Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[N:10][C:11]=2[CH:12]1[C:24]1[CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=1)=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncn2C(=O)OC(C)(C)C)C1c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(4-Bromo-phenyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-1,5-dicarboxylic acid di-tert-butyl ester (0.55 g, 1.14 mmol) and Zn(CN)2 (0.13 g, 1.14 mmol) were stirred in anh. DMF (10 mL) and degassed with Ar for 15 min. Tetrakis(triphenylphosphine)-palladium(0) was added to the solution and stirred at 80° C. under Ar overnight. The solution was concentrated in vacuo, partitioned between EtOAc and sat. NaHCO3 soln, washed with H2O, brine, and dried over MgSO4. Filtration, concentration, and silica gel chromatography (0-2% MeOH/CH2Cl2 with NH4OH) gave the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH:15][NH2:16])[CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[NH2:9][C:8]1[N:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:16]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: CCCCCNN
Solvent: CCO
Product: CCCCCn1ncc(C#N)c1N
Yield: 88 %

Procedure:
A warm solution of 6.02 g (49.3 mM) ethoxymethylenemalononitrile in 20 ml of ethanol was added via a cannula with stirring to a solution of 6.04 g (59.1 mM) of pentylhydrazine in 20 ml ethanol maintained at 50°. The mixture was then heated to reflux for 30 minutes, then cooled in a refrigerator (ca 3°) for 18 hours. The white crystalline precipitate was filtered to afford 7.73 g (88%) of the title compound; mp, 143°-144°; tlc, Rf =0.50, silica gel, methanol:chloroform (1:19).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:18][Mg]Br>O1CCCC1.C(OCC)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.60 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 30 ml of dry tetrahydrofuran, cooled to 0° C. is added dropwise, 2.61 ml of a 3.0M solution of methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 30 minutes and then quenched with 10 ml of aqueous ammonium chloride. After diluting with 10 ml of water, the reaction mixture is extracted with 9:1 chloroform-methanol. The combined extracts are dried with magnesium sulfate, filtered and concentrated to yield 0.64 g of the desired product. CI MASS SPEC 247(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14].CCN(CC)CC.[Cl:22][C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][O:14][C:23]([Cl:22])=[O:24]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCCc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
For 5 min, a solution of 2-(2,4-dichloro-6-nitrophenyl)ethanol (500 mg, 2.12 mmol) and Et3N (214 mg, 2.12 mmol, dist. over KOH) in THF (5 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (503 mg, 2.5 mmol) in THF (5 ml, see above). It was stirred for 1 h while being cooled in an ice bath and stirred for 2 h at room temperature. The mixture was then filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2,4-dichloro-6-nitrophenyl)ethoxycarbonyl chloride (597 mg, 94%) as a bright yellow solid.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[C:22]([CH3:24])([CH3:23])[C:21]2([CH3:26])[CH3:25])=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(Cl)Cl>O1CCOCC1>[CH3:25][C:21]1([CH3:26])[C:22]([CH3:23])([CH3:24])[CH:20]1[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C2C(C)(C)C2(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(C)C(C(=O)Nc2ccc(CN)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.6 %

