Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]#[N:19])=[O:8])=[CH:3][CH:2]=1.[OH2:21]>>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]([NH2:19])=[O:21])=[O:8])=[CH:5][CH:6]=1
Reactant: O
Reactant: Cc1ccc(C(=O)c2cccc3c2CCC3C#N)cc1
Product: Cc1ccc(C(=O)c2cccc3c2CCC3C(N)=O)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 2.3 g. of 4-(p-toluoyl)indan-1-carbonitrile is added 75 g. of polyphosphoric acid and the mixture is worked into a homogeneous solution by heating on a water bath at 90° C for 30 minutes and, then, on an oil bath at 120°-130° C for 30 minutes. Following the addition of water to decompose the polyphosphoric acid, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 5 % aqueous sodium hydrogen carbonate and water in the order mentioned and, then, dried. It is, then, treated with activated carbon and concentrated under reduced pressure. The resultant crystalline residue is recrystallized from a mixture of ethanol and ethyl acetate. The described procedure gives 4-(p-toluoyl)indan-1-carboxamide as crystals melting at 188°-191° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:46].O>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:37]=2[CH3:46])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round bottom flask containing (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (133 mg) was combined with methylene chloride (10 ml), methyl 4-amino-3-methylbenzoate and DiPea. The mixture was stirred at rt for 2 hrs and another 100 mg of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid was added and the mixture was stirred for another 2 hrs. The mixture was pardoned between water (10 ml) and methylene chloride (10 ml) and the organic layer was dried and concentrated to give a solid, which was treated with 3 ml of acetonitrile. The mixture was stirred and filtered. the solid was dried to give a white solid, 102 mg as the desired product. The filtrate was chromatographed on a reverse phase column (40 g, 30-100% acetonitrile) to give another 34 mg of desired product after removal of solvent. combined product: 102+34=136 mg. MS (ES+) m/z Calcd: [(M+H)+]: 614. found: 614.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][C:3]2[S:4][CH2:5][C:6](=[O:8])[N:7]=2)[CH2:12][CH2:11]1
Reactant: CSC1=NC(=O)CS1
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNC2=NC(=O)CS2)CC1

Procedure:
2-[2-(4-Methyl-piperazin-1-yl)ethylamino]-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and 2-(4-Methyl-piperazin-1-yl)-ethylamine following general procedure E.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:9]2[CH2:14][CH2:13][NH:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:33][C:32](=[O:35])[NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)[C:11]([CH3:16])([CH3:15])[CH2:10]2)=[CH:22][CH:21]=1
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: CC1(C)CN(C(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CN(C(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1cccc(F)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 283 mg of 1-[bis(4-fluorophenyl)methyl]-3,3-dimethylpiperazine and 204 mg of N-(3-fluorophenyl)chloroacetamide was dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide, and 1 g of anhydrous potassium carbonate was added to the resulting solution. The reaction mixture was then stirred at 80° C. for 16 hours, after which ethyl acetate was added, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to give a purified 1-[bis(4-fluorophenyl)methyl]-4-[(3-fluorophenyl)carbamoylmethyl]-3,3-dimethylpiperazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:32]=1[C:33](Cl)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[C:36]([F:40])=[CH:37][CH:38]=[CH:39][C:31]=3[Cl:30])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1CC(Oc2cccc(NC(=O)c3c(F)cccc3Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Combine 4-(6-Amino-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 63, 0.286 g, 0.93 mmol), 1,4-dioxane (10 mL), triethylamine (0.16 mL, 1.12 mmol) and 2-chloro-6-fluorobenzoyl chloride (0.215 g, 1.12 mmol) with stirring at ambient temperature. After 2 hr., partition between water (50 mL) and 4:1 hexane:ethyl acetate (100 mL). Separate aqueous layer and wash with 4:1 hexane:ethyl acetate (50 mL). Combine organic layers, dry over sodium sulfate, filter and concentrate to obtain the title compound (0.53 g>100%). Mass spectrum (electrospray): m/z=462.3 (M−1); 1H NMR (CDCl3): 7.9 (m, 2H), 7.65 (dd, 1H), 7.4 (m, 1H), 7.25 (m, 1H), 7.1 (dd, 1H), 6.5 (d, 1H), 5.25 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 1.9 (m, 3H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17].[CH3:19]O>O>[CH3:19][O:1][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: [OH-]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of KOH (1.12 g, 20 mmol, 1 equiv) in MeOH (20 ml) at 0° C. was added portionwise 4-chloro-3,5-dinitrobenzoic acid (D23) (4.93 g, 20 mmol, 1 equiv). The resulting mixture was refluxed for 1 h then cooled to room temperature. A second portion of KOH (1.12 g, 20 mmol, 1 equiv) was added and the mixture refluxed for 90 min, cooled to room temperature and diluted with H2O. The aqueous phase was acidified to pH 1 and extracted with AcOEt. The organic phase was dried over MgSO4 and concentrated in vacuo to give crude 4-methoxy-3,5-dinitro-benzoic acid (D24) (4.49 g, 93%) as a light brown solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([NH:35][C@H:36](C(O)=O)C)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([NH:35][CH2:36][CH2:2][C:3]([O:5][C:6]3[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=3[F:15])=[O:4])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)cc(F)c1F
Reaction time: 1 h

