Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1Cl.[Br:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1.[ClH:50]>O1CCCC1.O1CCOCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:19][C:20]=1[Cl:50])=[CH:46]/[C:45]1[CH:48]=[CH:49][C:42]([Br:41])=[CH:43][CH:44]=1
Reactant: Cl
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: O=Cc1ccc(Br)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)/C(=C/c1ccc(Br)cc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.047 g, 0.41 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 0.10 g, 0.21 mmol) and 4-bromobenzaldehyde (0.076 g, 0.412 mmol) in tetrahydrofuran (1.5 mL). Dioxane (1.5 mL) was added to bring everything into solution and the reaction mixture was stirred at room temperature for 15 h. The solution was then poured into 1N hydrochloric acid solution and the aqueous phase was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residual material was chromatographed over silica gel (45% ethyl acetate/hexanes) to give (Z)-3-(4-bromophenyl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (69 mg, 62% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].CC(C)([O-])C.[K+].Cl[C:17]1[N:18]=[N+:19]([O-:24])[C:20]([Cl:23])=[CH:21][CH:22]=1.O>O1CCOCC1.CS(C)=O>[Cl:23][C:20]1[N+:19]([O-:24])=[N:18][C:17]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[S:2][CH3:1])=[CH:22][CH:21]=1
Reactant: CSc1ccccc1O
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccccc1Oc1ccc(Cl)[n+]([O-])n1
Reaction time: 0.58 h
Yield: 56.8 %

Procedure:
In a mixed solvent of 1,4-dioxane (5 mL) and dimethylsulfoxide (5 mL) was dissolved 454 mg (3.24 mmol) of 2-(methylsulfanyl)phenol, to the solution was added 519 mg (4.63 mmol) of potassium tert-butoxide and the mixture was stirred for 35 minutes. To the mixture was added 424 mg (2.57 mmol) of 3,6-dichloropyridazine 1-oxide and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, eluted with hexane:ethyl acetate=3:1) to obtain 391 mg (1.46 mmol, Yield: 56.8%) of 6-chloro-3-[2-(methylsulfanyl)phenoxy]pyridazine 1-oxide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1F.Cl.CCO>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[O:18][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: CCCC[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCC[C@@H](Oc1cc(F)c(F)cc1F)[C@H]1CCNC1
Temperature: 90 °C

Procedure:
(S)-3-((R)-1-Hydroxypentyl)pyrrolidine-1-carboxylic acid t-butyl ester (40.0 mg, 155 μmmol) was dissolved in DMF (100 mL, 12.9 mmol). While stirring, 60% sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 311 μmmol) was slowly added, and the mixture was stirred for 15 minutes. 1,2,4,5-Tetrafluorobenzene (52.1 μL, 466 μmmol) was added. The mixture was then heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL), and the solvent was removed under reduced pressure. 1.25M HCl in EtOH (2.0 mL, 2.5 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19.2 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H20F3NO, 288.15; found 288.2.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)[N:12]=1.[CH3:28][C:29]([CH3:31])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:29]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)[N:12]=1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: CC(Nc1cc(-c2csc(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 75 mg (0.2 mmol) {4-[2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.15 mL (2mmol) acetone, 120 mg (2 mmol) NaBH3(CN) and 1 mL methanol consequently. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound as a yellow solid. MS (ES+): 420 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[N:50]=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[O:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:60][C:57]([F:58])([F:59])[C:54]1[CH:53]=[CH:52][C:51]([C:49]2[O:48][N:47]=[C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:13]5=[CH:14][C:15]6[O:19][CH2:18][O:17][C:16]=6[CH:20]=[C:12]5[O:11][CH2:10]4)[C:2]3=[O:21])[N:50]=2)=[CH:56][CH:55]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)no2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-chloromethyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (44%): 1H NMR (300 MHz, CDCl3) δ 8.22 (d, 2H), 7.76 (d, 2H), 7.30-7.18 (m, 2H), 7.06 (t, 1H), 6.91 (d, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 5.88 (s, 2H), 5.17 (ABq, 2H), 4.86 (ABq, 2H); MS (ES+) m/z 508.1 (M+1).
