Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1)=[O:25])[CH:9]([OH:22])[CH2:10][CH:11]([C:18]([NH:20][NH2:21])=[O:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]#[C:37]Br.C(=O)([O-])O.[K+]>O1CCOCC1.O>[NH2:36][C:37]1[O:19][C:18]([CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:22])[CH:8]([NH:23][C:24]([C:26]2[CH:35]=[N:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][N:21]=1
Reactant: N#CBr
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NN
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1nnc(N)o1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide (110 mg, 0.228 mmol) in dioxane (0.5 mL) and water (0.5 mL) was added cyanogen bromide (31 mg, 0.296 mmol) and potassium hydrogencarbonate (31 mg, 0.310 mmol). The reaction was heated to reflux for 1 hour then cooled to ambient temperature. The dioxane/water was removed by adding benzene (5 mL) and concentrating (2×). The remaining solid was dissolved in ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. Recrystallization of the crude product using a mixture of ethyl acetate, hexanes and methanol gave the title compound (64 mg, 55%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]1O)=S.C1(C)C=CC(S(Cl)(=O)=[O:28])=CC=1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(C)C1O
Solvent: c1ccncc1
Product: CNC(=O)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 67.3 %

Procedure:
A mixture of 0.42 g of N-methyl-6-nitro-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.58 g of p-toluenesulfonyl chloride, and 30 ml of pyridine was heated under reflux for 3 hours. The reaction mixture was concentrated, and 2N hydrochloric acid was added to the residue. The mixture was extracted with dichloromethane, and the extract was dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CH2Cl2) and then recrystalllzed from ethyl acetate to obtain 0.25 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]2[N:18]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19](=[O:21])[NH:20][C:16]=2[CH:15]=1.[I-].[Na+].C(OC(C)C)(C)C>CN(C)C=O.C(N(CC)CC)C>[ClH:13].[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([N:18]2[C:17]3[CH:28]=[CH:29][C:14]([Cl:13])=[CH:15][C:16]=3[NH:20][C:19]2=[O:21])[CH2:27][CH2:26]1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: BrCC1COc2ccccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: Cl
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2COc3ccccc3O2)CC1
Reaction time: 2 h

Procedure:
2.3 g of 2-bromomethyl-1,4-benzodioxane, 2.2 g of 4-(5-chlorobenzimidazol-2-on-1-yl)-piperidine, 1.4 ml of triethylamine and 0.3 g of sodium iodide were stirred in 25 ml of dry dimethylformamide at room temperature for 60 hours and the mixture was then poured onto water; diisopropyl ether was added and the mixture was stirred vigorously for 2 hours. The product which had precipitated was filtered off with suction, washed with water and diisopropyl ether and dried; the free base thus obtained has a melting point of 226°-228° C.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:14](OCC)[CH3:15]>>[C:1]([O:4][C@@H:12]([CH2:11][CH2:10][CH2:9][CH2:14][CH3:15])[C:13]#[N:8])(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Product: CCCCC[C@@H](C#N)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The purified cyanohydrin was dissolved in 5 ml of dry diethyl ether, and the solution was treated with 2 mol equivalents of acetic anhydride and 2 mol equivalents of pyridine and stirred at room temperature for 8 hours. It was then extracted with 10 ml each of 5% H2SO4, distilled water and saturated NaHCO3 solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. After purification by column chromatography, 182 mg of (S)-2-acetoxyheptanenitrile were obtained (98% isolated yield). e.e.=96% (determined by gas chromatography)
Reaction SMILES: BrC(Br)(C)C([O-])=O.[OH-].[K+].[O:10]=[C:11]1[N:19]([CH2:20][CH2:21][CH3:22])[C:18]2[NH:17][C:16]([C:23]3[CH:35]=[CH:34][C:26](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=3)=[N:15][C:14]=2[C:13](=[O:36])[N:12]1[CH2:37][CH2:38][CH3:39]>O>[O:10]=[C:11]1[N:19]([CH2:20][CH2:21][CH3:22])[C:18]2[NH:17][C:16]([C:23]3[CH:35]=[CH:34][C:26]([C:27]#[C:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)=[N:15][C:14]=2[C:13](=[O:36])[N:12]1[CH2:37][CH2:38][CH3:39]
