Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[S:2]1C=CC=C1CC(O)=O.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].[OH-].[Na+].Cl>CO>[SH:2][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Under inert atmosphere 2.0 gr of sodium metal suspension (40% in mineral oil) were slowly added to 100 ml of dry methanol at 0° C. At the end of the addition reaction mixture was stirred for 10 min at RT and 1.75 ml (21.58 mmole) of thiolacetic acid were added. After additional 10 min of stirring, 30 ml degassed methanolic solution of 6.1 gr (18.19 mmole) of 16-bromohexadecanoic acid were added. The resulted mixture was refluxed for 15 hrs, after which, allowed to cool to RT and 50 ml of degassed 1.0 M NaOH aqueous solution were injected. Additional refluxing for 3 hrs required for reaction completion. Resulted reaction mixture was cooled with ice bath and poured, with stirring, into a vessel containing 200 ml of ice water. This mixture was titrated to pH=7 by 1.0 M HCl and extracted with 300 ml of ether. The organic layer was separated, washed with 3×150 ml of water, 150 ml of saturated NaCl aqueous solution and dried over sodium sulfate. After removal of ether material was purified by recrystalization from n-hexane, filtering out and drying over high vacuum. 5.1 gr (97% yield) of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[N:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)[N:3]=2)=[CH:25][CH:24]=1
Reactant: CSc1ccc(N)cc1
Reactant: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Product: CSc1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)n2)cc1