Reaction SMILES: [ClH:1].N[N:3]1[CH2:7][C:6](=[O:8])[N:5](CCCCN2CCN(C)CC2)[C:4]1=[O:20].[Cl:21]C1C=CC(C2OC(C=O)=CC=2)=CC=1>CN(C)C=O>[ClH:21].[ClH:1].[NH:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:20]
Reactant: CN1CCN(CCCCN2C(=O)CN(N)C2=O)CC1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione, hydrochloride (0.0094 mole), dimethylformamide (75 ml) and 5-(4-chlorophenyl)-2-furancarbox aldehyde [prepared as described in U.S. Pat. No. 4,882,354, to Huang et al., assigned to Norwich Eaton Pharmaceuticals, Inc., issued Nov. 21, 1984; see Cols. 7 and 8 hereby incorporated by reference herein] (1.94 g, 0.0094 mole) is stirred at ambient temperature for 72 hours. The mixture is filtered, collecting the solid. Recrystallization from absolute ethanol/H2O and air-drying gives 2.63 g (0.0050 mole) of 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]3-[4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride.
Reaction SMILES: [CH2:1]([C:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:13]1CC1>>[CH3:3][C:2]([CH3:5])([CH2:1][C:6](=[CH2:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:4]
Reactant: C1CC1
Reactant: CC(C)(C)CC(=O)CC(C)(C)C
Product: C=C(CC(C)(C)C)CC(C)(C)C

Procedure:
The ratio between dineopentyl ketone and the cyclopropane derivative in this case was 2.26 g/g.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (531 mg), lithium hydroxide monohydrate (128 mg), tetrahydrofuran (6 ml), ethanol (4 ml) and water (4 ml) was stirred at room temperature for 2 hours and acidified by adding 1N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (451 mg, yield: 90%). This was recrystallized from ethyl acetate-hexane. Melting point: 124–125° C.
Reaction SMILES: [O:1]=[C:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1

Procedure:
1.5 Gram of 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]-butyl}-3,4-dihydrocarbostyril and 0.3 g of 5%-palladium-carbon were dispersed in 150 ml of ethanol and catalytically reduced under 2 kg/cm2 of hydrogen gas for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from methanol to obtain 0.7 g of 6-{1-hydroxy-4-[4-(4-aminophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in brown powdery crystals.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[O:13]([C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:14].[CH:36]([N:39](C(C)C)CC)(C)C.CN>C(Cl)Cl>[CH3:14][O:13][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]([C:5]([NH:39][CH3:36])=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Product: CNC(=O)N(Cc1ccccc1OC)c1ccccc1Oc1ccccc1
Yield: 220.2 %

Procedure:
To a solution of 751 mg of triphosgene in 14 ml of methylene chloride was added dropwise a solution of 2.03 g of N-(2-methoxylbenzyl)-2-phenoxyaniline and 1.03 g of diisopropylethylamine in 25 ml of methylene chloride with stirring, followed by stirring at room temperature for 5 minutes. Into the solution was blown an excess amount of methylamine with stirring, followed by stirring at room temperature for 5 minutes. After concentration under reduced pressure, the reaction mixture was poured into ethyl acetate, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate to give 2.02 g of N-(2-methoxybenzyl)-N-(N-methylaminocarbonyl)-2-phenoxyaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][CH2:13][C:14](=O)[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:15]2[C:16](=[O:18])[O:17][CH2:13][C:14]=2[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(O)C1=C(Nc2cccc([N+](=O)[O-])c2)OCC1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)C1=C(Nc2ccccc2)COC1=O

Procedure:
The title derivative was prepared by a procedure similar to that described in Example 8 starting with 2-[(m-nitrophenyl)amino]-4-oxo-3-furoic acid (7.4 grams, 0.028 mol), BOP-Cl (7.13 grams, 0.028 mol) and aniline (2.58 ml, 0.025 mol) dissolved in 90 ml methylene chloride. Yield: 6.71 g, mp 194°-195° C. (R2 =C6H4NO2 --m).