Reactant: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Agent: CC(Br)(Br)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCn1c(=O)c2nc(-c3ccc(C#CC(=O)O)cc3)[nH]c2n(CCC)c1=O

Procedure:
A suspension of the above dibromopropionate (3.00 g, 5.26 mmol) in an anhydrous ethanolic solution (150 ml) of potassium hydroxide (1.5 g, 26 mmol) was refluxed for 21 hours, then diluted over 3 hours with water (250 ml) as the ethanol was allowed to evaporate. The cooled solution was treated with 1N HCl until a precipitate formed (pH 10) which was extracted with methylene chloride (100 ml). The aqueous phase was made strongly acidic with 1N HCl. The thick precipitate was filtered and dried to yield a solid. A portion of this solid (0.65 g) was recrystallised from 50% ethanol (50 ml) to give the title compound as a yellow solid as the hemihydrate; mp slow dec. starting at 260° C. Analysis for (C20H20N4O4.5H2O): C, 61.69; H, 5.44; N, 14.39. Found: C, 61.85; H, 5.38; N, 14.45.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-])=[CH:3][CH:2]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: Cc1ccc(C=Cc2cccc[n+]2[O-])cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: Cc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
In a variation to the procedure referred to in example 1, 2-(2-p-tolyl-vinyl)-pyridine 1-oxide (9.8 g, 46 mmol) was reacted first with dimethylsulfate ( 5.8 g, 46 mmol) and then with NaCN (2.74 g, 56 mmol). After extraction and crystallization 6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (5.8 g, 57%) was obtained as a yellow crystalline material. Mp. 137-138° C. (isopropanol), MS: m/e=220 (M+)
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])[CH:19]=[CH:18][C:14]1=2
Reactant: CCCNCCC
Reactant: CS(=O)(=O)OCCOCCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)CCOCCc1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In 8 mL of N,N-dimethylformamide is dissolved 0.80 g of 2-(2-benzo[b]thiophen-5-ylethoxy)ethyl methanesulfonate, to which are added 0.73 mL of dipropylamine and 0.74 g of potassium carbonate. The resulting mixture is stirred at 80° C. for 3 hours. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=10:1). Thus, 0.60 of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N,N-dipropylamine is obtained as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C(OCC)(=O)C.N1C(C)=CC=CC=1C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitroaniline (PNA) (0.1 g, 0.724 mmol) and succinic anhydride (SA) (0.29 g, 2.898 mmol) were dissolved in ethyl acetate (EtOAc) (4 mL). Slight warming was required to dissolve both PNA and SA. The reaction was started by adding 2 drops of 2,6-lutidine. The reaction was held at a temperature of 70° C. overnight (19 hrs). The reaction vessel was placed in the refrigerator and the cold EtOAc was decanted from the solid reaction products. The reaction products were then rinsed with cold EtOAc (1 mL). The crude product, p-nitrosuccinanilic acid, was obtained by removing some reaction co-products using thin layer chromatography (TLC). The solid reaction products were dissolved in N,N-dimethylformamide (DMF) and spotted on Kieselgel 60 F254 HPTLC plates containing a concentration zone (EM Science No. 13728). The plates were developed using solvent system chloroform (CHCl3):EtOAc:methanol (MeOH):formic acid, 86:10:4:1%. The desired product remained at the origin. The origin band was scraped and eluted with DMF. The DMF was removed with a stream of argon gas. The sample was dissolved in 30% MeOH/H2O and made slightly basic using a solution of sodium hydroxide (4 N). The product was collected from HPLC using a 15 cm×4.6 mm, 5 μm, Supelcosil LC-ABZ column with a solvent system of 30% MeOH at a flow rate of 1 mL/min., at 254 nm; sodium p-nitrosuccinanilate (C10H9N2NaO5) in a yield of 59%. Accurate mass measurement was observed by Fast Atom Bombardment on the double sodium ion at 283.0326 (calculated for C10H9N2Na2O5+, 283.03069 (Δ1.91 ppm)).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][N:7]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:5].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([N:29]=[N+:30]=[N-:31])[CH2:8][N:7]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:5]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester-2-ethyl ester) (28) (2.6 g, 6.3 mmol) in dry DMF (15 ml) was added NaN3 (0.41 g, 6.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic layer was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness The resulting residue was purified by column chromatography using pet ether: CH2Cl2: MeOH (10:1) to give 1.8 g of desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 43 h