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (1.7 g, 6.5 mmol) was added dropwise to a solution of FMOC-alanine (2.0 g, 6.4 mmol) and triethylamine (1.0 ml, 7 mmol) in 20 ml of anhydrous CH2Cl2. After 1 hr., CH2Cl2 was removed by evaporation at reduced pressure using rotary evaporator, redissolved in 30 ml ethylacetate/hexane (1:1). Flash chromatography (4×20 cm, hexane/ethyl acetate, 3:1) afforded rude 4 as a white solid. It was recrystallized from hexane/ethyl acetate to give 4 as a white crystalline solid (2.3 g, 78%): 1H NMR (CDCl3, 200 MHz, ppm) 7.73 (d, 2H, J=7.1 Hz, aromatic protons), 7.75 (d, 2H, J=7.7 Hz, aromatic protons), 7.24-7.42 (m, 4H, aromatic protons), 7.01 (m, 1H, C6F4H), 5.21 (br s, 1H, —CONH—), 4.38 (d, 2H, J=7.1 Hz, —CH2OCO—), 4.20 (m, 1H, benzyl proton), 3.58 (m, −2H, NCH2), 2.93 (t, 2H, J=5.4 Hz, —CH2CO—). Anal. Calcd. for C24H17NO4F4: C, 62.75; H, 3.73; N, 3.05. Found: C, 62.52; H, 3.59; N, 3.01.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH2:9][O:10][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[CH:3][CH:2]=1.[CH2:22]1[CH:26]2[CH:27]3C=CC([CH:25]2[CH:24]=[CH:23]1)C3.[OH2:32]>>[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([OH:32])=[CH:2][CH:3]=1.[CH2:9]=[O:10]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: O
Reactant: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Product: C=O
Product: CCCCCCCCCc1ccc(O)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
300 g of rosin and 700 g of 75% strength dicyclopentadiene are heated to 260° C. in a 5 liter pressure apparatus. After five hours, the stirred melt is cooled to 160° C. and the apparatus is brought to atmospheric pressure. 710 g of a water-soluble resol obtained from 1,860 g of nonylphenol and 510 g of formaldehyde (processing viscosity 250 mPa.s, residue on drying 68% after heating for one hour at 135° C.) are metered into this melt. With constant removal of water, the mixture is heated to 250° C. until a 50% strength toluene solution reaches a viscosity of 100 mPa.s/23° C. 12.5 g of 3l-aminopropylimidazole are then added, stirring is continued for 1 hour and volatile components are distilled off in vacuo at 50 mbar. 2,100 g of a mineral oil having a boiling point of 240°-270° C. and an aniline point of 72° C. are then allowed to run in. After cooling, the varnish has a viscosity of 10 dPa.s/23° C. It can be used for flusing water-moist pigment cakes and for dispersing pigments.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]([CH:13]1[CH2:19][CH2:18][CH2:17][CH:16]([Cl:20])[CH2:15][C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C([BH3-])#N.[Na+].[CH3:26][NH:27][CH3:28].Cl.CNC>CO>[Cl:1][CH2:2][CH2:3][C:4]([N:6]([CH:13]1[CH2:19][CH2:18][CH2:17][CH:16]([Cl:20])[CH2:15][CH:14]1[N:27]([CH3:28])[CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CNC
Reactant: O=C1CC(Cl)CCCC1N(C(=O)CCCl)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CC(Cl)CCCC1N(C(=O)CCCl)c1ccccc1

