Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:5]1([CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:7]2[S:8][CH:9]=[CH:10][C:6]1=2)[CH3:2].[Li]CCCC.[CH2:33]([Sn:37](Cl)([CH2:42]CCC)[CH2:38]CCC)CCC.CCCCCC>C1COCC1>[CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:5]1([CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:6]2[CH:10]=[C:9]([Sn:37]([CH3:42])([CH3:38])[CH3:33])[S:8][C:7]=2[C:11]2[S:12][C:13]([Sn:37]([CH3:42])([CH3:38])[CH3:33])=[CH:14][C:15]1=2)[CH3:2]
Reactant: CCCCC(CC)CC1(CC(CC)CCCC)c2ccsc2-c2sccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(CC)CC1(CC(CC)CCCC)c2cc([Sn](C)(C)C)sc2-c2sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
The 4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b:3,4-b′]dithiophene (3.0 g, 7.45 mmol) prepared above was dissolved in anhydrous THF (20 mL) and kept at −78° C. under nitrogen flow. Then, n-BuLi (19 mL, 29.8 mmol, 2.5 M in hexane) was slowly added over 30 minutes. Subsequently, after stirring at −78° C. for 1 hour, tributyltin chloride (7.4 g, 37.1 mmol) was added and reaction was performed at room temperature for 17 hours. The resulting product was extracted with ether and distilled water, dried with anhydrous MgSO4 and filtered under reduced pressure. The final product 4,4-bis(2-ethylhexyl)-2,6-bis(trimethylstannyl)-4H-cyclopenta[2,1-b:3,4-b′]dithiophene (5.1 g, yield: 94%) was obtained by column chromatography (neutral alumina, n-hexane). 1H NMR (300 MHz, CDCl3, ppm): δ 7.01-6.88 (m, 2H), 1.93-1.76 (m, 4H), 1.04-0.81 (m, 18H), 0.74 (t, 6H), 0.59 (t, 6H), 0.49-0.22 (m, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][CH:17]=1>>[Cl:12][C:13]1[S:14][C:15]([CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:16][CH:17]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccc(Cl)s2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Chloro-5-chloromethyl-thiophene using the conditions described in Example 10C to provide 2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiophene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:11]1([N:7]2[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)[CH2:24][CH2:25]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1OC(CCCCl)CN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1OC(CCCN2CCN(c3ccccn3)CC2)CN1c1ccccc1
Yield: 56 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(3-chloropropyl)-3-phenyl-2-oxazolidinone (4.5 g, 0.0188 mol), 1-(2-pyridinyl)piperazine (3.07 g, 0.0188 mol), potassium carbonate (7.81 g, 0.0565 mol), and potassium iodide (1.0 g) in n-butanol (200 mL) gave a solid which was recrystallized from isopropanol/isopropyl ether and dried under high vacuum to give 3.86 g (56% yield), mp 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:33]=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:14]=2[CH:33]=[O:34])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C=O)n1-c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (2.0 g, 6.42 mmol) was dissolved in 50 mL THF and cooled to −70° C. Lithiumdiisopropylamide 2M/THF (4.8 ml, 9.6 mmol) was added, and the mixture stirred for 15 min at −70° C. Dimethylformamide (0.69 ml, 9.0 mmol) was added and stirring was continued at −70° C. for 3 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 1:2). The desired compound was obtained as a yellow solid (220 mg, 10%), MS: m/e=340.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:21])[C:19]=1[OH:20])[CH:15]=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:15][C:14]2[CH:17]=[C:18]([CH3:21])[C:19]([OH:20])=[C:12]([CH3:11])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1ccc(Br)cc1
Product: Cc1cc(C=CC(=O)c2ccc(Br)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4′-bromoacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].Cl[C:18]1[N:23]=[N:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=4)[CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:18]2[N:23]=[N:22][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=5)[CH2:32][CH2:31]4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, reacting 1-ethylpyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: OC([C:6]1([O:16][CH3:17])[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:7]1[C:8]([NH2:10])=[O:9])C(C)C.S(Cl)(Cl)=O>C(OCC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([O:16][CH3:17])=[C:7]([C:8]2[O:9][CH2:6][C:7]([CH3:11])([CH3:8])[N:10]=2)[CH:11]=1