Yield: 44.5 %

Procedure:
A suspension of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15 mg, 0.03 mM) and 0.03 mL (0.03 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 43 hours at 25° C., then cooled in an ice-bath. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 6.5 mg (43%) of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.6-7.0 (m, 11H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.35 (s, 2H). IR (KBr, cm−1) 3456, 3416, 3335, 1735, 1638, 1617, 1580, 1499, 1452, 1431, 1431, 1329, 1255, 1157, 772, 764, and 717. MS (ES) m/e 407, 409, 411.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(O)CC3)c2)c(F)c1
Reaction time: 2 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (169 mg) was dissolved in methanol (5 ml)-tetrahydrofuran (5 ml), and then 10% palladium carbon (200 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 2 hrs. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with ethyl acetate. The filtrate was concentrated under a reduced pressure to provide the titled compound (168 mg, quantitatively) as pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:25](O)[CH2:26]O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]2[O:12][CH2:25][CH2:26][O:11][C:10]=12)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(c(C(=O)OCC)n1Cc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
ADC01 (2.9 g, 16.9 mmol) was slowly added to a solution of N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylic acid diethyl ester (2.6 g, 7.7 mmol), ethylene glycol (0.5 g, 8.5 mmol), and PH02 (4.4 g, 16.9 mmol) in dry tetrahydrofuran (150 ml) at 0° C. The reaction mixture was allowed to warm to 25° C., stirred for 3 h, and then was refluxed for 21 h. The reaction mixture was then allowed to cool to 25° C. and was concentrated by rotary evaporator to remove the tetrahydrofuran. The residue was diluted with diethyl ether and allowed to stand overnight to enable the tributylphosphine oxide to precipitate out. The tributylphosphine oxide was then removed by filtration and the residue purified by chromatography on silica gel (eluant: ethyl acetate/hexane=3/1) to give 6-benzyl-2, 3-dihydro-6H-[1,4]dioxino[2,3-c]pyrrole-5,7-dicarboxylic acid diethyl ester as a colourless solid in 2.3 g (85%) yield as characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1([B-](F)(F)F)[CH2:11][CH2:10]1.[K+].Cl[C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH:9]1([C:18]2[C:23]3[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=3[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=2)[CH2:11][CH2:10]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Temperature: 110 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
To a suspension of potassium phosphate, tribasic (0.141 g, 0.665 mmol), potassium cyclopropyltrifluoroborate (0.049 g, 0.332 mmol), 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.05 g, 0.222 mmol) in toluene (Ratio: 5.00, 5 mL) and water (Ratio: 1.000, 1.0 mL) was added PdOAc2 (3.73 mg, 0.017 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.016 g, 0.033 mmol) at 23° C. The reaction was stirred at 110° C. for 14 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (0.25 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The late eluting fractions were dried in vacuo to provide the title compound as an off-white solid (0.0283 g, 0.122 mmol, 55.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69-0.81 (m, 2H) 0.91-1.04 (m, 2H) 1.48 (d, J=6.57 Hz, 3H) 2.15 (tt, J=8.49, 5.15 Hz, 1H) 4.85 (q, J=6.82 Hz, 1H) 7.13 (d, J=1.77 Hz, 1H) 7.19 (d, J=1.77 Hz, 1H) 9.79 (s, 1H) 10.89 (s, 1H). ESI-MS: m/z 232.1 (M+H)+.
