Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(Cl)cnc3[nH]c(-c4ccc(OCCN5CCOCC5)cc4)nc23)cc1
Temperature: 100 °C
Yield: 32.6 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.050 g, 0.13 mmol), 4-methylphenylboronic acid (0.027 g, 0.19 mmol), K2CO3 (0.097 g, 0.70 mmol) and Pd(PPh3)4 (0.029 g, 0.025 mmol) were mixed in a vial. Dioxane (3 ml) was added and the reaction mixture was heated to 100° C. under argon for 4 h. EtOAc (50 ml) was added and the solution was washed with water. Drying (Na2SO4) and evaporation gave crude material which was purified by column chromatography (dichloromethane/methanol, 95:5), giving the title product (0.019 g, 33%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:11][C:12](=[O:14])[CH3:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Nc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CCCc2cnccc21
Yield: 45.2 %

Procedure:
Reaction of N-(isoquinol-5-yl)acetamide (171 mg, 0.918 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroisoquinolin-5-yl)acetamide (79 mg, 45%): 1H NMR δ 1.60-1.70 (m, 1H), 1.70-1.09 (m, 2H), 1.98 (s, 3H), 1.98-2.08 (m, 1H), 2.65-2.68 (m, 2H), 5.03-5.11(m, 1H), 6.63 (br d, 1H), 7.08 (d, 1H, J=5 Hz), 8.17 (s, 1H), 8.20 (d, 1H, J=5 Hz); 13C NMR δ 20.7, 23.7, 26.4, 30.1, 47.1, 122.9, 133.3, 146.3, 147.5, 150.7, 170.1; MS m/z: 191 (M+H+). N-(1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide also was isolated (35 mg, 20%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8].[NH3:19]>C(O)C>[NH2:19][CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: N
Reactant: CCOC(C)(OCC)P(=O)(C[C@H](O)CCl)OCC
Solvent: CCO
Product: CCOC(C)(OCC)P(=O)(C[C@H](O)CN)OCC
Yield: 19 %