Procedure:
The 3,4-dichloro-N-[2-oxocycloheptyl]propionanilide from Part C above is treated with sodium cyanoborohydride and dimethylamine-dimethylamine hydrochloride in methanol in the presence of 3 A molecular sieves; the resulting mixture is worked up under basic pH conditions and the organic residue is chromatographed (column) on silica gel to isolate the cis isomer of 3,4-dichloro-N-[2-(dimethylamino)cycloheptyl]propionanilide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:24]2[CH:23]=[N:22][N:21]([CH3:20])[C:25]=2[CH3:26])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Product: Cc1c(-c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)c2)cnn1C

Procedure:
Following Steps 1 and 2 in Scheme 97, using methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 4-(2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoic acid was obtained. LCMS (m/z): 327.1 (MH+), 0.45 min.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[SH:20]>>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[S:20][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccncc1Cl
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccncc2Cl)s1
Yield: 16.9 %

Procedure:
Prepared by a similar procedure to that described for example 18 from the 1-(5-chloro-4-nitro-2-thienyl)ethanone (250 mg, 1.22 mmol) and 3-chloropyridine-4-thiol (178 mg, 1.22 mmol) to afford the title product as a solid (65 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (1H, s), 8.75 (1H, d), 8.57 (1H, s), 7.94 (1H, d), 2.54 (3H, s). MS m/z: 315.05 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].Br.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16]Br)[CH3:13]>CO>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][S:1][CH2:2][CH2:3][OH:4])[CH3:13]
Reactant: OCCS
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCSCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-mercaptoethanol (1.5 mL, 1.7 g, 22 mmol) in methanol (30 mL) was added with stirring sodium carbonate (4 g, 38 mmol), followed by 2-(diethylamino)ethyl bromide hydrobromide (5.0 g, 19 mmol). The reaction mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure to give 2-[2-(diethylamino)ethylthio]-ethanol as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6](=[O:8])[NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Reactant: NCCN1CCOCC1
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCOCC2)c(Cl)c1
Yield: 40 %

Procedure:
A mixure of 507 mg of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 407 mg of N-(2-aminoethyl)morpholine was stirred at 110°-115° C. (bath temperature) for 1 hour. The mixture was cooled and poured into water. The crystals which precipitated were collected by filtration. These crude crystals were recrystallized from a mixture of methanol and ethyl acetate to give 255 mg of the title compound as a white powder melting at 179°-181° C. (with decomposition). The filtrate was extracted with ethyl acetate, dried and concentrated by evaporation under reduced pressure, followed by trituration of the residue with ethyl acetate to give a further 91 mg of the title compound as crystals.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:7]=2[N:6]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:5]1=[O:38])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:14])[C:8]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:7]=2[N:6]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:5]1=[O:38]
Reactant: [H][H]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N=[N+]=[N-])C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Yield: 56.8 %

