Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:32]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:11]([CH2:13][C:14]([O:16][CH3:32])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1cccc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 1.0 g of 2-p-chlorophenyl-5-m-nitrophenoxy-4-oxazoleacetic acid in 20 ml of methanol was added 0.02 ml of concentrated sulfuric acid. The mixture was refluxed under heating for 45 minutes on a mantle heater. After the completion of reaction, the solvent was distilled off under reduced pressure. To the residue were added ice-cold water and potassium carbonate, and the mixture was extracted with ethyl acetate. After the organic layer was concentrated, recrystallization of the residue from a mixture of n-hexane and ethyl acetate gave 0.97 g of the title compound, melting at 97°-99° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>CO>[CH3:15][O:16][CH:17]([O:21][CH3:22])[N:11]1[CH2:12][CH2:13][CH2:14][CH:8]([CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH2:9][CH2:10]1
Reactant: C1CNCCC(CCC2=NCCN2)C1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(OC)N1CCCC(CCC2=NCCN2)CC1
Temperature: 90 °C

Procedure:
A mixture containing rac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine (1.95 g, 0.01M), methanol (50 ml) and dimethylformamide dimethylacetal (36 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine-1-carboxaldehyde dimethylacetal to the mixture of 6-aminopenicillanic acid (1.95 g, 0.009M) and diisopropylethylamine (1.52 ml) in dry chloroform (25 ml) was added the solution fo the above hexahydroazepine carboxaldehyde dimethylacetal in dry chloroform (10 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr. and at room temperature for 3 hrs. After the reaction solvent was removed and the residue dissolved in water (30 ml). The aqueous solution, washed with ethylacetate was acidified to pH 3 with dil. HCl and purified on Sephadex LH 20 columns to give [ 2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hyrochloride (1.03 g, 27% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24](B(O)O)[CH:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=2)[CH:25]=1
Reactant: CCOC(=O)C(CC1CC1)n1ccc(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(CC1CC1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
250 mg (0.8 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate) and 214 mg (0.96 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 35 mg (purity 87%, 9% of theory) of the title compound and 70 mg (22% of theory) of the product which is already hydrolysed (Example 6.1F)
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].I.CS[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[NH:21]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[NH:21])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15]
Reactant: Cc1cc2cc(N)ccc2n1CCN(C)C
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2cc(NC(=N)c3cccs3)ccc2n1CCN(C)C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
A solution of compound 24 (0.275 g, 1.266 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.72 g, 2.532 mmol) at room temperature and stirred for overnight (16 h). The reaction was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 25 (0.32 g, 78%) as a foam. 1H NMR (DMSO-d6) δ 2.22 (s, 6H), 2.39 (s, 3H), 2.46-2.51 (m, 2H, merged with DMSO peak), 4.14 (t, 2H, J=6.9 Hz), 6.09 (s, 1H), 6.20 (brs, 2H), 6.61 (dd, 1H, J=1.2, 8.4 Hz), 6.87 (s, 1H), 7.09 (t, 1H, J=4.2 Hz), 7.27 (d, 1H, J=8.7 Hz), 7.57 (d, 1H, J=5.1 Hz), 7.70 (d, 1H, J=3.3 Hz); ESI-MS (m/z, %) 327 (MH+, 100); ESI-HRMS calculated for C18H23N4S (MH+), calculated: 327.1637; observed: 327.1653; HPLC purity: 98% by area.
Reaction SMILES: [OH:1][C:2]1([C:27]#[C:28][C:29]([OH:31])=[O:30])[CH2:7][CH2:6][C@:5]2([OH:26])[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@@H:11]([CH2:12][C@@H:13]([O:21][CH2:22][O:23][CH2:24][CH3:25])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C>C(O)C.[Pd]>[OH:1][C:2]1([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:7][CH2:6][C@:5]2([OH:26])[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@@H:11]([CH2:12][C@@H:13]([O:21][CH2:22][O:23][CH2:24][CH3:25])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: CCOCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(O)(C#CC(=O)O)CC[C@]32O)C1
Agent: [Pd]
Solvent: CCO
Product: CCOCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(O)(CCC(=O)O)CC[C@]32O)C1

