Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:6][CH2:5]1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)Cl.CO.O.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].O1CCOCC1>[Br:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][F:1])[CH2:9][CH2:8]3)=[CH:15][N:14]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Nc1ccc(N2CCN(CCF)CC2)cn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCF)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 62 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 217c (402 mg, 1.79 mmol), 3,5-dibromo-1-methyl-pyridin-2(1H)-one (478 mg, 1.79 mmol), cesium carbonate (1.75 g, 5.37 mmol) and 1,4-dioxane (15 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (93 mg, 0.161 mmol) and tris(dibenzylideneacetone)dipalladium(0) (82 mg, 0.090 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 3 h. After this time, the mixture was cooled to room temperature and diluted with 90:10 methylene chloride/methanol (100 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with 90:10 methylene chloride/methanol (2×50 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol) to afford 217d in 62% yield (459 mg) as an amorphous yellow solid: mp 141-143° C.; 1H NMR (500 MHz, CDCl3) d 8.57 (d, J=2.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.74 (s, 1H), 7.24 (d, J=3.0 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 4.67 (t, J=5.0 Hz, 1H), 4.57 (t, J=5.0 Hz, 1H), 3.59 (s, 3H), 3.16 (t, J=5.0 Hz, 4H), 2.80 (t, J=5.0 Hz, 1H), 2.75 (t, J=5.0 Hz, 1H), 2.73 (t, J=5.5 Hz, 4H); MS (ESI+) m/z 410.1 (M+H)
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[S:5][CH:4]=1.[N:14]1([NH:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:18]=[CH:17][N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.[I-].[K+]>[N:14]1([N:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[CH2:2][C:3]2[C:7]3[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=3[S:5][CH:4]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: COc1ccc2c(CCl)csc2c1
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(CN(c3ccc(C#N)cc3)n3ccnc3)csc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
3-Chloromethyl-6-methoxy-benzothiophene (12.35 g, 58.06 mmol) was added to a mixture of 4[N-(1H-imidazol-1-yl)amino]benzonitrile (9.72 g, 52.78 mmol), K2CO3 (14.60 g, 105.56 mmol) and potassium iodide (0.10 g, 0.60 mmol) in dry DMF (70 ml) at room temperature. The mixture was then stirred at room temperature overnight and after poured into water and extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product as solid (14.30 g). Flash chromatography on silica gel (toluene/dioxan: 6/4) yielded the expected product (10.50 g, 55%, powder).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)=[CH:4][CH:3]=1.C1(P(Cl)([Cl:30])=O)C=CC=CC=1>>[Cl:30][C:12]1[CH:11]=[CH:10][C:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccc(Cl)cc2)c[nH]1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: Clc1ccc(C(c2ccccc2)c2ccc(Cl)nc2)cc1
Reaction time: 8 h

Procedure:
Combine 50 g. (0.174 mole) of the 5-substituted 2-pyridone from step A with 125 ml. of phenylphosphonic dichloride and heat at 210°-220° C. for about 7 hours with stirring. Allow to stand overnight and pour onto ice. Basify with ammonium hydroxide and extract with ethyl ether. Dry the ether solution and concentrate to a residue. Distill the residue and collect the fraction boiling at 205°-215° C. at 0.55 mm. (49 g.).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=C/C(O)=O)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].CN1CC[O:37][CH2:36][CH2:35]1.C(Cl)(=O)OCC(C)C.[BH4-].[Na+]>COCCOC.O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[C:36](/[OH:37])\[CH3:35])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CN1CCOCC1
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C(/C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (80 mg, 0.189 mmol) obtained in Example 2 was dissolved in 1,2-dimethoxyethane (0.7 mL), N-methylmorpholine (62 μL, 0.567 mmol) and isobutyl chlorocarbonate (49 μL, 0.378 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered, and the filtrate was added to a solution (0.6 mL) of sodium borohydride (36 mg, 0.945 mmol) in water at 0° C., and the mixture was stirred for 10 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give the title compound (compound 13) (43 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([C:19]2[S:20][C:21]([CH3:30])=[C:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:23]=23)=[O:18])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17](=[O:18])[C:19]2[S:20][C:21]([CH3:30])=[C:22]3[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][CH2:24][C:23]=23)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (170 mg, 0.38 mmol) in DCM (10 mL) and DIPEA (0.10 mL, 0.60 mmol) is added methane sulfonylchloride (0.04 mL, 0.45 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.04 mL, 0.45 mmol) is added and stirring is continued for 20 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2-chloro-6-methoxy-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl ester (196 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+1]+=529.17.