Procedure:
A solution of ethyl (2S)-(3-chloro-2-hydroxypropyl)(1, 1-diethoxyethyl)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 6 days and at 55° C. for one further day. The solution was evaporated and the residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (5-8% MeOH) containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. The aqueous layer was pH adjusted by the addition of a few mL of 10% aqueous Na2CO3 and repeatedly extracted with methylene chloride. The combined organic layers were dried over Na2SO4 and evaporated to give 0.9 g (19%) of ethyl (2R)-(3-amino-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate as a clear oil. Data: 1H NMR (500 MHz, CDCl3) δ 4.1-4.3 (m, 2H), 4.05 (b, 1H), 3.60-3.80 (m, 4H), 2.4-2.9 (m, 2H), 1.7-2.1 (m, 2H), 1.4-1.5 (dd, 3H), 1.3-1.4 (m, 3H), 1.2 (m, 6H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][N:7]=[C:8]1[C:20]2[C:15](=[N:16][C:17]([C:23](=[O:25])[NH2:24])=[C:18]([C:21]#[N:22])[N:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)C.O[Li].O.Cl>C1COCC1.O>[C:23]([C:17]1[N:16]=[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[N:7][O:6][CH2:5][C:4]([OH:26])=[O:3])[C:20]2=[N:19][C:18]=1[C:21]#[N:22])(=[O:25])[NH2:24]
Reactant: CCOC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NOCC(=O)O
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a solution of 37 (70 mg, 0.2 mmol) in THF/H2O (1:1, 15 ml) LiOH.H2O (41 mg, 1.0 mmol) was added and the mixture was stirred at room temperature. After 2 h 2N HCl was added up to pH=5. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (CH2Cl2/MeOH/AcOH 90:10:1) affording 38 (41 mg, 63%) as yellow solid. ESI+MS: calcd for C15H9N5O4: 323.27; found: 324.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH3:8])[C:3]1=[S:9].CNCC#N.CN=C=S.[CH3:19][N:20]=[C:21]=[O:22]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH:5]([NH:7][C:21]([NH:20][CH3:19])=[O:22])[N:4]([CH3:8])[C:3]1=[S:9]
Reactant: CN=C=O
Reactant: Cn1cc(N)n(C)c1=S
Agent: CN=C=S
Agent: CNCC#N
Solvent: c1ccncc1
Product: CNC(=O)NC1CN(C)C(=S)N1C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of 3.22 grams (0.0225 mol) of 1,3-dimethyl-4-amino-4-imidazoline-2-thione (prepared from methylaminoacetonitrile and methyl isothiocyanate by the method of T. Kinoshita et al, Bull. Chem. Soc. Japan., 53, 442 (1980)) in 12 mL of pyridine under an atmosphere of nitrogen was added with stirring 2.61 grams (0.0457 mol) of methyl isocyanate. The mixture became exothermic. Stirring was continued overnight whereupon a solid precipitate formed in the reaction mixture. The latter was collected by filtration and washed with isopropyl alcohol to obtain 2.11 grams of 1,3-dimethyl-4-(methylaminocarbonylamino)-imidazoline-2-thione, m.p. 200°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C1N2CN3CN(C2)CN1C3.[C:31](O)(C(F)(F)F)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:10]=1)[CH:31]=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dichloro-4-(4-methoxy-phenoxy)-nitrobenzene (3.14 g, 10.0 mmol) in TFA (30 ml) was added hexamethylenetetramine (2.10 g, 15.0 mmol). The resulting mixture was stirred at 75° C. for 2 h then concentrated to a viscous oil. The residue was taken up in 30 ml H2O and stirred at RT. To this suspension was added sufficient sat'd aqueous NaHCO3 to neutralize the residual TFA and the mixture was then extracted with EtOAc (3×30 ml). The combined EtOAc extracts were washed with sat'd aqueous NaHCO3 (2×30 ml) and dried over Na2SO4. Dried extracts were filtered and concentrated to give the title compound of step A (3.67 g) as a yellow solid. The title product of Step A was used in the next step without further purification. MS (APCl−) Calc.: 341.0. Found: 340.1 (M−1).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:6][C:5]=2[CH:4]=[CH:3]1.FC(F)(F)C(O)=O.C(Cl)[Cl:29]>>[ClH:29].[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)ccc2c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of (E)-tert-butyl 3-(7-oxo-7,8-dihydro-1,8-naphthyridin-3-yl)acrylate (500 mg, 1.84 mmol) in CH2Cl2 (7 mL) was treated with trifluoroacetic acid (7 mL). The mixture became homogeneous and it was stirred at room temperature for 1 h. The solution was concentrated to dryness and treated with 4M HCl in dioxane (5 mL). The suspension was sonicated for 20 min, diluted with Et2O (50 mL) and sonicated for an additional 20 min. The solid was filtered and dried under reduced pressure overnight. Yield: 450 mg (96.8%) 1H-NMR (300 MHz, DMSO-d6) δ 12.4 (br s, 1H), 8.82 (s, 1H), 8.52 (s, 1H), 7.91 (d, 1H, J=9.0 Hz), 7.67 (d, 1H, J=15.0 Hz), 6.67 (d, 1H, J=15.0 Hz), 6.61 (m, 1H); ESI MS m/z 217 [C11H8N2O3+]+
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:15])[O:12][CH2:13][CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:11]([O:10][N:9]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH2:8])=[O:15])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: NC(=NO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)ON=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of benzamide oxime (25.0 g, 184 mmol) in chloroform (250 ml) was added dropwise a solution of ethyl chlorocarbonate (8.79 ml, 92.0 mmol) in chloroform (60 ml), and the mixture was stirred at room temperature for 3 hours. Insolubles were filtered off, and then the filtrate was concentrated. The residue was recrystallized from a mixed solvent of ethanol and water to yield 18.2 g (94.8%) of the desired product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([C:10]1[NH:9][C:17]2[C:12]([C:11]=1[Br:1])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
A solution of N-bromosuccinimide (4.94 g, 27.7 mmol) in DMF (20 mL) was added dropwise to a stirred solution of ethyl 1H-indole-2-carboxylate (5.0 g, 26.4 mmol) in DMF (15 mL) at 0˜5° C. After the addition was completed, the reaction was warmed to room temperature and stirring was continued for an additional 1.5 h. The reaction mixture was poured over ice water and the resulting precipitate was collected and dried to give 3-bromo-1H-indolecarboxylic acid ethyl ester (6.68 g, 81%) as a white solid: 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 4.38 (q, J=7.2 Hz, 2H), 7.18-7.22 (m, 1H), 7.34-7.38 (m, 1H), 7.50 (dd, J=8.3, 0.8 Hz, 1H), 7.55 (dd, J=8.3, 0.8 Hz, 1H), 12.22 (br s, 1H); MS (ESI) m/z 268 (MH+); 266 ([M−H]−).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[Cl:17][C:18]1[CH:30]=[CH:29][C:21](CC2CCNCC2)=[CH:20][CH:19]=1.C([O:33][CH2:34][CH3:35])C>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:33][CH:34]2[CH2:35][CH2:2][N:6]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[O:16])[CH2:5][CH2:4]2)=[CH:29][CH:30]=1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Reactant: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)sc2c1)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-(4-chloro-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 245-247° C. (diethylether)
Reaction SMILES: F[C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O-:19].[Na+]>CO>[CH3:18][O:19][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(SC)c1F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c(SC)c1OC
Yield: 18.3 %