Procedure:
A solution of 17-hydroxy-17-carboxyethynyl-3beta-ethoxymethoxy-14-hydroxy-5beta,14beta-androstane (30 mg), prepared as described in Example 12, in ethanol (5 ml), was hydrogenated at 2.72 atmosphere in a Parr apparatus in the presence of 10% palladium over charcoal.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:40])[C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])=[N:26]2)=[C:20]([C:41]([F:44])([F:43])[F:42])[CH:19]=1>C1COCC1>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[C:31]([NH:30][C:27]1[CH:28]=[CH:29][N:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)=[CH:19][C:20]=2[C:41]([F:42])([F:43])[F:44])[N:26]=1)=[O:40]
Reactant: c1c[nH]nn1
Reactant: O=C(Nc1ccn(Cc2ccc(CBr)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(Cn3nccn3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1H-1,2,3-triazole (34 mg, 0.492 mmol, Alfa Aesar) in THF (2 ml) at ambient temperature under nitrogen was added 1.0 M lithium bis(trimethylsilyl)amide in THF (0.5 ml, 0.500 mmol). The resulting yellow cloudy mixture was stirred at ambient temperature for 10 min. To a solution of N-(1-{[4-(bromomethyl)-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide (for a preparation see Intermediate 22)(49 mg, 0.103 mmol) in THF (2 ml) at ambient temperature was added a solution of the 1H-1,2,3-triazole anion (0.5 ml, 0.167 mmol). After 1.5 h, a further amount of 1H-1,2,3-triazole anion (0.5 ml, 0.167 mmol) was added to the mixture and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a colourless gum (1.8 mg); LCMS: (System 4) MH+=463.1, tRET=2.85 min.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:36]([OH:44])[CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:36](=[O:44])[C:37]([C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)=[O:2])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccc(C(O)Cc2ccncc2)cc1OC1CCCC1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(=O)c2ccncc2)cc1OC1CCCC1
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
Pyridinium dichromate (3.6 g) in dry dichloromethane (40 mL) under nitrogen is treated with (±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (2.0 g), in one portion. The resulting mixture is stirred for 1.5 hours, and then filtered through a pad of diatomaceous earth, and the pad is washed with diethyl ether. The combined filtrate and ethereal washings are washed with saturated aqueous cupric sulfate solution (2×30 mL), followed by water (30 mL), and then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the resulting oily residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione (0.4 g), in the form of a yellow solid, m.p. 117-119° C. [Elemental analysis: C, 70.1; H, 6.0; N, 4.1%; calculated: C, 70.1; H, 5.9; N, 4.3%].
Reaction SMILES: C[N:2]([N:22]=O)[C:3]1[CH2:14][N+:13]([O-:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=1.[CH2:24]([OH:26])[CH3:25]>C(N(CC)CC)C>[C:24]([NH:22][NH:2][C:3]1[CH2:14][N+:13]([O-:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=1)(=[O:26])[CH3:25]
Reactant: CCO
Reactant: CN(N=O)C1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Solvent: CCN(CC)CC
Product: CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1