Reactant: COC1(C(O)C(C)C)C=CC(Cl)=CC1C(N)=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1ccc(Cl)cc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 5-chloro-o-anisic acid (50 g) in toluene (100 mL) was added thionyl chloride (50 mL). The reaction mixture was heated under reflux for 2 hrs and distilled using a short path distillation apparatus to give 5-chloro-o-anisyl chloride, which was used in the next step. To a solution of 2-amino-2-methyl-1-propanol (38 mL) in dichloromethane (200 mL) was added a solution of 5-chloro-o-anisyl chloride in dichloromethane (150 mL) dropwise. The reaction mixture was stirred at ambient temperature for 1 hr, dichloromethane was added and the mixture was washed with 2 N hydrochloric acid. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give N-(2-(1-hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide, which was used in the next step. To N-(2-(1 -hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide was added thionyl chloride (40 mL) at 0° C. The reaction mixture was stirred for 30 min, warmed to ambient temperature, diluted with diethyl ether (200 mL), and the mixture was stirred for 10 mins. The mixture was decanted, 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to afford 41 g (64%) of product, mp 50-51° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2N)c1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution containing 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (2.0 g, 5.5 mmol) and methanol (18.5 mL) was added 10% Pd/C (1.6 g, 0.76 mmol, wet, 50% water) in one portion under a nitrogen atmosphere. The reaction mixture was stirred for 2 h under an atmosphere of hydrogen gas (balloon), filtered and concentrated to afford 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a pale yellow oil which was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.47 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.85 (d, J=4.77 Hz, 1H), 7.81 (ddd, J=7.65, 1.63, 1.51 Hz, 1H), 7.52-7.61 (m, 2H), 7.36-7.41 (m, 2H), 7.24-7.30 (m, 2H), 7.15 (t, J=7.28 Hz, 1H), 7.04 (d, J=5.02 Hz, 1H), 5.15 (s, 2H), 1.64-1.70 (m, 6H). LCMS: retention time: 1.240 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 332 (MH+).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:8]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:9]([CH3:14])[CH2:10][N:11]=[N+]=[N-])(=O)=O.CCN(C(C)C)C(C)C>CO.[Pd]>[Si:16]([O:15][C@@H:8]1[C@@H:9]([CH3:14])[CH2:10][NH:11][CH2:6][C@H:7]1[NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of (2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentyl methanesulfonate (0.59 g, 1.3 mmol) in MeOH (10 mL) was deoxygenated with nitrogen for 20 min. DIPEA (0.55 mL, 3.2 mmol) was added, followed by 10 wt % Pd on carbon (0.1 g, 0.1 mmol). The mixture was hydrogenated under hydrogen gas at 1 atm. for 2 h. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give the sub-title compound (0.43 g, 98%). LCMS calc. for C17H37N2O3Si (M+H)+: m/z=345.3. found: 345.2. 1H NMR (500 MHz, CDCl3) δ 4.35 (bs, 1H), 3.32 (dt, J=13.1, 6.3 Hz, 1H), 3.25 (d, J=12.3 Hz, 1H), 3.04 (t, J=8.8 Hz, 1H), 2.94 (ddd, J=13.1, 4.1, 1.5 Hz, 1H), 2.33 (dd, J=12.6, 10.5 Hz, 1H), 2.24 (dd, J=13.1, 10.9 Hz, 1H), 1.76 (bs, 1H), 1.55 (tdd, J=8.9, 6.7, 4.2 Hz, 1H), 1.41 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=10.3 Hz, 6H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH3:20]
Reactant: O=C1NCCc2ccccc21
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCc2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 3,4-dihydro-2H-isoquinolin-1-one (0.250 g, 1.70 mmol) in toluene (5 mL) was added sodium hydride (60% in mineral oil, 0.049 g, 2.04 mmol) and the resulting suspension was heated at about reflux for about 1 h. The reaction mixture was cooled at room temperature and ethyl 2-iodoacetate (0.364 g, 1.70 mmol) was added dropwise and the mixture was again heated at about reflux for about 12 h. The reaction mixture was cooled at room temperature and filtered, rinsed with toluene. The filtrate was concentrated in vacuo to provide (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid ethyl ester as a peach oil (0.336 g, 1.44 mmol). The crude material was used in subsequent reactions without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7]Cl)=[CH:2]1.[C:9](#[N:11])[CH3:10].[Sn](Cl)(Cl)(Cl)Cl>O>[CH3:10][CH:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=[CH:7][NH:11]1
