Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11].[Cl-]>[OH-].[Na+].CC(C)=O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11° C. during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6)δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm−1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C 59.13; H, 7.19; N, 7.61.
Reaction SMILES: [Cl-].[CH:2]1([CH2:9][NH2+:10][CH2:11][CH2:12]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]=[S:27]>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]1[N:10]([CH2:9][CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:27]1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCCCC1
Agent: [Cl-]
Product: COc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])CCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH:30]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=Cc1cc(Br)cs1
Reactant: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC=Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxaldehyde (35.0), tetrakis(triphenylphosphine)palladium(O) (4.23 g), 2,6-di-t-butyl-4-methylphenol (a few milligrams) and dry toluene (150 ml) was added tri-n-butyl-1-dodecenylstannane (92.0 g), dropwise at room temperature, under nitrogen. The solution was heated under reflux for four hrs, with stirring. After cooling to room temperature, the solution was filtered through a bed of celite, and the filter cake was washed with ether. The filtrate was evaporated and the residue purified by flash chromatography (silica; 5% ethyl acetate-hexane). The appropriate fractions were collected and concentrated. The residue was distilled in a kugelrohr oven (170° C./0.3 mm mercury) to give 46.7 g (92%) of product, as an oil (ca. 4:1-trans:cis).
Reaction SMILES: [CH:1]1([N:5]([CH3:17])[CH:6]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[ClH:18].O1CCOCC1>C(Cl)Cl>[CH:1]1([N:5]([CH3:17])[CH:6]2[CH2:9][NH:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[ClH:18]
Reactant: CN(C1CCC1)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C1CCC1)C1CNC1
Temperature: 20 °C
Reaction time: 30 h

Procedure:
Combined a solution of tert-butyl 3-(cyclobutyl(methyl)amino)azetidine-1-carboxylate (285 mg, 1.186 mmol) in methylene chloride (6 mL) and added 4 M HCl in dioxane (1.186 mL, 4.74 mmol) and the solution stirred at 20° C. for 30 h. The solution was concentrated in vacuo and concentrated from heptane/methylene chloride to give the title compound as a hydrochloride acid salt (191 mg, 0.896 mmol, 76%) as a light yellow solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]=CC2C=CC=CC=2)[C:4](=[O:20])[C:3]=1[C:21](OCC)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34].Cl>C1(C)C=CC=CC=1>[NH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:21]2[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:34])(=[O:35])[N:36]=2)[C:4]1=[O:20]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ccccc2n(N=Cc2ccccc2)c1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
The product of Example 226C (4.51 g, 14.00 mmol) was reacted with 2-amino benzenesulfonamide (2.41 g, 14.00 mmol) in toluene (65 mL) at reflux for 6 hours. After cooling to 25° C., the solid (5.52 g) was collected by filtration and reacted further with aqueous 10% potassium hydroxide (100 mL) for 8 hours at 130° C. After cooling to 25° C., the reaction was poured into ice and acidified to pH 2 with 1 M hydrochloric acid. The resulting solid was isolated by filtration and dried to give the title compound (3.50 g, 71%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 5.31 (s, 2 H) 7.05 (t, J=8.09 Hz, 1 H) 7.27 (m, 2 H) 7.53 (m, 2 H) 7.67 (m, 2 H) 8.07 (dd, J=8.09, 1.47 Hz, 1 H) 16.38 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>C(Cl)Cl>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][O:6][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Dissolve 4,4,5,5,5-pentafluoropentanol (8.27 g, 46.42 mmol) in CH2Cl2 (100 mL) and cooled the solution to 0° C. Add triethylamine (20.00 mL, 143.49 mmol), followed by the drop wise addition of methanesulfonyl chloride (4.40 mL, 56.84 mmol). Stir the solution for 45 minutes, then pour into HCl (0.5 N, 100 mL). Wash the organic layer with HCl (0.5 N, 2×100 mL). Dry the organic layer (Na2SO4), filter, and concentrate in vacuo. Recovered 11.48 g (96%) of the desired methanesulfonic acid 4,4,5,5,5-pentafluoro-pentylester as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.31 (t, J=6.0 Hz, 2H), 3.03 (s, 3H), 2.2 (m, 2H), 2.08 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)(C)(C)C.Cl.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1)#[N:18]>Cl.O>[NH2:7][CH:8]1[CH2:13][CH2:12][C:11]2[NH:25][C:22]3[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][C:21]=3[C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(N)CC3
Yield: 82.1 %