Reaction SMILES: [Cl:1]C(C)C[NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].CC1C=C(C)C=C(C)C=1N>[I-].[K+].C(OCC)C>[ClH:1].[CH3:13][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[NH2:4]
Reactant: Cc1cc(C)c(NCC(C)Cl)c(C)c1
Agent: Cc1cc(C)c(N)c(C)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Product: Cl

Procedure:
32.75 g (0.155 moles) of N-(β-chloropropyl)-2,4,6-trimethyl-aniline, prepared as indicated in point (b) above, are reacted with 41.8 g (0.31 moles) of 2,4,6-trimethylaniline in the presence of 1.0 g (6 mmoles) of potassium iodide as described in Example 3, Method (b), point (b). The resulting mixture is admixed with 50 ml of diethyl ether, the separated precipitate is filtered off, washed with diethyl ether and dried. 24.8 g (46.6%) of 2,4,6-trimethylaniline hydrochloride are obtained. The filtrate is acidified with isopropanolic hydrochloric acid (acid content: about 15 g/100 ml), and the resulting mixture is maintained at 0° to +5° for 2 hours. The separated precipitate is filtered off, washed with cold isopropanol, and dried. 50.3 g (84.8%) of 1,2-bis(2',4',6'-trimethylphenyl-amino)-propane dihydrochloride are obtained; m.p.: 172°-173° C. The base is liberated from this salt as described in Example 3, Method (b), point (b), and is separated from the reaction mixture by chloroform extraction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:25][C:26]1([CH3:50])[CH2:35][CH2:34][C:33]2[N:32]=[CH:31][N:30]=[C:29]([N:36]3[CH2:42][C:41]4[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:40]=4[O:39][CH2:38][CH2:37]3)[C:28]=2[CH2:27]1>>[NH2:17][C@H:14]1[CH2:15][CH2:16][N:12]([S:9]([C:4]2[C:5]([OH:8])=[N:6][CH:7]=[C:2]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][CH2:37][N:36]([C:29]5[C:28]6[CH2:27][C:26]([CH3:25])([CH3:50])[CH2:35][CH2:34][C:33]=6[N:32]=[CH:31][N:30]=5)[CH2:42][C:41]=4[CH:43]=3)[CH:3]=2)(=[O:10])=[O:11])[CH2:13]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cc(Br)cnc2O)C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(O)c(S(=O)(=O)N6CC[C@H](N)C6)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 1,1-dimethylethyl {(3S)-1-[(5-bromo-2-hydroxypyridin-3-yl)sulfonyl]pyrrolidin-3-yl}carbamate (reagent preparation 40) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.53 (d, 2H), 8.00 (s, 1H), 7.57 (s, 1H), 7.41 (d, 1H), 7.03 (d, 1H), 5.12 (s, 2H), 4.45 (m, 1H), 4.29 (m, 1H), 3.93 (m, 1H), 3.72 to 3.55 (m, 6H), 2.85 (t, 2H), 2.56 (s, 2H), 2.35 (m, 1H), 2.06 (m, 1H), 1.69 (t, 2H), 0.93 (s, 6H); MS (EI) for C28H34N6O4S: 551 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=2)[CH2:2]1.B>>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=2)[CH2:2]1
Reactant: N#Cc1cccc(CO[C@H]2CCOC2)n1
Agent: B
Product: NCc1cccc(CO[C@H]2CCOC2)n1
Temperature: 25 °C
Yield: 118.2 %

Procedure:
(S)-6-(Tetrahydrofuran-3-yloxymethyl)pyridine-2-carbonitrile (0.206 mol, 1 eq) was added to borane (1-M in THF, 290 mL, 0.290 mol, 3 eq) at 0° C. under nitrogen. The reaction was then heated to reflux for 5 hours, cooled to room temperature and quenched with 100 mL methanol (exothermic) and evaporated. 2 M aqueous HCl (310 mL) was added (pH 1) to the combined residues. After the quench, the mixture was brought to pH 7 with 5 M NaOH (35 mL). The aqueous mixture was extracted with 2×500 mL dichloromethane. These organic extracts were discarded. The aqueous phase was brought to pH 14 with 5-N NaOH (100 mL) and extracted with 2×1000 mL DCM. The combined organic extracts (from alkaline solution) were washed with 100 mL saturated brine, dried over Na2SO4 and evaporated to give the title compound (50.70 g, 39% over 2 steps) as an amber oil; LC-MS Retention time 0.62 min; (M+H)+ 205.