Reaction SMILES: [Li+].[OH-].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]3[CH2:18][C@@H:19]([CH2:32][C:33]([O:35]C)=[O:34])[C:20](=[O:31])[N:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][C:16]=3[CH:15]=2)[CH:8]=[CH:7][CH:6]=1>C1COCC1.O>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]3[CH2:18][C@@H:19]([CH2:32][C:33]([OH:35])=[O:34])[C:20](=[O:31])[N:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][C:16]=3[CH:15]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CNc1cccc(CCOc2ccc3c(c2)CN(CCc2ccccc2)C(=O)[C@H](CC(=O)OC)C3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1cccc(CCOc2ccc3c(c2)CN(CCc2ccccc2)C(=O)[C@H](CC(=O)O)C3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
1.0N LiOH (0.62 mL, 0.62 mmole) was added to a solution of methyl (S)-8-[2-[6-(methylamino)pyridin-2-yl]ethoxy]-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (250 mg, 0.51 mmole) in THF (2.5 mL) and H2O (1.9 mL) at 0°0 C., and the reaction was allowed to stir at RT for 18 hr. The mixture was washed with Et2O (2×5 mL) then a mild vacuum was applied to remove residual organic solvents. The aqueous layer was passed through a 0.45 μm Acrodisk filter then was carefully acidified to pH 6 using 10% HCl in H2O at 0° C. The precipitate was collected, washed with H2O, and dried under vacuum at 50° C. to give the title compound (134 mg, 55%) as a white solid: MS (ES) m/e 474 (M+H)+. Anal. Calcd for C28H31N3O4.0.75 H2O: C, 69.05; H, 6.73; N, 8.63. Found: C, 69.23; H, 6.59; N, 8.55.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[NH:17][C:18]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:19]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (5.52 g., 0.041 mole) is converted to free base in benzene in the usual manner. Then 9.08 g. (0.041 mole) of 2,4,6-trichlorophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added with stirring. The reaction mixture is stirred for 2 hours and the solvent is evaporated in vacuo to give a solid residue of 1-(2,4,6-trichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 160°-162° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:47]C(Cl)C>C(=O)(O)[O-].[Na+]>[ClH:47].[ClH:47].[CH3:33][N:15]1[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[CH:24]=[C:23]([CH3:26])[S:22][C:21]=3[NH:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)[CH2:11][C@@H:10]1[CH2:9][CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cl)Cl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCSc2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCSc2ccccc2)C1
Product: Cl

Procedure:
Combine (S)-10-[3-(2-phenylsulfanyl-ethyl)piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene (0.118 g, 0.271 mmol), formaldehyde (24 μL, 0.299 mmol, 37% aqueous solution), and sodium triacetoxyborohydride (86 mg, 0.407 mmol) in dichloroethane (10 mL) and stir at room temperature for 2 hours. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 6% 2N ammonia-methanol in dichloromethane gives the free base of the title compound. Isolate clean product as the corresponding dihydrochloride by dissolving the free base in ethanol and adding a solution of 5 equivalents of hydrochloric acid in ethanol. Evaporating the solution and drying the salt provides the title compound (0.089 g, 0.189 mmol, 70%) as a brown solid. Mass spectrum (APCI): m/z=449.1 (M+1 of free base).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(O)C>>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)=[C:13]([NH:12][C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:18]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Clc1nccc2ncccc12
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2nccc3ncccc23)cc1
Temperature: 100 °C

Procedure:
The product from Example 228e (0.040 g, 0.24 mmol) was reacted with the product from Example 18b as a 1.5M solution in ethanol (0.162 mL, 0.24 mmol) for 17.5 h at 100° C. following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 228e (0.027 g, 0.16 mmol) and continued heating at 100° C. (24 h) giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.038 g, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H) 2.36 (s, 3H) 7.12-7.37 (m, 5H) 7.38-7.53 (m, 3H) 7.73-7.92 (m, J=8.64, 4.60 Hz, 2H) 8.94 (d, J=8.46 Hz, 1H) 9.18 (d, J=4.04 Hz, 1H) 9.99 (s, 1H); MS (ESI+) m/z 401.3 (M+H)+; (ESI−) m/z 399.0 (M−H)−.