Reaction SMILES: [Na].[CH3:2][C@H:3]([CH2:19][CH2:20][CH3:21])[CH2:4][C:5]([N:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])=[O:6].[CH3:22]I>C1COCC1>[CH3:22][C@H:4]([C@H:3]([CH3:2])[CH2:19][CH2:20][CH3:21])[C:5]([N:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])=[O:6]
Reactant: CI
Reactant: CCC[C@@H](C)CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a 1M THF solution of Sodium hexamethyldisylamide (16.2 g, 88.3 mmol) at −78° C. was added via canular a 0° C. solution of (R)-3-((R)-3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one (18.7 g, 67.9 mmol) in 70 mL dry THF. The resulting solution was stirred at −78° C. for 30 minutes. Methyl Iodide (48.2 g, 339.5 mmol) was added and stirring at −78° C. was continued for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted into CH2Cl2 and washed with 1M sodium Bisulfite. The solution was dried over MgSO4, concentrated and chromatographed in 10% ethylacetate in hexane to give the titled compound (11.1 g, 56.5% yield) as an oil. MS, m/z (relative intensity): 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (t, J=7.0 Hz, 3 H) 0.9 (d, J=6.6 Hz, 3 H) 1.0 (d, J=6.8 Hz, 3 H) 1.0 (d, J=8.5 Hz, 1H) 1.1 (m, 1 H) 1.4 (m, 1 H) 1.7 (m, 1 H) 3.7 (m, 1 H) 4.2 (dd, J=8.8, 3.4 Hz, 1 H) 4.6 (t, J=8.7 Hz, 1 H) 5.4 (dd, J=8.7, 3.3 Hz, 1 H) 7.2 (m, 2 H) 7.3 (m, 3 H). MS, m/z (relative intensity):290 [M+1H, 100%].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:22][C:11]3=[N:12][C:13]([NH2:21])=[C:14]([C:16]([O:18]CC)=[O:17])[CH:15]=[C:10]3[C:9](=[O:23])[C:8]=2[CH:24]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:22][C:11]3=[N:12][C:13]([NH2:21])=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9](=[O:23])[C:8]=2[CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C(C)=O)ccc3oc2nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc2oc3nc(N)c(C(=O)O)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
In ethanol (3 l) was suspended ethyl 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (46 g). To the suspension were added water (460 ml) and 1N sodium hydroxide (462 ml). The mixture was stirred at room temperature for 1.5 hour, then at 50°-55° C. for 2 hours. The precipitating crystals were collected by filtration, and washed with ethanol. The crystals thus obtained were suspended in warm water (about 2 l). To the suspension was added concentrated hydrochloric acid (20 ml), and the mixture was stirred for 20 minutes. Insoluble matter was collected by filtration, washed with water, followed by recrystallization from dimethylformamide-water to give 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid as colorless crystals (39.3 g). Melting point: >300° C.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].CCCCCC>CN(C)C=O>[F:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:2]([O:1][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]#[CH:4])=[CH:12][CH:11]=1
Reactant: C#CC(O)COc1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamide and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. The organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH2:3][CH2:4][CH3:5].O.[C:8]([OH:12])(=[O:11])[CH:9]=O.P(=O)(O)(O)O>C(OCC)C.ClCCl>[O:6]=[C:2]([CH2:3][CH2:4][CH3:5])[CH:1]=[CH:9][C:8]([OH:12])=[O:11]
Reactant: O=CC(=O)O
Reactant: CCCC(C)=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(=O)C=CC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2-pentanone (17.1 g, 198 mmol), glyoxylic acid monohydrate (8.05 g, 88 mmol) and about 85% phosphoric acid (12 ml) was warmed at ca. 80° for 19 hours. On cooling to room temperature the mixture was diluted with ethyl ether/dichloromethane (100 ml, 1:1) and washed thoroughly with brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow viscous oil, which on crystallization from ethyl ether/petroleum ether gave 4-keto-hept-2-enoic acid as colorless prisms: mp 100°-2°.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[NH:13][C:12]1=[O:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[I-].[Na+].Cl[CH2:33][C:34]([N:36]1[CH2:44][CH:43]2[CH2:45][CH:39]3[CH2:40][CH:41]([CH2:46][CH:37]1[CH2:38]3)[CH2:42]2)=[O:35]>CN(C)C=O>[CH:37]12[CH2:46][CH:41]3[CH2:40][CH:39]([CH2:45][CH:43]([CH2:42]3)[CH2:44][N:36]1[C:34]([CH2:33][N:13]1[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]1=[O:29])=[O:35])[CH2:38]2
