Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([CH3:25])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([CH3:25])[CH:16]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ccccc12
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) of 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 ml of dry DMF. The mixture is stirred for 60 h at 80° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(2-methyl-quinolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 316.12 (M+H, electrospray ionisation)) as an off-white foam after freeze-drying.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([N:19]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)[C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH3:18])[CH:12]=1.[Cl:43][CH2:44][C:45]([NH2:47])=[O:46].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CCOCC>[ClH:28].[ClH:43].[CH2:36]([N:33]1[CH2:34][CH2:35][CH:30]([N:19]([CH:17]([C:13]2[CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH2:4][NH:3][CH2:44][C:45]([NH2:47])=[O:46])[CH:16]=[CH:15][CH:14]=2)[CH3:18])[C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:31][CH2:32]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(c1cccc(-c2ccccc2CN)c1)N(C(=O)Cc1ccc(Cl)cc1)C1CCN(Cc2ccccc2)CC1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCOCC
Product: CC(c1cccc(-c2ccccc2CNCC(N)=O)c1)N(C(=O)Cc1ccc(Cl)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
To a solution of the compound obtained in Example 43 (100 mg) in acetonitrile (10 ml) was added 2-chloroacetic acid amide (22 mg) and potassium carbonate (66 mg), and the mixture was stirred at room temperature for 72 hours, and at 60° C. for 6 hours. The reaction mixture was diluted with saturated sodium bicarbonate (100 ml), and extracted with ethyl acetate (50 ml) twice. The extracted solutions were combined, washed with saturated brine, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give a colorless amorphous substance (60 mg, 62%). To a solution of this amorphous substance (60 mg) in ethyl acetate (10 ml) was added 1 M hydrochloric acid in ether (0.5 ml), and the mixture was concentrated under reduced pressure, and purified by reprecipitation from ethanol-diethyl ether to give the title compound (42 mg) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]1)[CH2:10][C:9]2=[O:26].Cl>C(O)(=O)C>[CH2:15]([N:13]1[CH2:14][C:11]2([CH2:10][C:9](=[O:26])[C:8]3[C:23](=[CH:24][CH:25]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:27])=[O:2])[CH:7]=3)[O:22]2)[CH2:12]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2
Temperature: 85 °C
Yield: 94.8 %

Procedure:
(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (540 mg, 1.48 mmol) was dissolved in acetic acid (10 ml), then 6 M HCl (10 ml) was added and the resulting suspension was heated to 85° C. for 4 h. The solvents were evaporated and the residue was dried under vacuum, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (490 mg, hydrochloride salt) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.S(=O)(=O)([OH:23])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:23])=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Temperature: 25 °C
Yield: 114 %

Procedure:
In a flask 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.11 g, 8.74 mmol) was dissolved in dioxane (120 mL) and H2O (30 mL) and the mixture cooled at 0° C. Sulfamic acid (5.09 g, 52.4 mmol) was added, followed by a solution of sodium chlorite (1.28 g, 11.4 mmol) and potassium dihydrogen phosphate (14.3 g, 104.9 mmol) in H2O (75 mL) via an addition funnel over 15 min. The mixture was allowed to warm to room temperature over 2 h. The resulting yellow solid was filtered off, washed with H2O and hexane and dried. The filtrate was then extracted with EtOAc, and the combined organics washed with brine, dried over MgSO4 and concentrated to give additional product. In total 3.71 g of 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid was obtained as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.52 (s, 1H), 8.42 (s, 1H), 5.73 (s, 2H), 3.56-3.65 (m, 2H), 0.90-1.02 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C=O.[C:17]([O-])(=[O:19])C.[Na+].[OH-].[Na+]>C(O)(=O)C.ClCCl>[OH:19][CH2:17][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cn2ccccc2n1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1nc2ccccn2c1CO
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (5.0 g) in acetic acid (30 ml) were added 37% formaldehyde (14 ml) and sodium acetate (8.0 g) at room temperature, and the reaction mixture was heated under reflux for 15 hr. The reaction mixture was cooled to room temperature and dissolved in dichloromethane. The mixture was adjusted to pH 8 with 10% aqueous sodium hydroxide solution at 0° C. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with dichloromethane-methanol (15:1) was concentrated under reduced pressure to give the object product (2.1 g).
Reaction SMILES: Cl.C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)(=O)C>CO>[CH3:18][O:17][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[NH:5][CH2:6][CH2:7]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])NCC2
Yield: 95.2 %