Procedure:
A mixture of 3.3 g. of N-nitrosochlordiazepoxide, 30 ml. of ethanol, 3 ml. of triethylamine and 2 g. of acetyl hydrazide was refluxed for 24 hours. The solvent was removed and replaced by n-butanol. After additional 24 hours of reflux, the reaction mixture was evaporated. The residue was slurried with methylene chloride. The insoluble material was collected and recrystallized from methylene chloride/ethanol to yield 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine 4-oxide. The methylene chloride soluble part was chromatographed over 70 g. of silica gel using 10 percent ethanol in methylene chloride. Crystallization of the clean fractions from ethyl acetate yielded 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,5-a][1,4]benzodiazepine 5-oxide with a melting point of 278°-282°.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:23]=[C:22]1[CH3:31]>>[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([CH3:27])[C:28]#[C:29][C:2]2[C:3]([F:19])=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[N:23]=[C:22]1[CH3:31]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cn(C)c(C)n1
Product: Cc1nc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)cn1C
Yield: 4 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1,2-dimethyl-1H-imidazol-4-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (5 mg, 4%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.[CH2:11]([N:18]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:30]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: Cc1ncc(B(O)O)cn1
Product: Cc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 58% yield, starting from (2-methylpyrimidin-5-yl)boronic acid and (2R)-N,N-dibenzyl-8-bromo -1,2,3,4-tetrahydronaphthalen-2-amine; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 2 H), 7.22-7.32 (m, 8 H), 7.11-7.21 (m, 4 H), 7.03 (dd, 1 H), 3.50-3.70 (m, 4 H), 2.88-3.02 (m, 2 H), 2.71 (s, 3 H), 2.66-2.83 (m, 2 H), 2.42-2.53 (m, 1 H, obscured by DMSO), 2.05-2.14 (m, 1 H), 1.64-1.79 (m, 1 H); MS (ESI) m/z 420[M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:24][CH2:25][CH2:26]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:26][CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(Br)c(O)c1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(OCCOCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A mixture of 1-bromo-2-hydroxy-4-methoxy benzene (68.3 g, 0.336 moles), anhydrous potassium carbonate (51.2 g 0.37 moles) and 0.5 L of N,N-dimethylforrnamide was heated to 65° C. Benzyloxyethylbromide (76.0 g, 0.353 moles) was added dropwise over 0.5 hr. After stirring for 1.5 hr. at 65° C., the reaction mixture was cooled and filtered. The filtrate was diluted with 1 L of deionized water, and extracted with 3×0.5 L ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Distillation gave 93 g (83%) of product as a yellow liquid (b.p. 170-175° C., 0.5 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.0 g (10.72 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 2.25 g (11.79 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 10.71 g (equivalent to 32.2 mmol PPh3) of triphenylphosphine derivatized polystyrene and 5.6 g (32.2 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/6).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].O=C1CCC(=O)N1[O:41][C:42]([NH:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Nc1cccnc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4cccnc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, (2,5-dioxopyrrolidinyloxy)-N-(3-pyridyl)carboxamide (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (25 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide (0.23 g 30%). 2N HCl/ether was added to a stirred solution of N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide (0.23 g) in methanol (5 mL) and ethyl acetate (10 mL). The mixture was stirred for 2 hours and filtered to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide hydrochloride (0.2 g) as a white solid: mp 263-265° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 10.43 (s, 1H), 9.08 (d, J=1.7 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.33-8.29 (dd, J=1.2 and 8.5 Hz, 1H), 7.93-7.78 (m, 4H), 7.55 (t, J=6.0 Hz, 1H), 5.21-5.14 (dd, J=5.a and 12.5 Hz, 1H), 4.80 (d, J=5.9 Hz, 2H), 2.97-2.84 (m, 1H), 2.65-2.50 (m, 2H), 2.10-2.06 (m, 1H); 3C NMR (DMSO-d6) δ 172.78, 169.83, 167.54, 166.96, 154.78, 139.97, 139.51, 134.80, 134.37, 133.35, 132.34, 131.60, 130.43, 127.17, 127.10, 121.99, 48.88, 38.68, 30.94, 21.99; Anal. Calcd. For C20H18N5O5Cl: C, 54.12; H, 4.09; N, 15.78; Cl, 7.99. Found: C, 54.11; H, 4.10; N, 15.44; Cl, 7.81.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:26])[CH:3]=1.[CH3:27][C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1>>[CH:23]1([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[C:6]([F:8])=[CH:7][C:2]([N:29]5[C@H:28]([CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: C[C@@H]1COC(=O)N1c1cc(F)c(C(=O)N2CCN(c3ccc(C4CC4)cn3)CC2)c(F)c1
Yield: 58.1 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (422 mg) described in Preparation Example 189 and (R)-4-methyloxazolidin-2-one (134 mg) described in Preparation Example 25, the title compound (257 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>CCOCC.CCOCC.CC#N>[I:37][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: OCCCc1ccc(F)c(F)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: Fc1ccc(CCCI)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of 2.00 g (11.6 mmol) of 3-(3,4difluorophenyl)propanol (from EXAMPLE 199, Step A), 3.96 g (15.1 mmol) of triphenylphosphine and 1.03 g (15.1 mmol) of imidazole in 2:1 v/v ether/CH3CN at 0° C. was treated with 4.10 g (16.3 mmol) of iodine. The resulting mixture was warmed to rt and stirred for 1 h. The mixture was diluted with 200 mL ether, and washed with sat'd Na2S2O3 (2×30 mL) and sat'd CuSO4 (30 mL). The organic phase was dried over MgSO4 and concentrated. The residue was partially dissolved in ether and filtered to remove triphenylphosphine oxide. The filtrate was concentrated. Flash chromatography on silica gel using 4:1 v/v hexanes/EtOAc afforded 3.25 g (99%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:16](=[CH:22][NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: COc1cc(O)ccc1N
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccc(O)cc1OC)C(=O)OCC
Yield: 99.4 %

