Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=O.[Cl:22]N1C(=O)CCC1=O>O1CCOCC1>[O:19]=[C:17]1[CH2:16][C:3]2[C:2](=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[CH:6]=[C:5]([Cl:22])[CH:4]=2)[NH:1]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: O=C1Cc2cc(Cl)cc(Oc3ccccc3Cl)c2N1

Procedure:
Ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (1.50 g.), N-chlorosuccinimide (700 mg.) and dioxane (30 ml.) were treated in a similar manner to that of the Preparation 31 to give crystals of the captioned compound (0.50 g.), mp 196° to 198° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([F:23])=[CH:25][CH:26]=1)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol (0.30 g, 0.944 mmol) in N,N-dimethylformamide (5 ml) were added 4-fluoronaphthalene-1-carboxylic acid (0.189 g, 0.99 mmol) and 1-hydroxybenzotriazole monohydrate (0.152 g, 0.99 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.190 g, 0.99 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, 0:1) and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.245 g, 53%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14]([O:5][CH2:4][CH2:3][OH:6])=[N:15]2)=[CH:10][CH:9]=1
Reactant: Clc1cnc2ccc(Br)cc2n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: OCCOc1cnc2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Suspend sodium hydride (310 mg, 13 mmol) in a solution of ethylene glycol (800 mg, 13 mmol) in DMF (50 mL) previously cooled to 0° C. Allow the mixture to warm to room temperature and stir for 30 min. Add 7-bromo-2-chloroquinoxaline (610 mg, 2.5 mmol) and stir the resulting mixture for 2 h at room temperature. Dilute the mixture with 3:1 chloroform/isopropyl alcohol and wash the resulting solution with saturated sodium chloride solution. Dry and concentrate the organic phase in vacuo and purify the residue via silica gel chromatography to provide 564 mg (85%) of the titled compound. MS ES+ m/e 268 (M+1). 1H NMR (400 MHz, CDCl3) δ 8. (s, 1H), 8.0 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.8, 2.0 Hz, 1H), 7.7 (d, J=8.8 Hz, 1H), 4.6 (t, J=4.8 Hz, 2H), 4.39 (t, J=4.8 Hz, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(Br)c1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 225 ml. of 40% hydrobromic acid and cooled to 0° C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of cuprous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 3-bromo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][C:27]([NH2:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:26][C:27]([NH2:29])=[O:28])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
A mixture of 1-benzyl-3-(4-chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.05 mmol), 2-bromo-acetamide (8 mg), and Na2CO3 (15 mg) in acetone (2 mL) was stirred at 25° C. for 16 h. After concentration, purification by flash chromatography (2 M NH3/MeOH in CH2Cl2) provided the desired compound (6 mg). MS (ESI): exact mass calculated for C22H23ClN4O, 394.16. found, m/z 395.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H), 2.93-2.87 (m, 2H), 2.76-2.74 (m, 2H).
Reaction SMILES: [OH-].[K+].C(O)(C)C.Cl[CH2:8][C:9]([N:11]([CH2:15][CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:12][CH2:13][CH3:14])=[O:10]>O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:16]2[CH2:15][N:11]([CH2:12][CH2:13][CH3:14])[C:9](=[O:10])[CH2:8][O:25]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCCN(CC(O)c1cccc(OC)c1)C(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN1CC(c2cccc(OC)c2)OCC1=O
Yield: 100 %

Procedure:
Potassium hydroxide (4.2 g, 0.07 mol), isopropyl alcohol (500 ml) and the amide from example 4 (17.8 g, 0.06 mol) were stirred together as an opaque solution with water (15 ml) for 2 hours. The reaction mixture was concentrated in vacuo and the yellow residue dissolved in ethyl acetate (200 ml). This was partitioned with water (200 ml) then brine (200 ml). The organic fraction was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (15.8 g, 0.06 mol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.96 (t, 3H), 1.62 (m, 2H), 3.36 (m, 2H), 3.51 (q, 2H), 3.81 (s, 3H), 4.30-4.62 (bq, 2H), 4.79 (d, 1H), 6.85 (d, 1H), 6.91 (d, 1H), 6.95 (s, 1H), 7.29 (t, 1H). LRMS: m/z 272. Analysis found C, 66.80; H, 7.78; N, 5.52%. C14H19NO3.0.1H2O requires C, 66.96; H, 7.71; N, 5.58%.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:29][CH2:30][OH:31])[C:21]([NH2:28])=[C:22]([CH2:24][NH:25]C=O)[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C(OCC)(=O)C>CO>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:29][CH2:30][OH:31])[C:21]([NH2:28])=[C:22]([CH2:24][NH2:25])[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CNC=O)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 18.9 %