Procedure:
To the solution of conc. HCl (20 mL) in methanol (40 mL) was added 1-acetyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (7.8 g, 33 mmol) and the resulting mixture was refluxed for 4 hours. After cooling, the solvent was removed in vacuo, the residue was neutralized with saturated aqueous sodium hydrogencarbonate solution, and a brown precipitate formed. The precipitate was filtered via Buchner funnel, washed with water, and dried under reduced pressure to give 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a brown solid (6.1 g, 94% yield). 1H-NMR (DMSO, 300 MHz) δ 7.11 (s, 1H), 6.87 (s, 1H), 5.59 (brs, 1H), 3.78 (s, 3H), 3.43 (t, 2H), 2.97 (t, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:25][CH2:24][C:6]2[N:7]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)O)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].S(=O)(=O)(O)O.[OH-].[K+]>>[CH2:1]([N:3]1[CH2:25][CH2:24][C:6]2[N:7]([CH:14]=[CH:15][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2c(c3ccccc3n2CC(O)c2ccc(C)cc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CCN1CCc2c(c3ccccc3n2C=Cc2ccc(C)cc2)C1
Temperature: 5 °C

Procedure:
2-(2-Ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[N:7]=1)=[O:5].[N:14]([Si](C)(C)C)=[N+:15]=[N-:16]>CN(C=O)C.ClCCl>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:14]=[N+:15]=[N-:16])[N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(N=[N+]=[N-])n1
Temperature: 110 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
A mixture of 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (1.19 g, 6.47 mmol) and azido-trimethylsilane (2.0 g, 16.8 mmol) in DMF (10 mL) was stirred at 110° C. for 72 h. The reaction mixture was diluted with 50 mL of dichloromethane and washed with water (3×50 mL). The organic layer was separated, evaporated to dryness, and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 6-azido-pyridine-2-carboxylic acid methoxy-methyl-amide (0.335 g) in 25% yield. ESMS m/z (relative intensity): 208 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20])=[O:11].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:29]([C:32]#[N:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[C:32]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:25]=[CH:24][CH:23]=[C:22]2[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])=[C:14]([F:20])[CH:15]=1)#[N:33]
Reactant: O=C(Nc1ccc(O)cc1F)Nc1ccc(F)cc1F
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)ccnc2cc1OCc1ccccc1
Yield: 16.1 %

Procedure:
N-(2,4-Difluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)urea (227 mg, 0.8058 mmol) and 4-chloro-6-cyano-7-benzyloxyquinoline (250 mmol, 0.8482 mmol) were used for reaction in the same manner as the second method in Example 86, and after cooling, extraction and washing with water, the solvent was distilled off under reduced pressure and the obtained crystals were suspended in diethyl ether, washed and filtered. They were then dissolved in tetrahydrofuran and filtered with silica gel, and the solvent was distilled off under reduced pressure. These crystals were then suspended in diethyl ether, washed with water and filtered, and then washed with diethyl ether and dried by aspiration to obtain the title compound (70 mg, 0.1295 mmol, 16.07%) as light brown crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:23][O:22][CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:19][C:20]3([CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:23][O:22][CH2:21]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)CC1(N)COC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-(3-aminooxetan-3-yl)-N-methyl-acetamide (example 231a) as starting materials and isolated (25 mg, 43%); MS (ESI, m/z): 388.6 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:26]3[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=3[O:24][N:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C=O)C.O>[OH:31][C:29]1[CH:28]=[CH:27][C:26]2[C:22]([CH:19]3[CH2:18][CH2:17][N:16]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH2:11][CH2:12][CH2:13][CH2:14][C:7]5=[N:6][C:5]=4[CH3:15])[CH2:21][CH2:20]3)=[N:23][O:24][C:25]=2[CH:30]=1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2
Reactant: Oc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2
Temperature: 25 °C

Procedure:
A solution of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (14.4 g, 0.05 mmol), 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol (14.0 g, 0.05 mmol), sodium carbonate (16.0 g, 0.15 mmol) and potassium iodide (spatula point) in DMF (150 mL) was stirred for 5 h at 80° C. The mixture was allowed to cool down to room temperature and water was added. The precipitate was removed by filtration, and the filtrate was extracted with chloroform (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was crystallized with isopropyl alcohol (70 mL), filtered, and washed with isopropanol/diisopropyl ether 50/50 mixture (10 mL). The residue was dried overnight at 100° C. yielding the title compound and was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1.[CH3:24][NH:25][CH3:26]>>[F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH2:20][N:25]([CH3:26])[CH3:24])=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1
Reactant: CNC
Reactant: O=Cc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1
Product: CN(C)Cc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1