Procedure:
4-Amino-3-methoxyphenol (21 g) and ethyl 2-butyryl-3-ethoxyacrylate (36 g) were heated together at 90°-110° for 30 minutes to afford ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (46.1 g, 77%) as a brown solid, m.p. 140°-142°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:13]([CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:16]([OH:18])=[O:17])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)N(C(CC(=O)O)c1ccccc1)C2=O
Yield: 54.6 %

Procedure:
A stirred mixture of 4-methylphthalic acid anhydride (1.62 g, 10.0 mmol) and 3-amino-3-phenylpropionic acid (1.65 g, 10.0 mmol) in 15 mL of acetic acid under nitrogen was heated to reflux for 6 hours. The resulting reaction solution was concentrated in vacuo to an oil which was crystallized from 20 mL of a 1/1 mixture of ethyl acetate/hexane to afford 1.69 g (55%) of 3-(4-methylphthalimido)-3-phenylpropionic acid as an off-white powder: 1H NMR (DMSO-d6) δ12.5 (br s, 1H, COOH), 7.85-7.55 (m, 3 H, Ar), 7.55-7.2 (m, 5H, Ar), 5.68 (dd, 1H, J=9, 7 Hz, CH), 3.51 (dd, 1H, J=9, 16.5 Hz), 3.29 (dd, 1H, J=9, 16.5 Hz), 2.47 (s, 3H, CH3). Anal. Calcd for C18H15N104. Theory; C, 69.89, H, 4.89, N, 4.53. Found: C, 69.45, H, 4.93, N, 4.55. HPLC: 95%.
Reaction SMILES: [C:1]([C:4]1[C:16](O)=[CH:15][C:14]2[N:13](CCCN(C)C)[C:12]3[CH:11]=[CH:10][C:9]4[C:24](=[O:27])[CH2:25]C[C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]>O.Cl.C(O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[C:7]([C:6]=2[CH:5]=1)=[CH:8][C:9]([C:24](=[O:27])[CH3:25])=[CH:10][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c3c4c(ccc3n(CCCN(C)C)c2cc1O)C(=O)CC4
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc2[nH]c3ccc(C(C)=O)cc3c2c1
Yield: 157.1 %

Procedure:
9-Acetyl-8-hydroxy-1,2-dihydro-6-(3-dimethylaminopropyl)-cyclopenta[c]carbazole-3-one (7.81 g, 21.46 mmol, 1 eq) was dissolved in a mixture of water (20 mL) and 10% HCl solution (20 mL) in ethanol (200 mL), and the homogeneous solution evaporated to dryness. The residue was dried in vacuum overnight to give 8.47 g of Example 4 as a gray solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:25](=[O:29])[C:26]([NH2:28])=[O:27])=[C:9]([CH2:23][CH3:24])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.[OH-].[Na+].[Na]>CO>[NH2:28][C:26](=[O:27])[C:25]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:9]=1[CH2:23][CH3:24])=[O:29]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(Cl)c1
Yield: 64.6 %

Procedure:
Using the procedure described in Example 2, Part E, 418 mg (1 mmol) of [[3-(2-amino-1,2-dioxoethyl)1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester was hydrolyzed in 5 mnL of 1N NaOH and 15 mL of MeOH to give 268 mg (61% yield) of [[3-(2-amino-l,2-dioxoethyl)1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic acid, sodium salt, mp, >265° C.