Procedure:
Add 4M hydrogen chloride in dioxane (6.1 mL) to a solution of N-(tert-butoxycarbonyl)-4-[(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-amino]-benzylamine (0.678 g, 1.958 mmol) in anhydrous 1,4-dioxane (12.2 mL) at room temperature. After stirring at room temperature for 3 h, the reaction is a solid mass. Add more 1,4-dioxane (12.2 mL), DCM (24.4 mL) and more 4M hydrogen chloride in dioxane (6.1 mL), and stir overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 (200 mL) and DCM (500 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. The aqueous phase was extracted with DCM/iso-propanol (3:1, 4×200 mL). Dry the combined organic extracts over Na2SO4, filter, combine with the organic fraction isolated above and concentrate in vacuo. Purify by SCX chromatography eluting with DCM and DCM/2M ammonia in methanol (1:1) to obtain the title compound (0.519 g, 100%). MS (ES+) m/z: 247.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39]Cl)[CH3:36]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:39][C:38](=[O:41])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)N(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 15.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 250 ml. of hexamethylphosphoric acid triamide is treated under nitrogen at 5° C. with 0.055 mol. of sodium hydride (2.5 g. of a 55% dispersion in mineral oil) and then stirred at the same temperature for 15 minutes. At 5°-10° C. a solution of 15 g. of N,N-diethylchloroacetamide in 40 ml. of ethanol is added thereto and the mixture stirred for 30 minutes at room temperature and subsequently heated for 4 hours at 80° C. The mixture is cooled and poured into 2.5 liters of ice-water. After the addition of 150 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and evaporated to dryness. The residue is triturated with 100 ml. of ether, the unreacted starting material crystallizes out. The latter is removed by filtration under vacuum and washed with ether. The ethereal filtrate is evaporated to dryness. The oily residue is cooled and triturated with ether, crystals being obtained. Recrystallization from ethanol yields 5-chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 118°-120° C.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.I[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:19]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:18][C:5]([C:6]([N:8]=[S:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Oc1cccc(I)c1
Reactant: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=NC(=O)c1cnc(N)c(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (60 mg, 0.2 mmol), 3-iodophenol (66 mg, 0.3 mmol), triethylamine (0.07 mL, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol), triphenylphosphine (1.3 mg, 0.005 mmol) in 1.8 mL DMF at room temperature was degassed using a H2/N2 (1:1) mixture and then copper(I) iodide (2 mg, 0.01 mmol) added. The reaction was heated at 60° C. for 15 minutes and then partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to a brown oil. Before chromatography a different lot of product (23 mg) was added and the combined lots were purified by chromatography (silica gel, EtOAc/EtOH) to the title compound as an off-white solid (91 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:25]>>[O:25]=[C:20]1[C:21]2[C:17](=[C:16]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc3c2CCC3=O)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (94 mg, 0.50 mmol) and 4-bromo-2,3-dihydro-1H-inden-1-one (116 mg, 0.55 mmol) according to the general procedure IF to give 110 mg (69%) of an yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.34 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.76-7.68 (m, 2H), 7.55-7.43 (m, 2H), 7.38 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 3.68 (s, 1H), 3.29-3.21 (m, 2H), 2.98 (t, J=7.7 Hz, 3H), 2.77-2.71 (m, 2H), 2.65 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 206.6, 173.0, 157.1, 141.5, 137.3, 136.8, 131.8 128.5, 127.5, 123.3, 122.3, 120.7, 94.8, 85.3, 51.7, 36.1, 35.3, 30.8, 25.5; ESI-MS m/z 341.1 (M+Na+).
Reaction SMILES: [C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C@H:8]([CH3:12])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:32]C(OCC)=O>ClCCl>[C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C@H:8]([CH3:12])[C:9]([Cl:32])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)Cl
Reaction time: 1 h

Procedure:
(S)-(+)-3-(tert-Butyl-diphenyl-silanyloxy)-2-methylpropionic acid (0.44 g; 1.20 mmol) (from Example 13a supra) was dissolved in dichloromethane (3 mL, dried over molecular sieves). Triethylamine (0.36 mL; 2.58 mmol) (Aldrich) was added and the solution was cooled in an ice-water bath. Ethyl chloroformate (0.16 mL; 1.63 mmol) (Aldrich) was added dropwise and the mixture was stirred in the cold for 1 hour. The mixture was then diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Pt]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc(F)cc2)cc1
Yield: 98.7 %

