Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:28]([C:30]3[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=3)[C:33]#[N:34])[CH2:27][C:26](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccc4Cl)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-2′-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G22) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white powder (43 mg).
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:8][CH2:9][CH2:10][CH3:11])[CH2:6][NH2:7])[CH2:2][CH3:3].Br[CH2:13][CH:14]1[O:19][CH:18]([CH3:20])[CH2:17][CH2:16][O:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][NH:7][CH2:13][CH:14]1[O:19][CH:18]([CH3:20])[CH2:17][CH2:16][O:15]1)[CH2:10][CH3:11]
Reactant: CC1CCOC(CBr)O1
Reactant: CCCOC(CN)OCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCOC(CNCC1OCCC(C)O1)OCCC
Temperature: 25 °C

Procedure:
2,2-Dipropoxyethylamine (0.11 mole), 2-bromomethyl-4-methyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Reactant: Nc1ccccc1Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Br)c1=O
Temperature: 25 °C
Yield: 18.7 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.39 g, 1.4 mmol) and 2-bromoaniline (0.36 g, 2.09 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, and a precipitate formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. Titration from acetone and hexanes gave 106 mg (19%) of 3-(2-bromoanilino)-4-(2-hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione. LCMS(H+) 404
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2)=[O:15])([CH3:12])[CH3:11]>ClCCl>[Br:1][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:14]([O:13][C:10]([CH3:9])([CH3:11])[CH3:12])=[O:15])[CH:18]=2)[NH:22][C:21]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
N-Bromosuccinimide (0.095 g, 0.536 mmol) was added to a solution of ethyl 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.163 g, 0.536 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.186 g, 48%) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.97 (br. s., 1H), 7.70 (s, 1H), 7.28-7.39 (m, 2H), 6.54 (br. s., 1H), 4.33-4.54 (m, 2H), 1.54 (s, 9H), 1.39-1.48 (m, 3H). ES MS: m/z 381, 383.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH:40]=O)[CH:32]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[CH2:40][CH2:39][CH2:38][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNCc2ccccc2)c1
Reactant: O=CCCCc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 48 h
Yield: 72.4 %

Procedure:
A mixture of benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}amine (700 mg) and 4-pyridin-3-yl butyraldehyde (314 mg) were solvated in 30 mL dry methanol to which ca. 2 g powdered 3 Å molecular sieves were added. The pH of this mixture was adjusted to 5 by the addition of trifluoroacetic acid and then 441 mg sodium cyanoborohydride was added and the mixture atirred at room temperature. After 48 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:0; then 96:4:1) to give the title compound (676 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:23][CH2:22][C:21](=[O:24])[C:20]4=[CH:25][N:26]([CH3:28])[CH:27]=[C:19]4[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:23][CH2:22][CH:21]([OH:24])[C:20]4=[CH:25][N:26]([CH3:28])[CH:27]=[C:19]4[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2O
Yield: 86.5 %