Reaction SMILES: [S:1]([O:11][C:12]1[CH:28]=[CH:27][CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[NH:29][C:30](=[O:32])[CH3:31])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N+:33]([O-])([OH:35])=[O:34].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[S:1]([O:11][C:12]1[CH:28]=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[NH:29][C:30](=[O:32])[CH3:31])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1c(OS(=O)(=O)c2ccc(C)cc2)cccc1OS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(OS(=O)(=O)c2ccc(C)cc2)cc([N+](=O)[O-])cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
A solution of 2-acetamidoresorcinol ditosylate (11.9 g, 0.025 mole) in acetic anhydride (75 ml) was cooled to below 15° C. Meanwhile, nitric acid (1.9 ml, 0.029 mole) was slowly added to cold acetic anhydride (20 ml) with stirring so that the temperature did not exceed 25° C. The nitric acid solution was then added to the cold acetanalide solution. Finally, the sulfuric acid (0.75 ml) was added. The mixture was stirred an additional six hours, during which time the reaction temperature rose to 30° C. The mixture was pured into ice water (1500 ml) and stirred one hour. The resulting precipitate was collected, air dried, and recrystalllized from isopropyl alcohol (100 ml) to yield a tan crystallline solid (9.9 g, 76.0 percent). TLC showed the product to be pure.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:91][CH2:92][C:93]([O:95][C:96]1[CH:97]=[C:98]([CH:102]=[C:103]([O:110][C:111](=[O:114])[CH2:112][Cl:113])[C:104]=1[O:105][C:106](=[O:109])[CH2:107][Cl:108])[C:99](Cl)=[O:100])=[O:94]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:99](=[O:100])[C:98]2[CH:97]=[C:96]([O:95][C:93](=[O:94])[CH2:92][Cl:91])[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])=[C:103]([O:110][C:111](=[O:114])[CH2:112][Cl:113])[CH:102]=2)[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCl)Oc1cc(C(=O)Cl)cc(OC(=O)CCl)c1OC(=O)CCl
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4cc(OC(=O)CCl)c(OC(=O)CCl)c(OC(=O)CCl)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To an ice-cooled solution of (6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.7 g) in dry dichloromethane (17 ml) was added potassium carbonate (0.1 g) all at once, followed by dropwise addition of a solution of 3,4,5-tris(chloroacetoxy)benzoyl chloride (0.376 g) in dry dichloromethane (10 ml) over a period of five minutes, and the yellow mixture was stirred at 0° C. for 30 minutes. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the yellow residue was crystallized with ether (50 ml), giving 0.92 g of the objective compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([CH3:29])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([CH3:29])[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[Sn](C)(C)C.[OH:22][CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=2)[CH2:25]1>O1CCOCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[C:33]1[CH:32]=[CH:31][C:30]([N:26]2[CH2:25][C@H:24]([CH2:23][OH:22])[O:28][C:27]2=[O:29])=[CH:35][CH:34]=1
Reactant: CC(=O)NCC1CC(c2ccc([Sn](C)(C)C)c(F)c2)=NO1
Reactant: O=C1O[C@H](CO)CN1c1ccc(I)cc1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(=O)NCC1CC(c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3)c(F)c2)=NO1
Temperature: 90 °C
Reaction time: 16 h
Yield: 0.9 %

Procedure:
N-({3-[3-Fluoro-4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazol-5-yl]methyl}acetamide (600 mg, 1.5 mmol), (5S)-5-(hydroxymethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (319 mg, 1.0 mmol) and 2-trifurylphosphine (23 mg, 0.1 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture placed under an atmosphere of argon. Tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (52 mg, 0.05 mmol) was added and the reaction mixture stirred for 16 hours at 90° C. Silica gel (0.5 g) was added and the mixture concentrated in vacuo. Purification by column chromatography (10 g silica gel bond elut: 0% to 5% methanoydichloromethane) yielded an off white solid. This was dissolved in dimethylsulphoxide (0.5 ml) and purified by reverse phase preparative HPLC using a gradient from 20% acetonitrile/water to 70% acetonitrile/water to give 3.7 mg of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:8]([C@@H:22]([N:24]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:23])=[CH:7]2.O.NN.CCO>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:19])=[O:20])[C:8]([C@@H:22]([NH2:24])[CH3:23])=[CH:7]2
Reactant: C[C@@H](c1cc2cccc(F)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C[C@H](N)c1cc2cccc(F)c2nc1-c1ccccc1S(C)(=O)=O
Temperature: 65 °C
Yield: 91.7 %

Procedure:
2-((1S)-1-(8-Fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (9.10 g, 19.2 mmol), and hydrazine hydrate (9.32 mL, 192 mmol) were added to EtOH (190 mL). After heating at 65° C. for 3 h, the resultant slurry was cooled to rt, diluted with 900 mL of EtOAc, and filtered through a fritted funnel. The filtrate was washed with H2O (3×200 mL), brine(1×200 mL) and then dried over MgSO4 before being concentrated under vacuum to give (1S)-1-(8-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethanamine (6.06 g, 17.6 mmol, 92% yield) as a light orange solid. The proton NMR reflects a 73/27 ratio of atropisomers at 25° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.55 (d, J=1.5 Hz, 0.73H), 8.50 (d, J=1.5 Hz, 0.27H), 8.26 (dd, J=8.1, 1.2 Hz, 0.27H), 8.23 (dq, J=7.8 1.2 Hz, 0.73H), 7.73 (m, 3H), 7.52 (m, 1.27H), 7.40 (m, 1.73H), 4.16 (q, J=6.6 Hz, 0.27H), 4.03 (q, J=6.4 Hz, 0.73H), 3.36 (s, 0.79H), 3.17 (s, 2.21H), 1.36 (m, 3H). Mass Spectrum (ESI) m/e=345.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[C:3]1=2.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:36])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[C:3]1=2
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3ccc(C)cc3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(COc2cc([Se]C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 1g, by reacting 650 mg (1.2 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 240 mg of sodium hydroxide. A yellow crystallized solid is obtained (m=580 mg; yield=91%; m.p.=254° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:25]C=C)[CH2:22]CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[C:21]([C:12]1[C:13]2[C:18](=[O:19])[NH:17][N:16]=[CH:15][C:14]=2[N:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=1)(=[O:25])[CH3:22]
Reactant: O=c1[nH]ncc2c1c(I)cn2COCc1ccccc1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 40 %

Procedure:
To 43 ml of dehydrated N,N-dimethylformamide solution containing 6.48 g (17.0 mmol) of 1-benzyloxymethyl-3-iodo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 21-(b) were added 0.19 g (0.46 mmol) of 1,3-bis(diphenylphosphino)propane, 94 mg (0.42 mmol) of palladium acetate and 8.4 g (83.9 mmol) of butyl-vinyl ether, and after degassing under reduced pressure, 4.7 ml of triethylamine was further added to the mixture under nitrogen atmosphere, and the mixture was stirred at 100° C. for 7.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.02 g of the title compound as a pale yellowish solid. (Yield: 40%)