Procedure:
To a solution of 56.6 gm (0.217 mole) 4-(4-fluorobenz-oyl)aminonitrobenzene in 875 mL tetrahydrofuran were added 5.7 gm 5% platinum on carbon. The reaction mixture was hydrogenated at room temperature for 18 hours at initial hydrogen pressure of 60 p.s.i. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure to give 49.3 gm (98.5%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:16])[CH3:19])[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C=O)cccc1OCC(=O)OC(C)(C)C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(OCC(=O)OC(C)(C)C)cccc1C(C)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
(3-Formyl-2-methylphenoxy)acetic acid tert-butyl ester (0.94 g, 3.75 mmol) was dissolved in freshly distilled tetrahydrofuran and cooled to −78° C. Methyl magnesium chloride (2.62 mL, 7.88 mmol) was added dropwise and the mixture was allowed to stir at −78° C. for two hours. The mixture was allowed to warm to room temperature, stirred for an additional six hours, then carefully quenched with water, and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography, eluting with hexane/acetone, gave [3-(1-hydroxyethyl)-2-methylphenoxy)acetic acid tert-butyl ester as a clear oil (594 mg, 59.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:20]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCCCC1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a 3-neck round-bottomed flask was added zinc powder (0.40 g, 6.12 mmoL) followed by anhydrous THF (15 mL). To the stirred suspension was slowly added TiCl4 (0.32 mL, 0.55 g, 2.9 mmoL) at RT under a nitrogen atmosphere. The reaction mixture was heated at reflux for 2 h. To the reaction mixture was added a solution of methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.193 g, 0.75 mmoL) and cyclooctanone (0.31 g, 2.46 mmoL) in anhydrous THF (5 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere to 2 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. To the reaction mixture was added H2O (5 mL) followed by 10% K2CO3 (5 mL). The reaction mixture was filtered through a pad of Celite with the aid of H2O and EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was dried (MgSO4), filtered, and the filtrate was concentrated to give a yellow oil. The crude product was purified by flash chromatography on silica gel with a CH2Cl2:MeOH gradient (100:0 to 95:5) to give 0.159 g (60%) of compound 158 as an oil. 1H NMR (400 MHz, DMSO-d6): δ 1.36-1.54 (m, 8H), 1.59 (m, 2H), 2.14 (m, 2H), 2.20 (m, 2H), 3.80 (s, 3H), 6.67 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.1 Hz, 2H), 9.30 (s, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[OH:12].Br[CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[O:12][CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]
Reactant: CCC(Br)C(=O)O
Reactant: Oc1cc(Cl)cc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(Oc1cc(Cl)cc(Cl)c1Cl)C(=O)O
Temperature: 15 °C
Yield: 69.1 %

Procedure:
44.0 g (0.55 mole) of 50% aqueous sodium hydroxide was added to a mixture of 42.5 g (0.22 mole) of 2,3,5-trichlorophenol and 43.4 g (0.26 mole) of 2-bromobutyric acid, with rapid stirring at an initial temperature of 15° C. The temperature rose to 45° C over the course of the addition during which time a cold water bath was applied. At the completion of the sodium hydroxide addition, the cold bath was removed and the mixture was heated to 110° C for a 15-minute period. Then 50 ml of water, 53 ml of perchloroethylene, and 42 ml of concentrated hydrochloric acid were added and the mixture was heated to 85° C, then phase-separated. The organic layer was cooled and the product, α-(2,3,5-trichlorophenoxy)butyric acid, crystallized. The acid was isolated by filtration to give 43.1 g (69.1% yield) of α-(2,3,5-trichlorophenoxy)butyric acid, m.p. 106°-114° C.
Reaction SMILES: C(OC(OCC)[C:5]([CH:21]=O)([CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]#[N:7])C.[NH2:26][C:27]([NH2:29])=[NH:28]>C(O)C>[NH2:29][C:27]1[N:28]=[C:6]([NH2:7])[C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:21][N:26]=1
Reactant: CCOC(OCC)C(C#N)(C=O)Cc1cc(OC)c(OC)c(OC)c1
Reactant: N=C(N)N
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reaction time: 8 h
Yield: 67.2 %