Procedure:
To a suspension of 174 mg (0.4 mmol) of Compound 24 in 8 ml of ethanol, 151 mg (4 mmol) of sodium borohydride were added gradually under ice-cooled stirring. The resulting mixture was stirred under ice cooling for 1 hour and further at room temperature for 13 hours. Water (80 ml) was added to the reaction mixture. The thus-obtained mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Post treatment and purification were conducted as in Example 15, whereby 151 mg of the title compound were obtained (yield: 86%).
Reaction SMILES: O.[Na].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.S(/[CH:13]=[CH:14]\[C:15](=[O:17])[CH3:16])C#N>C(O)C>[SH:3][C:4]1[N:8]([CH3:9])[N:7](/[CH:13]=[CH:14]\[C:15](=[O:17])[CH3:16])[NH:6][N:5]=1
Reactant: CC(=O)/C=C\SC#N
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(=O)/C=C\N1NN=C(S)N1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-mercapto-1-methyltetrazole sodium salt hydrate (1.1 g., 0.008 mole) in aqueous ethanol (15 ml), a solution of cis-4-thiocyano-3-buten-2-one (Compound 28) in ethanol was added dropwise over 5 minutes. A solid suspension was observed forming over the next 2 hours which was stirred at 25° C. for 18 hours. The volatiles were removed in vacuo and the residue was extracted into ethyl acetate and washed thoroughly with water. After drying (MgSO4), the solution was concentrated. The solid residue was purified via column chromatography on silica gel using hexanes/ethyl acetate (3:2) as eluant to yield 1.1 g of a white solid, mp 112°-114° C. IR (nujol) uc=o 1660 cm-1.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]([OH:16])=O)[C:4]1=[O:17])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:23]1([C:31](=[O:32])[NH:30][C:29](=[O:33])[NH:28]1)[CH2:22]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:33]=[C:29]1[NH:28][C:23]2([CH2:22][C:21]3[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:14](=[O:16])[CH2:13][N:5]4[C:4](=[O:17])[CH:3]([CH2:1][CH3:2])[O:8][C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]4=5)[CH:20]=3)[CH2:24]2)[C:31](=[O:32])[NH:30]1
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reactant: CCC1Oc2ccccc2N(CC(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1Oc2ccccc2N(CC(=O)Nc2ccc3c(c2)CC2(C3)NC(=O)NC2=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-ethyl-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acid (0.2 mmol, 47 mg), 5′-amino-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (0.2 mmol, 43 mg) and DIPEA (0.6 mmol, 104.5 μl) in DMF (1 ml) was added HATU (0.2 mmol, 76 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=435.2; tR=2.71. H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.24 (q, 1H), 7.03 (d, 1H), 6.87-6.92 (m, 4H), 4.65 (q, 2H), 4.41 (q, 1H), 3.34 (q, 2H), 3.00 (q, 2H), 1.78 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [CH2:1](/[N:8]=[CH:9]/[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([N:8](/[CH:9]=[CH:10]/[CH3:11])[C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC/C=N/Cc1ccccc1
Solvent: CCN(CC)CC
Product: C/C=C/N(Cc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To benzyl-prop-(E)-ylidene-amine (6.0 g, 40 mmol) in triethylamine (5.67 mL, 40 mmol) at 0° C. was slowly added acetic anhydride (3.81 mL, 40 mmol), and the reaction was stirred for 30 minutes at 0° C. and then overnight at room temperature. The mixture was concentrated, and the residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([OH:44])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH2:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:46][NH:45][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:44])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
HATU (8.3 g, 21.7 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) and tert-butyl hydrazinecarboxylate (3.5 g, 27.2 mmol) in DCM (60 mL) at 0° C., followed by the addition of DIPEA (7.0 g, 54.3 mmol). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then diluted with DCM, washed with water (2×), and saturated sodium chloride, then dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 4:1 petroleum ether/EtOAc) to afford tert-butyl 2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinecarboxylate (6 g, 85%). ESI-MS (EI+, m/z): 391 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.S(Cl)([Cl:25])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([Cl:25])=[O:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: O=C(Cl)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
A 5.85 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid in 30 ml of thionyl chloride was refluxed on a steam bath for one hour, then evaporated to dryness. The residue was boiled with dimethoxyethane, then cooled and the solid recovered and washed with ether, giving 6.90 g of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid chloride.
Reaction SMILES: [N+]([CH:4](O)C1C=CC=CC=1)([O-])=O.C[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][P+:29]1([O-:41])[O:39][C:38]([CH3:40])=[C:37]2[C@H:32]([CH2:33][O:34][C:35]2=[O:36])[CH2:31][O:30]1>>[CH3:40][C:38]1[O:39][P+:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH3:13])[CH3:4])([O-:41])[O:30][CH2:31][C@H:32]2[CH2:33][O:34][C:35](=[O:36])[C:37]=12
Reactant: O=[N+]([O-])C(O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCO[P+]1([O-])OC[C@H]2COC(=O)C2=C(C)O1
Product: CC1=C2C(=O)OC[C@@H]2CO[P+]([O-])(OCCCCCCCCCCCCCC(C)C)O1

Procedure:
By high-resolution FAB mass spectrometry using a nitrobenzylalcohol matrix, the following molecular weight was found: 445.2721 amu, corresponding to (M+H)+ for cyclipostin P of C23H42O6P. From this, an empirical formula for cyclipostin P 2 of C23H41O6P resulted, molecular weight: 444. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 445 amu, corresponding to (M+H)+ was found; moreover the characteristic peak at 221 amu, corresponding to C7H10O6P, was found. In the ESI negative mode, 443 amu (M−H)−, 321 amu (C16H34O4P) and 219 amu (C7H8O6P) were found.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:30][OH:31]>>[OH:31][NH:30][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([C@@:18]2([CH3:20])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:22][CH2:23]1)=[NH:28]
Reactant: NO
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: Cl
Product: C[C@@]1(C2CCN(C(=N)NO)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 42; the configuration of the stereocenter is arbitrarily assigned) and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 4): tR=0.46 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28]>>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)Nc2ccc(Br)cc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(Br)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-bromo-phenyl)-benzamide. mp 117-120° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:24])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][C:15]([Cl:23])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])=[CH:5][CH:6]=1.C([O-:27])C.O>>[CH2:13]1[CH:12]2[CH:11]([NH:10][C:8]([C@H:7]([NH2:24])[C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[O:9])[C:18](=[O:19])[N:17]2[C:16]([C:20]([OH:22])=[O:21])=[C:15]([Cl:23])[CH2:14]1.[OH2:27]
Reactant: CC[O-]
Reactant: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Solvent: O
Product: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Reaction time: 0.5 h