Procedure:
Combine (4-oxocyclohexyl)carbamic acid tert-butyl ester (40.9 g, 192 mmol) and 4-cyanophenylhydrazine hydrochloride (25.0 g, 147 mmol) in concentrated hydrochloric acid (100 mL) and water (200 mL) and heat at reflux for 18 h. Allow to cool and collect the precipitate. Wash with Na2CO3 solution and azetrope with CHCl3, absolute EtOH, and CHCl3 again to obtain 25.5 g of a white solid (82%). MS (ES): m/z 212 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 43 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.200 g, 0.79 mmol), methyl 2-(4-hydroxyphenyl)acetate (0.131 g, 0.79 mmol) and potassium carbonate (0.546 g, 3.95 mmol) in acetonitrile (5 mL) was heated to 85° C. for 7 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0.130 g, 65%). MW=382.84. 1H NMR (CD3OD, 500 MHz) δ 8.21 (t, J=1.8 Hz, 1H), 8.16-8.12 (m, 1H), 7.46-7.35 (m, 4H), 7.21-7.17 (m, 2H), 6.77 (s, 1H), 3.73 (s, 2H), 3.72 (s, 3H), 2.83 (q, J=7.6 Hz, 2H), 1.35 (t, J=6.4 Hz, 3H); APCI MS m/z 383 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19](S(C3C=CC=CC=3)(=O)=O)[CH:18]=[CH:17][C:16]=2[O:30][CH2:31][CH2:32]Br)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:34]1([S:40](C2C=CC3OCCN(C4CCNCC4)C=3C=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([S:40]([C:18]2[CH:19]=[CH:20][C:15]3[N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:32][CH2:31][O:30][C:16]=3[CH:17]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)N(C1CCNCC1)CCO2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(S(=O)(=O)c3ccccc3)ccc2OCCBr)CC1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCNCC1

Procedure:
Similarly prepared using 4-[5-benzenesulfonyl-2-(2-bromo-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester, was 6-Benzenesulfonyl-4-piperidin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine, MS: 359 (M+H)+, mp: 147.0-149.8° C.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:5])[CH3:4].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[C:3]([N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N(C)c1ccccc1
Product: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
(Based on the procedure of O. K. Stojanovic et al. Chem. Abstr. 1973, 78, 3902s.) N-Methyl-N-phenyl-acetamide (10.0 g, 67 mmol) is heated with 50 ml of ClSO3H at 70° C. for 90 min. The mixture is poured into 200 ml of ice, and the resulting product is filtered and washed with 2×25 ml of H2O to the give the title compound as an off-white solid.
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Al+3:20].[K+]>O.S(O)(O)(=O)=O>[O-:3][Si:1]([O-:4])=[O:2].[O-:3][Si:1]([O-:4])=[O:2].[Na+:6].[Al+3:20]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Product: O=[Si]([O-])[O-]
Temperature: 55 °C

Procedure:
Sodium aluminosilicate was prepared as follows. Approximately 5990 L of sulfate water (4% concentration) were added to a 36,000-L reactor. While mixing, the reactor contents were heated to 55° C., and 119.8 L of sodium silicate were added to the reactor and mixed. A 25-min simultaneous addition step with alum and silicate solution followed, using a sodium silicate addition rate of 398.8 L/min and an alum addition rate of 145.1 L/min. After the simultaneous addition step, a reduced alum flow rate was used to bring the batch pH to about 5.3. After digesting the batch for 10 min, the product slurry was washed and filtered using a press filter. The collected filtered cake was reslurried and zirconium oxysulfate powder was manually added. The zirconium treated cake slurry was then fed into a vertical bead mill. The bead-milled Zr-treated cake slurry was then spray dried and hammer milled to an average 3-5 micron particle size. Two batches were run, one resulting in a final amount of 0.3 wt. % Zr (Example 25), and the other resulting in a final amount of 0.45 wt. % Zr (Example 26), based on the Zr-treated sodium aluminosilicate weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.Br[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:36][CH:37]=2)[CH:8]=1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)cc1)=C2
Yield: 85.1 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (150 mg) and 1-[2-(4-bromophenoxy)ethyl]piperidine (155 mg) according to an analogous synthetic method to Example 116, the title compound (220 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([OH:14])[CH2:3][CH2:2][N:26]2[CH2:25][CH2:24][N:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:28][CH2:27]2)=[CH:8][CH:9]=1
Reactant: OC(CCCl)COc1ccc(F)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(N2CCN(CCC(O)COc3ccc(F)cc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 110. A mixture of 5.8 g (0.0267 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.1 g (0.0267 mole) of 1-(4-methoxyphenyl)-piperazine, 9.4 g (0.089 mole) of anhydrous sodium carbonate, and 0.16 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a brown oil. Upon trituration with petroleum ether (30°-60° C.), the oil solidified. The collected solid was recrystallized from isopropyl ether to yield 6.4 g (64%) of white, crystalline solid, m.p. 78°-80° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].F[C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:32])[N:26]([CH3:31])[CH2:27][O:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:31][N:26]1[C:25](=[O:32])[C:24]2[C:29](=[CH:30][C:21]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:22][CH:23]=2)[O:28][CH2:27]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reactant: CN1COc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (0.27 g, 1 mmol), 9-fluoro-4-methyl-2-oxa-4-azabicyclo[4.4.0]deca-6,8,10-trien-5-one (CAS no. 915771-24-3) (200 mg, 11 mol) and potassium carbonate (276 g, 2 mmol) in acetonitrile (20 mL) was heated in a microwave at 160° C. for 12 hours. The mixture was evaporated and the residue partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, washed with water (10 mL) and brine (20 mL), dried (MgSO4) and evaporated. The aqueous phase was acidified to pH 1 with 2N hydrochloric acid extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (2×20 mL), brine (20 mL), dried (MgSO4) and evaporated. The residue was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M TMS-diazomethane (0.14 mL) stirred for 30 minutes. The mixture was evaporated and the residue combined with that from the initial extraction and purified by flash chromatography on silica eluting with 0 to 100% ethyl acetate in isohexane to afford the product (232 mg, 54%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.25 (m, 1H), 2.53-2.66 (m, 1H), 2.93 (s, 3H), 3.09 (s, 3H), 3.32-3.58 (m, 2H), 3.89 (s, 3H), 4.91 (t, 1H), 5.17 (s, 2H), 6.51 (s, 1H), 6.72 (d, 1H), 6.97 (s, 1H), 7.34 (s, 1H), 7.52 (s, 1H), 7.93 (d, 1H); m/z 427 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[CH:21][N:22]([CH3:24])C)#N>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)[N:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 148 °C