Procedure:
α-Diethoxymethyl-α-formyl-β-(3,4,5-trimethoxyphenyl) propionitrile (35.1 g, 0.10 mol) was added to an ethanolic solution of guanidine (from 0.35 mol of guanidine hydrochloride). The mixture was heated at reflux for a total of 6.5 hours during which time enough ethanol was allowed to boil off to bring the reaction temperature up to 85°. The dark solution was allowed to cool and stand overnight. The mixture was filtered, and the solid was washed with cold ethanol and dried to yield crude product (24.4 g, 84.1%). Purification was effected by dissolving the crude product in hot aqueous acetic acid and reprecipitation with concentrated ammonium hydroxide. The precipitate was washed twice with water, once with cold acetone, and dried to yield 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (19.5 g, 67.2%), m.p. 197°-198° C. (identity confirmed by nmr). The acetone was concentrated in vacuo to dryness yielding additional though somewhat less pure trimethoprim (2,5 g, 8.6%, m.p. 194°-196° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:17][C:18](O)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14](O)=[O:15]>O1CCCC1>[OH:15][CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:17][CH2:18][OH:19]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccccc1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium aluminum hydride (0.332 mol) and tetrahydrofuran (THF, 175 mL) are placed in a dry 500-mL three-necked round-bottom flask fitted with a condenser, addition funnel, nitrogen inlet, and magnetic stirrer. The mixture is cooled with an ice bath and 1.2-phenylene diacetic acid (0.165 mol) in THF (100 mL) is added dropwise to the stirring mixture. After the addition is complete, the flask is removed from the ice bath and allowed to warm to room temperature. The reaction mixture is heated at reflux for two hours, then stirred overnight at room temperature. After cooling the mixture with an ice bath, water (12.6 mL) is added dropwise, followed by the successive dropwise addition of 15 percent aqueous sodium hydroxide (12.6 mL) and water (38 mL). The resulting mixture is warmed to room temperature, and the solids separated by vacuum filtration. The filtrate is placed on a rotary evaporator to remove the solvent. The remaining solid is recrystallized from toluene-hexane to give the 1,2-di(hydroxyethyl)benzene.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 74.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (200 mg), 167.6 mg 6-chloro-2-oxindole, and 166 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 246 mg (74%) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Br.BrBr.[Br:22]C(Br)=O>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[Br:22])=[CH:6][CH:7]=1
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: O=C(Br)Br
Agent: Br
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
A 1 L three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with the intermediate from Step 2, (55.5 g, 0.21 mol), acetic acid (250 mL) and 33% HBr in acetic acid (120 mL). The solution was stirred and treated with bromine (11.1 mL, 0.21 mol) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca. 15 minutes. After an additional 10 minutes at room temperature, the solution was filtered through a Buchner funnel and the filtrate concentrated in vacuo to give an orange solid. The crude bromoketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone as a yellow solid which was used directly without further purification. The crude bromoketone was dissolved in 300 mL acetone and 150 mL of water and heated to reflux for 2.5 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and reconcentrated in vacuo to give a light yellow solid that was crystallized from a mixture of dichloromethane and isooctane to provide 37.8 g (65%) of pure 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-hydroxy-ethanone: mp 90°-92° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][Cl:22])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: ClCCCC#CCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC#CCCCCl)ccc(C(C)=O)c1O
Yield: 87.2 %

Procedure:
A mixture of 3.10 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.13 g of 1-bromo-6-chloro-2-hexyne and 3.30 g of anhydrous potassium carbonate in 35 ml of anydrous acetone was stirred at reflux for 2.5 hours. The solvent was removed in vacuo, water was added to the residue and the pH was adjusted to 4.0. The product was extracted with ether and the dried (over magnesium sulfate) extract was chromatographed on 250 g of silica gel. Elution with 25% ethyl acetate-hexane gave 4.30 g (88% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne, the titled compound.