Procedure:
The title compound was prepared by treating 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol (0.3 g, 1.04 mmol) with 4-methylsulfanyl-phenylamine (0.14 g, 1.04 mmol) according to the procedure described above.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:36]=[CH:35][C:7]([C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:36]=[CH:35][C:7]([CH:8]([OH:9])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][O:17][Si:18]([C:31]([CH3:33])([CH3:32])[CH3:34])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](OCc1nccn1CC(=O)c1ccc(F)cc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](OCc1nccn1CC(O)c1ccc(F)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
Sodium borohydride (0.41 g; 1.06 mmol) was added portionwise at 0° C. to a solution of 1-(4-fluorobenzoylmethyl)-2-(tert-butyldiphenylsilyloxymethyl)imidazole (4.81 g; 1.01 mmol) in methanol (100 ml). The mixture was stirred at ambient temperature for 16 hours. 12N HCl (0.84 ml) added and then evaporated to dryness and purified by flash column chromatography eluting with dichloromethane/ethanol (96:4) to give 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-(tert-butyldiphenylsilyloxymethyl)imidazole.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:30][CH3:31])[CH:12]=2)[C:8]2[CH:32]=[C:33]([NH:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH:34]=[CH:35][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:13]([O:30][CH3:31])[CH:12]=2)[C:8]2[CH:32]=[C:33]([NH:36][C:37]([N:39]([CH3:40])[CH3:41])=[O:38])[CH:34]=[CH:35][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)N(C)C)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(NC(=O)N(C)C)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(OC)c1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]-3-methoxybenzyl]-6-dimethylaminocarbonylamino-benzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]=O)[CH:8]=[CH:9][CH:10]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:12]=2[CH2:21][NH:26][CH2:24][CH3:25])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: N#CCc1ccc(O)cc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(CC#N)cc1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
4-Hydroxybenzyl cyanide (5.0 g) and 1-bromobutane (5.7 g) were dissolved in dimethylformamide (100 mL), and potassium carbonate (6.2 g) was added to the resultant solution, followed by heating at 80° C. for one hour, to thereby allow reaction to proceed. After completion of reaction, the resultant reaction mixture was cooled, and then partitioned between brine and ethyl acetate. The resultant ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated. The thus-concentrated product was purified by use of a silica gel column employing hexane/ethyl acetate (4:1), to thereby produce 4-butoxybenzyl cyanide (5.1 g, yield: 70%). The thus-produced 4-butoxybenzyl cyanide (2.0 g) and the 4-methoxyethoxymethoxybenzaldehyde (2.2 g) produced in the production process for compound 1 were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (0.7 g, yield: 23%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(#N)C.[Cl-].[Zn+2].[Cl-]>[S:7]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: c1ccsc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)c2cccs2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture of p-toluenesulfonyl chloride (3 g, 15.7 mmol) and zinc chloride (3 g, 21.3 mmol) in acetonitrile (30 mL) was heated to reflux and thiophene (2.4 g, 28.5 mmol) was added dropwise. After refluxing for 4 h the mixture was cooled to rt and filtered through Celite. The filtrate was concentrated in vacuo and then 100 mL of sodium hydroxide (2 N) was added. The mixture was extracted with ethyl acetate (3×60 mL) and the combined organic layers were washed with hydrochloric acid (10%, 50 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with dichloromethane/hexane (2:3) to give the title compound (0.54 g, 15 mmol).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=O)C1.[I:21][C:22]1[C:30]2[O:29][CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([S:31]([Cl:34])(=[O:33])=[O:32])[CH:23]=1.C(#N)C>ClC1C=CC=CC=1>[I:21][C:22]1[C:30]2[O:29][CH:28]=[CH:27][C:26]=2[CH:25]=[C:24]([S:31]([Cl:34])(=[O:32])=[O:33])[CH:23]=1
Reactant: O=S(=O)(Cl)c1cc(I)c2c(c1)CCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: Clc1ccccc1
Product: O=S(=O)(Cl)c1cc(I)c2occc2c1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
AIBN (270 mg, 1.3 mmol) and NBS (2.5 g, 14 mmol) were added to 7-iodo-2,3-dihydro-benzofuran-5-sulfonyl chloride (4.4 g, 13 mmol; Intermediate 55) in chlorobenzene (30 mL) at 70° C. The heating was turned off one hour after the addition. Acetonitrile (30 mL) was added and the organic phase was washed with sodium sulphite in water. The organic phase was separated and the volatiles were evaporated to give 4 g (90%) of the title compound as yellow crystals. 1H NMR 270 MHz (CDCl3) δ ppm 7.07 (d, J=2.23 Hz, 1H) 7.90 (d, J=2.23 Hz, 1H) 8.29-8.37 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@H:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:42])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 167-169° C.; MS m/e 524 (M+);
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][C:26]#[N:27])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:21]([F:22])([F:23])[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:7][CH2:25][C:26]#[N:27]
Reactant: CC(C)(C)OC(=O)N(CC#N)c1cnccc1-c1ccccc1OC(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCNc1cnccc1-c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyanomethyl-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (185 mg, 0.47 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL) at 0° C. The reaction mixture was stirred at 25° C. for 2 hours and then concentrated under vacuum. The residue was dissolved in 10 mL aqueous sodium bicarbonate solution and 20 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted again with 10 mL CH2Cl2. The combined organic layer was washed with 20 mL brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting light yellow solid was pure enough to be used in the next step without further purification (115 mg, 83%). LC-MS (ESI): m/z=294.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[Cl:36].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=4[Cl:36])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4ccc(C(=O)O)cc4Cl)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-3-chloro-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-3-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H31ClN2O3 (m/e) 490, obsd 491 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[H-].[Na+].[CH2:14]([N:21]1[C:25]2[N:26]=[C:27]([NH2:31])[N:28]=[C:29](Cl)[C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1C=CC=CC1=O>[NH2:31][C:27]1[N:28]=[C:29]([O:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[C:24]2[CH:23]=[CH:22][N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:25]=2[N:26]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (1.62 mg, 11.0 mmol) in 1-methyl-2-pyridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3.67 mmol) in 1-methyl-2-pyridone (5 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc 75:25) yielded 1.12 mg (83%) of 4-(2-amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6]>O>[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3:2].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3:2]
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])[O-]
Temperature: 150 °C

Procedure:
The process 300 begins with a reaction step 308 wherein the aluminum hydroxide is fed, either as a wet cake or as a dry powder, with a slurry water 310 and an acid 312 into a pressure cooker. The acid 312 can be sulfuric acid. The temperature is raised to approximately 150° C. to produce an aluminum sulfate in a molten hydrate form. The pressure is held high enough to maintain a liquid state, e.g., 1100 kilo-Pascals. The residence time is between one to ten minutes, and preferably about two minutes.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:29]>C1C=CC=CC=1.CN(C)C=O>[CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4]([NH2:29])=[O:5]
Reactant: N
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(N)=O