Procedure:
Loracarbef ethanolate, (4.0 g, 97.1% potency), was slurried in 56 ml of water (containing 0.004 eq sodium, ~0.02 g editate) at 50° C. for 2 hours. Within 30 minutes the slurry became very thick, indicating conversion to monohydrate. The product was vacuum filtered, washed with a minimum amount of water, and dried in a 40° C. vacuum oven. X-ray-confirmed as monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(Cl)c1
Yield: 86.7 %

Procedure:
A solution of 187 g (0.974 mole) of 2,6-dichloroisonicotinic acid, 1650 ml of methanol and 5 ml of concentrated sulfuric acid was heated at reflux for 24 hours. Most of the solvent was removed in vacuo, leaving crude product which was dissolved in 750 ml of methylene chloride and washed with water and 1N sodium hydroxide. The organic layer was dried (Na2SO4) and solvent removed in vacuo affording 174 g (86.7% yield) of methyl 2,6-dichloroisonicotinate, m.p. 79°-81° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][C:24]=3[F:33])[CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)[CH:17]=2)=[C:24]([F:33])[CH:25]=1
Reactant: CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Yield: 89.9 %

Procedure:
A mixture of N-(4-(6-(4-(benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)acetamide (150 mg, 0.34 mmol), 6 M HCl (0.5 mL) and MeOH (3 mL) was heated at reflux for 2 h. The mixture was concentrated to remove the MeOH and the residue treated with saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (123 mg, 90%) as a pink solid. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.24 (s, 1H), 7.46-7.31 (m, 7H), 6.99-6.92 (m, 3H), 6.48 (dd, 1H, J=12.5, 2.7 Hz), 6.39 (dd, 1H, J=8.6, 2.7 Hz), 5.97 (s, 1H), 5.39 (br s, 2H), 5.08 (s, 2H); MS (ESI+) m/z 403.09 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]2[C:31]([CH3:32])=[CH:30][CH:26]=[C:27]2[CH3:29])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: CC(=O)CCC(C)=O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 62.2 %

Procedure:
A mixture of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (8.0 g) and acetonylacetone (4.34 g) in toluene (250 ml) containing p-toluenesulphonic acid (0.5 g) was heated under reflux with a Dean and Stark take-off head fitted to the flask. After 311/2 hours evaporation in vacuo gave a dark solid, which was dissolved in dichloromethane (100 ml) and washed in turn with water (100 ml) and saturated sodium carbonate solution (50 ml). The organic layer was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a dark semisolid. Purification by dry column chromatography (Kieselgel 60G) eluting with dichloromethane/hexane (1:3) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethyl- phenyl)-5-(2,5-dimethylpyrrol-1-yl)-4-trifluoromethylthiopyrazole as a white solid (5.9 g), m.p. 142.3°-144° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:5]
Reactant: COCC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(=O)NCC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g tert-butyl 4-[(2-methoxyacetylamino)-methyl]-4-phenylpiperidine-1-carboxylate are placed in 4 ml dichloromethane. Then 1.7 ml trifluoroacetic acid are added and the mixture is stirred overnight at ambient temperature. The reaction mixture is made basic with potassium carbonate and the organic phase is evaporated to dryness. 610 mg (V-12) are obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:17](Cl)=[O:18]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[NH:1][C:17](=[O:18])[NH:6][C:4]2=[O:5]
Reactant: COc1cc(C(N)=O)c(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
108 mg (0.5 mmol) of 2-amino-5-methoxy-4-nitrobenzamide were dissolved in 5 ml of tetrahydrofuran and 5 ml of chloroform, and oxalyl chloride (solution in toluene) was added. The mixture was stirred at 60° C. for 5 hours and then concentrated in vacuo. Addition of toluene was followed by renewed concentration. 120 mg (100%) of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:17][NH:18][O:19][CH3:20]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:18]([CH2:17][C:16]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:14]([F:13])[CH:15]=2)[O:19][CH3:20])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(C)c(F)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 100 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluoro-4-methyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (100% yield): mp 131° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 2.25 (3H, broad s, CH3), 3.69 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.39 (1H, s, CH), 7.0-7.03 (2H, m, aromatics), 7.13 (1H, m, aromatic). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.51; H, 5.60; N, 4.24.