Procedure:
A mixture of 19.9 g (74.2 mmol) of methyl 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoate and 40.1 g (30% by weight, 223 mmol) of sodium methoxide in 250 ml of methanol was heated under reflux for 6 h. For work-up, the mixture was concentrated, the residue was taken up in water and the mixture was extracted with dichloromethane. The organic phase was dried and the filtrate was freed from the solvent. This gave 15.9 g of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate as residue. The aqueous phase from the extractive work-up was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and the filtrate was freed from the solvent. This gave an additional 3.80 g of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate as residue.
Reaction SMILES: C[Si](Cl)(C)C.C(O[C:9]1(O[Si](C)(C)C)[CH2:11][CH2:10]1)C.Cl.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[C-:23]#[N:24].[K+]>CO>[N:18]1([C:9]2([C:23]#[N:24])[CH2:10][CH2:11]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: [C-]#N
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: C1CCNC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [K+]
Solvent: CO
Product: N#CC1(N2CCCC2)CC1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A mixture containing a drop of trimethylsilyl chloride and 67.8 g of [(1-ethoxycyclopropyl)oxy]trimethylsilane in 65 ml of methanol is added to 62.6 g of pyrrolidine hydrochloride and 28.7 g of potassium cyanide dissolved in 260 ml of methanol. After stirring for 20 minutes at 20° C., and then for 20 hours at 50° C., the reaction mixture is concentrated to dryness, taken up in dichloromethane, filtered and concentrated to dryness again. The residue is chromatographed over silica gel (CH2Cl2) allowing the desired product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:21][C:20]([CH3:22])=[CH2:19])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(Cl)cc1C(C)=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A suspension of 5′-chloro-2′-hydroxyacetophenone (0.86 g, 5.0 mmol), potassium carbonate (1.4 g, 10 mmol) and 3-bromo-2-methylpropene (0.56 mL, 5.5 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred at 60° C. for 4 hours. After cooling, the reaction mixture was diluted with water (100 mL), and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title reference compound (1.1 g) as orange oil (Yield 96%).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](OCC)=[O:20].C(O)(=O)C>CCCCCC.O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](=[O:20])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCOC(=O)COc1cccc(Cl)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
A solution of n-butyl lithium (16.0 g) in hexane (160 ml) was added to a stirred solution of dimethyl methylphosphonate (26.9 g) in anhydrous tetrahydrofuran (150 ml) at -60° C. in an atmosphere of nitrogen during 20 minutes. The solution was maintained at -60° C. for a further period of 10 minutes and was then treated with a solution of ethyl 3-chlorophenoxyacetate (23.4 g) in anhydrous tetrahydrofuran (50 ml) at -60° C. during a further period of 10 minutes. This solution was stirred at -60° C. for 90 minutes and then stirred at ambient temperature for 2 hours. The solution was treated with acetic acid (21 ml) and the solvents were evaporated under reduced pressure. Water (60 ml) was added to the residue and the mixture was extracted with diethyl ether. The ethereal solution was washed with water, with aqueous sodium bicarbonate solution (10% w/v) and with water, dried over magnesium sulphate, and evaporated. The resulting residue was left to stand at ambient temperature overnight. The resulting colourless crystals were filtered off, washed with a small volume of diethyl ether, and recrystallised from a mixture of petroleum ether (b.p. 40°-60° C.) and toluene, to give dimethyl 3-(3-chlorophenoxy)-2-oxopropylphosphonate (18.6 g) in the form of colourless needles, m.p. 78°-79° C. [elemental analysis: C, 44.9; H, 5.1; P, 10.7%. C11H14ClO5P requires C, 45.1; H, 4.8; P, 10.6%. νmax 825, 865, 1030, 1160, 1270, 1335, 1600 and 1735 cm-1 ].
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH:22]4[CH2:25][CH:20]3[C:21]4([CH3:27])[CH3:26])=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].COC(C1CN(CC2C=CC(OCC3C4C=C(Cl)C=CC=4OC=3)=CC=2)C1)=O>>[CH3:26][C:21]1([CH3:27])[CH:20]2[CH2:25][CH:22]1[CH2:23][CH2:24][CH:19]2[CH2:18][CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1CN(Cc2ccc(OCCC3CCC4CC3C4(C)C)cc2)C1
Agent: COC(=O)C1CN(Cc2ccc(OCc3coc4ccc(Cl)cc34)cc2)C1
Product: CC1(C)C2CCC(CCOc3ccc(CN4CC(C(=O)O)C4)cc3)C1C2
Yield: 87 %

