (2.0 g) was dissolved in a mixture of methanol (20 mL), acetic acid (20 mL) and EtOAc (50 mL) in a Parr vessel. Palladium on activated carbon (1.0 g, 10% Pd) was added, and the vessel was purged with nitrogen. The reaction mixture was stirred at room temperature under 60 atm (4.14 Bar) hydrogen for 18 hours. The vessel was purged with nitrogen, and the reaction mixture was removed and filtered through Celite. The filtrate was evaporated under reduced pressure to give 2.0 g of 3-[6-(3-fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionic acid ethyl ester.
Reaction SMILES: C(OC(=O)N[C@H:8]([C:13](=O)[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19]NC[CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])C)(C)(C)C.S(Cl)(Cl)(=O)=[O:26]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:14]1[C:13]2[C:19](=[CH:12][CH:10]=[CH:9][CH:8]=2)[CH:20]=[CH:21][C:15]=1[C:16]([OH:22])=[O:26]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNCC1O
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1ccc2ccccc2n1

Procedure:
To a solution of [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester of Example 1g (2.5 g, 7.28 mmol) in CH2Cl2 (100 mL) and sat. NaHCO3 (400 mL) was added the solution of 2-pyridinesulfonyl chloride-N-oxide (27 mL, 102 mg/mL) dropwise in portions. As the addition proceeds additional sat. NaHCO3 is added in order to maintain the pH at approximately 8-9. Upon complete addition of the sulfonylchloride the reaction is stirred for an additional hour whereupon the organic layer was removed and washed with brine. The organic layer was evaporated and the residue chromatographed (5% methanol:dichloromethane) to provide 2.5 g of the title compound: MS (El) 500 (M+H+).