Procedure:
To a solution of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-formamidomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (97 mg) in methanol (1 ml) was added concentrated hydrochloric acid (0.1 ml) at room temperature. The mixture was stirred at room temperature for 4.5 hours and poured into ethyl acetate. The resulting precipitate was collected by filtration and dried in vacuo. The obtained powder was dissolved in a phosphate buffer (pH 7), and the solution was adjusted to about pH 6 with saturated aqueous sodium hydrogencarbonate solution. The solution containing the objective compound was purified by preparative HPLC utilizing ODS column. The eluate containing the desired product was concentrated in vacuo. The concentrate was adjusted to about pH 2 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was concentrated in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (17.5 mg).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][C:10](=[O:23])[N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:3][CH:4]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(I)nc3)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(C#C[Si](C)(C)C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
According to Scheme 33 Step 2: A mixture of 1-((6-iodopyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.48 mmol, 200 mg), PdCl2(PPh3)2 (33 μmol, 23 mg), CuI (24 μmol, 4.5 mg), iPr2EtN (0.99 mmol, 1.72 μl), trimethylsilylacetylene (1.43 mmol, 203 μL) and DMF (3 mL, previously deoxygenated) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 3% yielding 5-(4-methoxyphenyl)-1-((6-(2-(trimethylsilyl)ethynyl)pyridin-3-yl)methyl)pyridin-2(1H)-one (174 mg, 93%).
Reaction SMILES: [C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]3[CH2:15][CH2:14][CH2:13][C:11]3=[N:12][C:8]=2[CH:7]=1)([O:3]CC)=[O:2].C(O)(=O)C>C(O)C.[OH-].[Na+]>[C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]3[CH2:15][CH2:14][CH2:13][C:11]3=[N:12][C:8]=2[CH:7]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)nc1n2CCC1

Procedure:
A solution of 5 g of 6-carbethoxy-2,3-dihydro-1H-pyrrolo [1,2-a]benzimidazole (1A06) in 15 cm3 of ethanol and 25 cm3 of 2,5 N sodium hydroxide are refluxed for 5 min. After cooling the reaction mixture is slightly acidified with diluted acetic acid and the precipitate formed is sucked off and washed with water and ethanol. Yield: 4 g. Melting point: 300°c.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([NH2:12])[CH2:7]2.[CH3:15][CH2:16][C:17](=O)[CH2:18][CH3:19].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[NH3:12].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([NH:12][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])[CH2:7]2
Reactant: CCC(=O)CC
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)N[C@H]1COc2c(F)ccc(OC)c2C1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 176.4 %

Procedure:
To a stirred solution of (R)-8-fluoro-5-methoxy-3-aminochroman (3.13 g, 15.9 mmol) and 3-pentanone (2.2 ml, 20.8 mmol) in 100 ml dry MeOH, NaBH3CN (1.31 g, 20.8 mmol) was added during 10 min. The pH was adjusted to pH was adjusted to pH 6 with acetic acid and the solution was stirred at room temp. After 18 hours, 3-pentanone (0.5 ml, 4.7 mmol) was added and the solution was stirred at room temp. for 3 hours. Concentration and extraction with 100 ml 2M NH3 and 2×250 ml EtOAc, drying of the combined organic phases (Na2SO4) and evaporation gave a crude product that was purified by flash chromatography on silica with hexane:EtOAC:NH3, 60:40:0.5, to give 3.75 g of (R)-8-fluoro-5-methoxy-3-(N-3-pentylamino)chroman as an uncolored oil. [α]D22 -25° (c 1.14 in MeOH).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([CH2:21][OH:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2.[Mn]([O-])([O-])(=O)=O.[Ba+2].C(Cl)Cl>CCOC(C)=O.C1COCC1>[CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([CH:21]=[O:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2
Reactant: OCc1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Yield: 71.7 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added acenaphtho[1,2-b]quinoline-10-methanol (14A, 2.25 g, 8 mmol), barium manganate (Aldrich, 4.0 g, 16 mmol) and dry CH2Cl2 (1 L). The mixture was refluxed for 24 h, filtered and the resulting dark yellow solution filtered and the solvent removed by rotary evaporation to give a dark green solid. This material was dissolved in a mixture of EtOAc (700 mL) and THF (200 mL) and passed through a small plug of SiO2 using EtOAc as the eluting solvent. The appropriate fractions were combined and the solvent removed by rotary evaporation to give a 71.7% yield of acenaphtho[1,2-b]quinoline-10-carbaldehyde, mp 245-246°, (C,H,N).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NCCc1ccccc1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1NCCc1ccccc1