Procedure:
A solution of 152 mg of 2-(3-azido-7-fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 10 mL of ethyl acetate was combined with 60 mg of palladium on carbon (10 wt %) and hydrogenated under a balloon of hydrogen gas for 16 hrs. The mixture was filtered, evaporated in vacuo and purified on flash grade silica gel using 3:7 methanol/ethyl acetate. The appropriate fractions were combined, evaporated in vacuo and dried under high vacuum to provide 82 mg of the title compound as a foam. Low resolution MS (FAB)m/e 492 (MH+); TLC (silica) 95:5 dichloromethane/methanol Rf=0.30.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1C=C(C)C=C[C:5]=1C(=O)C.[C:14](=[O:21])([O:18][CH2:19][CH3:20])OCC.Cl.[C:23]1([CH3:29])[CH:28]=[CH:27]C=C[CH:24]=1>>[OH:3][C:4]1[C:14](=[O:21])[O:18][C:19]2[C:20]([CH:5]=1)=[CH:27][CH:28]=[C:23]([CH3:29])[CH:24]=2
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: CCOC(=O)OCC
Reactant: Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2cc(O)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 80° C. suspension of NaH (60 g, 1500 mmol, 60%) in toluene was added 1-(2-hydroxy-4-methylphenyl)ethanone (100 g, 666 mmol; also known as 2′-hydroxy-4′-methylacetophenone) in 800 mL of toluene over 1 h. This was followed by the dropwise addition of diethyl carbonate (157 g, 1.3 mol) in 1000 ml of toluene over 1 h. The reaction mixture was left at 80° C. overnight. After cooling to rt, the solution was poured into 1.6 L of HCl (2N). The precipitate formed was filtered, collected and stirred in MeOH (minimum amount). After filtration, the title compound was dried overnight (at 55° C., under high vacuum) to yield the title compound. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (1H, s), 7.58 (1H, d), 7.13 (2H, m), 6.53 (1H, s) and 2.39 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2)[C:29]([CH3:30])=[O:31]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 14 (200 mg, 1.25 mmol), dimethylaminopyridine (20 mg) and triethylamine (0.94 mL) in THF cooled to 0° C. was added a solution of acetyl chloride (0.30 mL, 4.16 mmol) in THF (5 mL) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 3 h. THF was removed in vacuo and ethyl acetate (40 mL) was added. The solution was washed with water (20 mL×2). The solution was dried using sodium sulfate and solvent was removed in vacuo. The residue was dissolved in methanol (5 mL) and 3N NaOH solution(1 mL) was added. The reacted was allowed to proceed overnight. The reaction mixture was evaporated and water (10 mL) was added. The product was extracted with ethyl acetate (30 mL×3) and the solvent was removed in vacuo. The product was crystallized in acetate and washed with ether. 128 mg (50% yield) of grew powder 15 was obtained. mp: 161° C. 1H NMR (DMSO-d6, ppm): 10.84 (s, 1 H, NH), 9.62 (s, 1 H, NH), 7.75 (d, 1 H, J=2.1 Hz, Ar--H), 7.22-7.10 (m, 2 H, Ar--H), 6.20 (s, 1 H, Ar--H), 6.43-6.40 (dd, 1 H, J=2.4, 8.5 Hz, Ar--H), 5 5.18-5.15 (t, 1 H, J=5.5 Hz, OH), 4.57-4.56 (d, 2 H, J=5.4 Hz, CH2OH), 2.01 (s, 3 H, CH3), Anal. (C11H12N2O2), C, H, N.
Reaction SMILES: B(O)(O)O.[N+:5]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[N+:23]([O-:25])=[O:24])[C:13](=[O:26])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-])=O.[S].S(=O)(=O)(O)[OH:29]>OS(O)(=O)=O.O=S(=O)=O.O>[OH:29][C:11]1[C:12]2[C:13](=[O:26])[C:14]3[C:19](=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([NH2:5])=[CH:9][CH:10]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O
Temperature: 25 °C

Procedure:
50 parts of crystalline boric acid are dissolved in 1,000 parts of 30% strength oleum. 100 parts of 1,8-dinitroanthraquinone (analysis: 97.6% of 1,8-DNA; 0.8% of 1,5-DNA) are then added at room temperature with stirring. 15 parts of pulverulent sulphur are then added in portions at a temperature of 50° C. in the course of 45 minutes. The reaction mixture is further stirred for 1 hour at 50° C., cooled down to room temperature and then diluted with cooling by means of 211 parts of 78% strength sulphuric acid and then with 525 parts of water. The precipitated reaction product is filtered off with suction and washed with 133 parts of 60% strength sulphuric acid and thereafter with warm water until neutral. 64.5 parts of 1-hydroxy-4-amino-5-nitroanthraquinone are obtained which after recrystallisation from N-methylpyrrolidone melts at 270° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C@@H:12]([OH:25])[C@@H:13]2/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[O:9]1)([OH:3])=O.[C:26]([O:29]C(=O)C)(=O)[CH3:27].[N:33]1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:26]([NH:33][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C@@H:12]([OH:25])[C@@H:13]2/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[O:9]1)=[O:3])(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: CC#CCC[C@H](O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)O)O[C@H]2C[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: O
Product: CC#CCC[C@H](O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)NC(C)=O)O[C@H]2C[C@H]1O

Procedure:
400 mg. of (1S,5R,6R,7R,3R)-3-(4-carboxy-1-butyl)-7-hydroxy-6-[(E)-(3S)-3-hydroxy-1-octen-6-ynyl]-2-oxabicyclo[3,3,0]octane, 100 mg. of 4-dimethylaminopyridine, 0.5 ml. of acetic anhydride, and 1 ml. of pyridine are stirred for 16 hours at 20°, then combined with 0.2 ml. of water, agitated for another 2 hours, diluted with 50 ml. of water, and extracted repeatedly with methylene chloride. The extract is shaken in succession with dilute sulfuric acid and brine, dried over magnesium sulfate, and evaporated under vacuum. The dried residue (1 hour at 40° and 0.01 torr) is dissolved in 15 ml. of acetonitrile and, at 0°, a solution of 150 mg. of acetylisocyanate in 10 ml. of acetonitrile is added dropwise thereto. The mixture is stirred for another 2 hours at 20°, concentrated under vacuum, acidified with dilute sulfuric acid to pH 5, extracted repeatedly with ether, and the extract washed neutral with brine, dried over magnesium sulfate, and evaporated under vacuum.