Procedure:
A solution of 23.74 mL of 3-bromo aniline and 40.5 g N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine in 100 mL of glacial acetic acid was stirred and heated in an oil bath at 148° C. for 1.5 hours. On cooling, filtration of the resulting solid gives a quantitative yield of N-(3-bromophenyl)-6-nitro-4-quinazolinamine: mp=267-270° C.; mass spectrum (m/e): 345.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])=[C:10]([CH3:17])[CH:9]=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:17])[C:11]=1[O:12][CH2:13][CH:14]([NH:16][C:1](=[O:3])[CH3:2])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C)c1OCC(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)COc1c(C)cccc1C
Temperature: 17.5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Acetyl chloride (99 ml, 1.39 mol, 1.5 eq) was added to a stirred suspension of mexiletine hydrochloride (200 g, 0.927 mol), ethyl acetate (750 ml), and 5N sodium hydroxide (750 ml) over a period of 35 minutes while keeping the temperature at ≤10° C. After the addition was complete, the reaction was allowed to stir for 45 minutes at 15-20° C. The mixture was then added to water (1 1) and the ethyl acetate layer separated. The aqueous layer was washed with ethyl acetate (2×300 ml) and the combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate until the washings were no longer acidic. The ethyl acetate solution was then washed with brine, dried over MgSO4, and concentrated to give N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide (197 g, 96% yield, mp 85-85.8° C.).
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:16]([C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]O>>[CH3:25][O:23][C:22]([CH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:14][CH2:15]1)=[O:24]
Reactant: COc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(OC)cc21

Procedure:
Analogously to the description in Example 2, 4.7 g of 5-benzoyl-6-methoxy-indane-1-carboxylic acid methyl ester and 20 ml of N sodium hydroxide solution in 50 ml of methanol give 5-benzoyl-6-methoxy-indane-1-carboxylic acid of melting point 126°-128° C (from ether-petroleum ether).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:33][C:34]2[CH:39]=[C:38](Cl)[N:37]=[CH:36][N:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:33][C:34]2[N:35]=[CH:36][N:37]=[C:38]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:39]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOC4)nc3c2)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2C2(CCN(c3cc(Oc4cc(Cl)c5[nH]c(C6CCOC6)nc5c4)ncn3)CC2)O1

Procedure:
36 mg (0.14 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 50 mg (0.14 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 50 μL (0.30 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by chromatography. The fractions containing product were combined and lyophilised.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[N:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=O)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[CH2:32](P(=O)(OCC)OCC)[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:20](/[CH:21]=[CH:32]/[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cccnc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 63.2 %

Procedure:
To a mixture of 2-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]nicotinaldehyde (0.30 g), tetraethyl methylenediphosphonate (0.21 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-{2-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]pyridin-3-yl}ethenylphosphonate as a colorless oil (0.25 g, yield 64%).