Reactant: ClCCc1ccsc1
Reactant: CC#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CC1NC=Cc2ccsc21
Yield: 51 %

Procedure:
To a solution of 2-(3-thienyl)chloroethane(20 g, 0.136 mol) prepared in the above Step 1 and anhydrous acetonitrile(350 ml) was added tin(IV) chloride(20 ml, 0.17 mol) at room temperature. The reaction mixture was heated to reflux for 16 hours and cooled, to which water was added to remove excess tin(IV) chloride. And then the reaction mixture was washed by dichloromethane. The water layer was separated and basified with aqueous K2CO3 solution under ice-cooling and then extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and concentrated to give 10.56 g of the titled compound. (Yield: 51%)
Reaction SMILES: C[O-].[Na+].[I:4][C:5]1[C:6]([O:19][CH2:20][C:21]([C:23]2[S:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]=2)=O)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[Br-].[CH3:33]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.C1COCC1>[I:4][C:5]1[C:6]([O:19][CH2:20][C:21]([C:23]2[S:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]=2)=[CH2:33])=[CH:7][C:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1
Reactant: COC(=O)c1csc(C(=O)COc2cc3c(cc2I)C(C)(C)CCC3(C)C)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1cc(C(=O)OC)cs1

Procedure:
A 30% solution of sodium methoxide in methanol (1.68 ml) was added over 8 hours to a mixture of methyl 5-[(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetyl]-3-thiophenecarboxylate (4.1 g, 8 mmol) and methyltriphenylphosphine bromide (3.8 g, 10.8 mmol) in THF (50 ml).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[C@H:10]([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19]>ClCCl.C(OCC)C>[ClH:19].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:18])(=[O:15])=[O:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CNCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of (R)-4-methanesulfonyl-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (924 mg) in dichloromethane (20 mL) at 0° C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 2 h. The precipitate formed was then collected by filtration and dried to afford (R)-1-methanesulfonyl-2-methyl-piperazine hydrochloride salt as a white solid (520 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][C:30](=[O:31])[C:29]([C:21]1[CH:20]=[C:19]([C:18]([F:17])([F:35])[F:36])[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=1)([CH3:34])[CH3:33])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCCl
Product: CC(C)(C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 233 mg (1 mmol) of 2-amino-5-chlorobenzophenone in 2 ml of 1,2-dichloroethane were added 360 mg (1.2 mmol) of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid and the reaction mixture was shaken at 80° C. for 1 h. Dicyclohexyl carbodiimide (194 mg, 1.2 mmol) was added and shaking was continued overnight at the same temperature. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel to yield 298 mg (58%) of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].BrC1C=CC(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(OCC)OCC)=CC=3OC)N=2)=C2C=1CN(C)[C:58]2=[O:63]>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:50])([F:49])[F:51])=[CH:19][N:18]=2)=[C:14]([O:63][CH3:58])[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Compound 246A using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 4-(4,4,5,5-ttramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708). MS (ES+): m/z 761.33 (100) [MH+]; HPLC: tR=1.56 min (UPLC, analytical).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:12])=[CH:8][C:9]=1[Cl:10])=[O:4].I(O)(=O)(=O)=[O:14]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:14])=[O:12])=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1sc(CO)cc1Cl