Reactant: O=C(CCl)N1CC2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CC4CC(C3)CC2C4)C1=O
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a suspension of sodium hydride (0.035 g of a 60% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.293 g) in dry N,N-dimethylformamide (2 ml) under stirring at cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature and stirred for 2 hours. To the the mixture was added sodium iodide (0.129 g) and followed dropwise a solution of N-chloromethylcarbonyl-2-azatricyclo-[4.3.1.14,8 ]undecane (0.215 g) in dry N,N-dimethylformamide (2 ml) under stirring at cooing in an ice-bath for 1 hour and then at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate and water. The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent gave (3RS)-1-[(2-azatricyclo[4.3.1.14,8 ]undec-2-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.537 g), which was used in a following reaction step without further purification.
Reaction SMILES: C(S)CCC.[H-].[Na+].Cl[C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1.O>O1CCCC1>[S:12]1[N:13]=[CH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11]1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCS
Product: c1cncc(-c2cnsn2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-butanethiol (2.7 g, 30 mmol) and sodium hydride (1.2 g, 30 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (1.2 g, 6 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at -10° for 0.5 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated. The residue was purified by column chromatography (SiO2, eluent: ethyl acetate/-methylene chloride (1:1)) to give the title compound.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([O:15]C)[CH:6]=1)(C)(C)C.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.C1(C)C(C)=CC=CC=1>[N:17]1([S:11]([C:8]2[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=2[OH:15])(=[O:12])=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 4-tert-butyl-2-methoxybenzenesulfonyl chloride (258 mg, 0.99 mmol) in DMF (6 ml) was added pyrrolidine (70 mg, 0.99 mmol) and the solution was stirred at ambient temperature for 30 minutes, and concentrated in vacuo. The residue was dissolved in xylene (10 ml) and then added to mixture of AlCl3 (525 mg, 3.39 mmol) in xylene (5 ml). The resulting mixture was stirred for 18 h at 70° C. After colling the mixture was poured into stirred ice-cold water, and extracted with ether (2×30 ml). The ether layer was dried over sodium sulfate, filtered and concentrated to give 120 mg of subtitle compound.
Reaction SMILES: N1C2C(=C([S:11]([N:14]3[CH2:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][O:17][CH2:16][C@H:15]3[CH2:26][OH:27])(=[O:13])=[O:12])C=CC=2)C=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].CC(=O)O[CH2:36][CH3:37]>C1COCC1>[CH3:28][S:29]([O:27][CH2:26][C@H:15]1[N:14]([S:11]([C:22]2[CH:23]=[CH:24][CH:25]=[C:37]3[C:36]=2[N:14]=[CH:21][CH:20]=[CH:19]3)(=[O:13])=[O:12])[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH2:18][O:17][CH2:16]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(C)=O
Reactant: O=S(=O)(c1cccc2ncccc12)N1Cc2ccccc2COC[C@H]1CO
Solvent: C1CCOC1
Product: CS(=O)(=O)OC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To the mixture of compound 15 (200 mg, 0.52 mmol) and TEA (0.2 mL, 1.5 mmol) in THF (25 mL) at rt, methanesulfonyl chloride (71 mg, 0.62 mmol) was added. The resulting mixture was stirred at rt for overnight. The reaction mixture was poured in ice water (100 mL), extracted with EA (3×100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4. Concentration in vacuo and purified by CC, eluting with PE:EA=2:1 afforded compound 17a as white solid (210 mg, 87% yield).