Procedure:
A suspension of 0.40 g. (0.12 mmol) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid in 12 ml. of dry benzene was stirred at 23° C. under argon while about 5 mg. of dimethylformamide were added thereto followed by 0.24 g. (0.19 mmole) of oxalyl chloride in 3 ml. of dry benzene. After 1 hour of stirring dry ammonia was bubbled into the resulting orange solution until a bright yellow color persisted. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered, and evaporated to give a crude orange solid. This material was purified by chromatography on silica gel using ethyl acetate-hexane (2:3 parts by volume) as the elutant. One crystallization from ethyl acetate gave 70 mg. (18% yield) of pure 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenamide, m.p. 212°-215° C.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:18]P(=O)(OCC)OCC)[CH:8]=[CH:7][C:6]([CH2:9]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.O>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:27][C:28]1[CH:35]=[CH:34][C:31](/[CH:32]=[CH:18]/[C:3]2[CH:4]=[CH:5][C:6](/[CH:9]=[CH:32]/[C:31]3[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=3)=[CH:7][CH:8]=2)=[CH:30][CH:29]=1
Reactant: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)cc1)OCC
Reactant: O=Cc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc(/C=C/c2ccc(/C=C/c3ccc(Br)cc3)cc2)cc1

Procedure:
50% aqueous sodium hydroxide (20 ml) was added to a solution of tetraethyl p-xylylenebisphosphonate (2.40 g, 6.35 mmol) (25) and 4-bromobenzaldehyde (2.41 g, 13.02 mmol) in 10 ml of benzene. Tetra-n-butylammonium iodide (148 mmg) was added and the mixture was refluxed under nitrogen for 1 hour. The reaction mixture was allowed to cool and diluted by the addition of water (25 ml). A yellow solid was collected and washed three times with water, methanol and ether. The product was purified by recrystallization from xylenes and was isolated in 61.9% (1.73 g) yield (Product is insoluble in standard solvents).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH3:8])=[CH:6][C:5]=1[CH2:9][OH:10]
Reactant: ClCc1ccccc1
Reactant: Cc1cc(CO)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCc2ccccc2)c(C)cc1CO
Yield: 99 %

Procedure:
A mixture of 18.0 g (118 mmol) of 4-hydroxy-2,5-dimethyl-benzenemethanol (Example H), 14.9 g (118 mmol) of benzyl chloride and 18.0 g (1.1×118 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours overnight. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed on a rotary evaporator. A diethyl ether solution of the residue is washed with 2×50 mL of 2N potassium hydroxide solution, brine, dried (magnesium sulfate) and evaporated leaving 28.3 g of a pale yellow viscous residue. Distillation through a short path apparatus affords the title compound; mp 58°-59° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[CH:7]([C:1]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To 100 g. of cumene at 10° C. is slowly added over a period of 2.5hours to a mixture of 70.5 ml. of concentrated nitric acid and 109ml. of concentrated sulfuric acid. The reaction mixture is stirred at 5° to 10° C. for 1 hour following the addition. The reaction mixture is poured onto 250 ml. of ice water and extracted with ether. The ether is dried and evaporated in vacuo and the residue distilled at 9.5 to 10.5 mm./Hg. The fraction boiling at 130° C. is taken and used as is in the next step.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+]([O-])=O.C[CH2:18][O:19]C(C)=O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:19][CH3:18]
Reactant: CCOC(C)=O
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Product: COCCOc1cc(C=O)ccc1O
Yield: 97 %

Procedure:
Followed the procedure described in Step 3 of Intermediate 65, where the reaction was refluxed for 2 days. Isolated 900 mg, yield 97% after column chromatography (PE: EtOAc=10:1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:44][C:45]1([F:49])[CH2:48][NH:47][CH2:46]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:47]3[CH2:48][C:45]([F:49])([F:44])[CH2:46]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: FC1(F)CNC1
Agent: Cl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)N4CC(F)(F)C4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 3,3-difluoroazetidine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:18]([CH2:25][C:26]([N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:19](=[O:24])[CH2:20][N:21]=[C:22]=[O:23])[CH:15]=[CH:16][CH:17]=1>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[NH:21][CH2:20][C:19]([N:18]([CH2:25][C:26]([N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=2)=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CN=C=O)c1
Product: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CNC(=O)Nc2cccc(CO)c2)c1
Yield: 61.1 %

Procedure:
Using a procedure similar to that described in Example 31, but starting with 3-(hydroxymethyl)aniline (1.1 g) and 2-[N-(3-methoxyphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (3.2 g), and after recrystallisation in ethyl acetate, 2-[2-{3-[3-(hydroxymethyl)phenyl]ureido}-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (2.6 g), m.p. 142° C., is obtained.