Procedure:
The title compound was prepared following the procedure described in Example 32 from aldehyde 97a and dimethylamine (2M/MeOH) to give 0.10 g (60%) of a white solid: mp=240° C. (dec); Rf=0.08 (7% methanolic ammonia/CHCl3); IR (KBr) 1669, 1607, 1487, 1458 cm−1; 1H NMR (DMSO-d6) δ 2.20 (s, 6H), 3.51 (s, 2H), 3.54-3.55 (m, 2H), 4.45-4.47 (m, 2H), 7.50 (d, 2H, J=8.2 Hz), 7.57-7.61 (m, 1H), 7.73-7.76 (m, 1H), 7.82 (d, 2H, J=8.2 Hz), 8.59-8.63 (m, 1H). HRMS calcd for C19H19N4OF 338.1543 (M+), found 338.1558. Anal. (C19H19N4OF0.2H2O) C, H, N. found 412.2124. Anal. (C25H25N5O.0.5 H2O, 3.5 TFA) C, H, N.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:7]2[C:9]([O:11]CC2C=CC([N+]([O-])=O)=CC=2)=[O:10])[CH2:3]1.C(=O)(O)[O-].[Na+:34]>O1CCOCC1.[Pd]>[O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:7]2[C:9]([O-:11])=[O:10])[CH2:3]1.[Na+:34]
Reactant: Cc1ccc(OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(OC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 53 mg of 4-nitrobenzyl 7-oxo-3-(4-tolyloxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan was added an aqueous solution of 10 mg of sodium bicarbonate, and 50 mg of palladium on charcoal (10%). The mixture was hydrogenated with shaking at 50 p.s.i. for 90 minutes.
Reaction SMILES: C(O)CCC.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([C:12]1[S:16][C:15](=[NH:17])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)[N:13]=1)[CH3:11].S(=O)(=O)(O)O>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[CH2:10]([C:12]1[S:16][C:15](=[NH:17])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:8]=[N:7][N:6]=3)=[CH:21][CH:20]=2)[N:13]=1)[CH3:11]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
In a 500-ml glass-made reactor equipped with a thermometer and a reflux condenser, 200 ml of n-butanol, 37.5 g of zinc chloride and 50.7 g of sodium azide were charged, followed by stirring for 30 minutes. To the reactor, 50 g of 5-ethyl-2-imino-3-(2'-cyanobiphenyl-4-yl)methyl-1,3,4-thiadiazoline were charged further, followed by heating the internal temperature to 110 to 120° C. at which the reaction was effected for 20 hours. After the completion of the reaction, the reaction mixture was cooled. After the internal temperature decreased to 100° C. or lower, adequate amounts of chloroform and 10% sulfuric acid were added to the reaction mixture, followed by stirring for 30 to 60 minutes. The reaction mixture was cooled and then separated. To the organic layer, a 5% aqueous solution of sodium hydroxide was added. The resulting mixture was stirred for several hours, followed by separation into layers. The aqueous layer was adjusted to pH 7 with 3N hydrochloric acid. The white crystals so precipitated were collected by filtration. The crude crystals so obtained were washed with chloroform under heating and then cooled to room temperature. After cooling to room temperature, the reaction mixture was collected by filtration and dried, whereby about 44.8 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[OH:19][CH2:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][OH:19])[CH:22]=4)[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1cccc(CO)c1
Product: O=C1Cc2cnc(Nc3cccc(CO)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to method I, 8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(3-(hydroxymethyl)phenyl)-guanidine were converted to I-79 (51%): HRMS Calcd. for C19H15ClN4O2: 367.0961, Found 367.0973.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:9]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(Cc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 17, Step 1, using (3-benzyl-phenyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1
Reactant: N#Cc1cccc(Br)c1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(N2CCSCC2)c1
Temperature: 85 °C
Yield: 81.4 %

Procedure:
A 10 dram vial was charged with 3-bromo-benzonitrile (280 mg, 1.54 mmol), thiomorpholine (190 mg, 1.85 mmol), NaOtBu (207 mg, 2.15 mmol), BINAP (14.4 mg, 0.023 mmol), toluene (3 mL), Pd2(dba)3 (7 mg, 0.0077 mmol), and flushed with argon. The reaction mixture was heated to 85° C. for 48 h, and then cooled to RT. The resulting mixture was diluted with Et2O (10 mL), filtered through celite, and washed with Et2O (7 mL) two times. The filtrate was concentrated in vacuo and purified by silica gel chromatography (20% EtOAC/Hexane) to give compound 387A as a yellow oil (256 mg). HPLC retention time=2.48 min. (Condition A), M+=205.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N+:20]=[N-:21].C[O-].[Na+].[Na]>CO>[CH3:26][O:25][C:23](=[O:24])[C:22]([N:19]=[N+:20]=[N-:21])=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:17][CH3:18])[CH:11]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1ccc(OCc2ccccc2)c(OC)c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.5 %

Procedure:
A solution of the 4-Benzyloxy-3-methoxy-benzaldehyde (12.0 g, 49.6 mmol) and methyl azidoacetate (23 g, 0.200 mol) in methanol (50 mL) was added over 30 min to a cooled (ice-salt bath) solution of sodium methoxide which had been prepared from addition of methanol (80 mL) to sodium (3.4 g, 0.149 mol). The reaction mixture was stirred at 0° C. for 45 min, during this time a thick cream precipitate formed, and then stood in the freezer overnight. Ice-cold water was added and the precipitate was removed by filtration and dried to give methyl-2-azido-3-[4′-(benzyloxy)-3′-methoxyphenyl]prop-2-enoate (55) (12.2 g, 73%) which was used in the next step without purification.