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1sc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 3-chloro-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (1.3 g, 6.29 mmol) and Periodic Acid (3.15 g, 13.84 mmol) in MeCN (40 ml) was stirred for 30 min. A solution of PCC (0.027 g, 0.13 mmol) in MeCN (2 ml) was added. After 5 h, the reaction mixture was diluted with EtOAc (250 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 1.20 g (86%) of yellow solid product.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Yield: 91 %

Procedure:
4-Benzoylbenzoic acid (BBA), 1.0 kg (4.42 moles), was added to a dry 5 liter Morton flask equipped with reflux condenser and overhead stirrer, followed by the addition of 645 ml (8.84 moles) of thionyl chloride and 725 ml of toluene. Dimethylformamide, 3.5 ml, was then added and the mixture was heated at reflux for 4 hours. After cooling, the solvents were removed under reduced pressure and the residual thionyl chloride was removed by three evaporations using 3×500 ml of toluene. The product was recrystallized from 1:4 toluene:hexane to give 988 g (91% yield) after drying in a vacuum oven. Product melting point was 92-94° C. Nuclear magnetic resonance (NMR) analysis (1H NMR (CDCl3)) was consistent with the desired product: aromatic protons 7.20-8.25 (m, 9H). All chemical shift values are in ppm downfield from a tetramethylsilane internal standard. The final compound was stored for use in the preparation of a monomer used in the synthesis of Compound III.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:32][CH2:33][CH:34]1[CH2:38][C:37](CO)=[CH:36][CH2:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Si:25]([O:32][CH2:33][CH:34]1[CH2:35][C:36]([CH2:1][Br:5])=[CH:37][CH2:38]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
The carbon tetrabromide (1.39 g, 4.2 mmol) and triphenylphosphine (1.37 g, 5.2 mmol) were added in dichloromethane solution of (4-t-Butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl alcohol (0.85 g, 3.5 mmol) under ice bath and then stirred for 30 min at 0° C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product (0.53 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@@H:6]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20]1.[Cl-].[NH4+]>ClC(Cl)C>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:8](=[O:9])[CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:14])[F:13])[C:11]([OH:12])=[O:10])=[CH:27][C:22]=2[CH2:21][CH2:20]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Product: O=C(CC(NC(=O)C(F)(F)F)C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 36 h
Yield: 88 %

Procedure:
0.1 mole of the compound obtained in Example 1 and 0.05 mole of aluminum chloride suspended in 100 ml of dichloroethane are added to a solution of 12 ml of dichloroethane containing 0.05 mole of 2,3-dihydrobenzofuran. The mixture is stirred for 36 hours at room temperature and then hydrolyzed with saturated ammonium chloride solution. The mixture is extracted with dichloromethane and the extract washed with water, dried over magnesium sulfate, filtered and concentrated to obtain the expected product.
Reaction SMILES: CN.Cl[C:4](=[O:10])[C:5]([O:7]CC)=[O:6].[CH2:11]([N:13](CC)[CH2:14]C)[CH3:12]>C1COCC1>[CH2:11]([N:13]([CH3:14])[C:4](=[O:10])[C:5]([OH:7])=[O:6])[CH3:12]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CCN(C)C(=O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Methylamine (1.5 g, 23 mL of a 1 M THF solution, 48.38 mmol) solution was added dropwise to a −10° C. solution of ethyl chlorooxoacetate (5.0 g, 36.76 mmol) and triethylamine (5.6 g, 7.6 mL, 55.44 mmol) in dry THF (100 mL) under an argon atmosphere. After stirring at 0° C. for 1 h, then reaction was quenched with water (5 mL). Following another 20 min, the reaction mixture was extracted into ethyl acetate (2×30 mL) and the combined organic extracts were washed with water (2×100 mL), dried and concentrated in vacuo. The residue was purified by column chromatography using 40% EtOAc/hexanes to give monoethyl N-methyloxalamic acid (3.95 g, 82%) as a white powder. TLC: 75% EtOAc/hexane, Rf≈0.4; 1H NMR (CDCl3, 300 MHz) δ 4.35 (q, 2H, J=7.0 Hz), 2.92 (d, 3H, J=5.2 Hz), 1.37 (t, 3H, J=7.3 Hz).