Procedure:
When the product of Step B was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 87% yield, as creamy paste. 1H-NMR (CDCl3+CD3OD) 7.21 (d, 2H, J=7.98 Hz); 6.79 (d, 2H, J=7.99 Hz); 3.94-3.71 (m, 8H); 3.27-3.25 (m, 1H); 2.36-1.20 (m, 10H); 1.14 (s, 3H); 0.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[ClH:1].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]4[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1cccc2c1NC(=O)C2(CCCCCl)CC(C)C
Product: Cc1cccc2c1NC(=O)C2(CCCCN1CCN(c2ccc(Cl)cc2)CC1)CC(C)C
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-isobutyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].[OH:5][C@H:6]1[CH2:10][CH2:9][NH:8][C@@H:7]1[C:11]([OH:13])=[O:12]>>[ClH:4].[OH:5][C@H:6]1[CH2:10][CH2:9][NH:8][C@@H:7]1[C:11]([O:13][CH2:1][CH3:2])=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Product: CCOC(=O)[C@H]1NCC[C@@H]1O
Product: Cl
Temperature: 100 °C

Procedure:
Acetyl chloride (10.8 mL, 153 mmol) was slowly added to ice cold 100% Ethanol (100 mL). (3S)-3-hydroxy-L-proline (5 g, 38.2 mmol) was added and heated at 100° C. for 16 hours. The ester was concentrated to a solid and used without purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (t, J=8.1 Hz, 3H), 1.9 (m, 2H), 3.3 (m, 2H), 4.1 (m, 1H), 4.2 (q, J=7.1 Hz, 2H) 4.4 (m, 1H), 9.0 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Cl[CH2:12][P:13]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15][O:14]1>>[O:19]=[P:13]1([CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[O:18][CH2:17][CH:16]=[CH:15][O:14]1
Reactant: O=P1(CCl)OCCCO1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CP1(=O)OC=CCO1)OCC

Procedure:
Diethyl (2-oxo-1,3,2-dioxaphosphorin-2-yl)methylphosphonate was prepared by the Arbuzov reaction of triethyl phosphite and 2-chloromethyl-2-oxo-1,3,2-dioxaphosphorinan. (IR: 1260 and 1030 cm-1).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.CO.O>C1COCC1>[C:5]([OH:15])(=[O:4])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(C(=O)O)cc1
Yield: 44.3 %

Procedure:
LiOH (26 mg, 0.6 mmol) was added to a stirred solution of terephthalamic acid methyl ester (73 mg, 0.41 mmol) in THF:MeOH:water mixture (3:1:1, 1 mL) and the resulting mixture was stirred at room temperature overnight. The THF and MeOH were then evaporated and the resulting residue was acidified to pH 2 using 10% citric acid solution. The product was extracted using EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 30 mg (53.6% yield) of terephthalamic acid. LCMS Purity: 92.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1OC)[CH:6]=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13].[C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])(=[O:22])[CH:20]=[CH2:21].[OH-].[K+].CN(C)[CH:36]=[O:37]>O>[CH3:36][O:37][C:4]1[C:3]([O:2][CH3:1])=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[C:8](=[O:13])[N:9]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])[C:10](=[O:12])[NH:11]1
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OC
Reactant: CN(C)C=O
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)COC(=O)CCN1C(=O)NC(=Cc2cccc(OC)c2OC)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
20 g (80.6 mmol) of 5-(3,4-dimethoxybenzylidene)-hydantoin, 17.8 g (96 mmol) of 2-ethylhexyl acrylate and 0.90 g (1.6 mmol) of potassium hydroxide were added to 150 ml of dimethylformamide, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 200 ml of water and extracted with 500 ml of ethyl acetate. The extract was dried with sodium sulfate and then the solvent was distilled off under reduced pressure. The residue was recrystallized with toluene-n-hexane (1:1) and the precipitated crystals were dried to obtain 27.1 g of 2-ethylhexyl 4-(2,3-dimethoxyphenylmethylene)-2,5-dioxo-1-imidazolidinepropionate (yield: 77.8 %).