Procedure:
A mixture of 3-amino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid (3.35 g), benzyl bromide (5.3 g), and anhydrous ethanol (30 ml) was refluxed for 48 hours. After cooling, the precipitated ethyl ester was collected by suction, recrystallized from ethanol and saponified by heating in 1N sodium hydroxide (30 ml) for 1 hour. The 3-benzylamino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was precipitated at room temperature by addition of 4N hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol, the compound was obtained with a melting point of 203°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:17]1([CH2:20][C:21]([NH2:29])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C:21]([NH:29][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 66e) as starting materials and isolated (89 mg, 58%) as colorless oil; MS (ESI, m/z): 463.4 (M+H+).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Mg].[C:8]([O:13][C:14]1([CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH:15]1CC)(=[O:12])[C:9]([O-])=[O:10].[Cl-].[NH4+]>C(OCC)C>[OH:10][C:9]([CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])([CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([O:13][C:14]1([CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: C[Si](C)(C)CCl
Reactant: CCC1CCCC1(CC)OC(=O)C(=O)[O-]
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1(OC(=O)C(O)(C[Si](C)(C)C)C[Si](C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Under a nitrogen atmosphere, a Grignard reagent solution was prepared from 100 g of chloromethyltrimethylsilane, 20 g of magnesium and 500 ml of diethyl ether. Under a nitrogen atmosphere, the Grignard reagent solution was slowly added dropwise to a solution of 80 g of ethyl(1-ethylcyclopentyl) oxalate (which had been prepared by reacting ethyl chloroglyoxylate and 1-ethylcyclopentanol in pyridine) in 360 ml of diethyl ether at −40° C. After 2 hours of stirring at the temperature, the solution was warmed up to room temperature and stirred for further 8 hours. An aqueous solution of ammonium chloride was added for hydrolysis, followed by usual work-up procedure including extraction, washing, drying and concentration to give 102 g (crude yield 79%) of crude 1-ethylcyclopentyl 2-hydroxy-3-trimethylsilyl-2-trimethylsilylmethylpropionate.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1
Agent: Cc1cccnc1N
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1 mmol, aniline 0.3 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various kinds of acids 0.03 mmol as shown in the following table 4, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products from various acids and the results are given in Table 4, below.
Reaction SMILES: CCO[CH:4](OCC)[CH2:5][CH:6]([O:10]CC)OCC.C([O-])(=O)C.[NH4+:20].[C:21]1(C)[C:22](C)=[CH:23][CH:24]=[CH:25][CH:26]=1>O>[N:20]1[C:21]2[CH2:26][CH2:4][CH2:5][C:6](=[O:10])[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: Cc1ccccc1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: O=C1CCCc2ncccc21
Temperature: 160 °C
Reaction time: 18 h

Procedure:
In a nitrogen atmosphere, 24 mL of malonaldehyde tetraethyl acetal and 7.71 g of ammonium acetate were added in that order to xylene (80 mL) solution of 11.2 g of 1,3-cyclohexadione, and a reflux condenser tube fitted with a Dean-Stark water separator was attached to the reactor, and this was stirred at 160° C. for 18 hours. The reaction liquid was cooled to room temperature, the solvent was evaporated off under reduced pressure, the residue was extracted with chloroform, and the chloroform layer was washed with saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (chloroform/methanol=97/3) to obtain 2.21 g of the entitled compound.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:16][C:17]1[C:18]([C:14]#[C:13][C@@H:12]2[CH2:11][C@H:10]([OH:15])[CH2:9][NH:8]2)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: C#C[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3C[C@H](O)CN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (3S,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (132 mg, 0.62 mmol) (Example 103A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated, and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 4 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4S)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 58%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[N:26][OH:27])=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([O:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][C:25]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:27][N:26]=2)=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)nc2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
To a solution of 3-ethynyl-pyridin-2-ylamine (400 mg, 3.39 mmol) described in Manufacturing Example 1-2-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (2.50 g, 9.03 mmol) under nitrogen atmosphere at room temperature. Triethylamine (1.89 mL, 13.6 mmol) was then added dropwise thereto, and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3 then 1:2) to obtain the title compound (315 mg, 26%).