Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18]C)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.[Cl-].[Na+].O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
A mixture of 9-fluoro-6-methoxybenzo[g]isoquinoline-5,10-dione (0.072 g) and aluminum trichloride (0.112 g) in dry methylene chloride (40 mL) is stirred at room temperature for 4 hours under a nitrogen atmosphere. An additional portion of aluminum chloride (0.190 g) is added and the mixture is allowed to react at reflux for 1.5 hrs and at room temperature overnight. Following addition of brine (15 mL) the aqueous phase is separated and extracted with methylene chloride (3×5 mL). The combined organic solutions are dried over anhydrous sodium sulphate and the solveht is removed by distillation at reduced pressure to give an approximately 1:1 mixture (0.070 g) of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione (slower moving yellow spot on silica gel TLC plate, eluant methylene chloride/ethyl acetate 70/30) and 9-chloro-6-hydroxybenzo [g]isoquinoline-5,10-dione (faster moving yellow spot on the above chromatographic system) which is used without further purification for the next step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>CN(C)C=O>[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]cc(I)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (140 mg, 3.5 mmol) was added to an ice-cold solution of 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine (5) (820 mg, 2.9 mmol) in dimethylformamide (7 ml) under nitrogen. After 30 minutes tosyl chloride (570 mg, 3 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with water (˜15 ml). An off white solid was filtered off and dried in vacuo (950 mg, 75%). MS (ES+) 434.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:27]>>[ClH:27].[NH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CCc1ccccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(CCc1ccccc1[N+](=O)[O-])C(=O)O

Procedure:
A solution of diethyl 2-acetamido-2-(o-nitrophenethyl)malonate (80 g) in 3N hydrochloric acid (900 ml) was refluxed for 12 hours. The solution was cooled and extracted with ethyl acetate (200 ml). The aqueous solution was filtered, and evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol/ether to give 2-amino-4-(2-nitrophenyl)butyric acid hydrochloride, m.p. 219°-221° (dec).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:7]2.[C:19]1(C)C=C(C)C=C(C)C=1.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH:14]([CH3:18])[C:15]([O:17][CH3:19])=[O:16])[CH:5]=[CH:4]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1Br
Reactant: Cc1cc(C)cc(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
16.1 Grams of the methyl ester of the 2-(5-bromo-6-methoxy-2-naphthyl)propionic acid are dissolved in 65 ml of methylene chloride and then 10.4 ml of mesitylene and 12 ml of anhydrous titanium tetrachloride are added while keeping the temperature at about 20° C. The reaction mixture is kept under stirring at room temperature for 80 hours and then is poured into a mixture made of 68 g of crushed ice and of 15 ml of a 35% (w/v) aqueous solution of hydrochloric acid. The layers are separated after 15 minutes of stirring, the aqueous layer is extracted with 30 ml of methylene chloride and then is discarded. The organic layers are collected, first washed with 50 ml of a 1N aqueous solution of hydrochloric acid, then with 50 ml of water and lastly with 50 ml of a 8% (w/v) aqueous solution of sodium bicarbonate. The organic solution is dried over anhydrous sodium sulfate and then is evaporated under vacuum. The residue is crystallized first with n-hexane and then with methyl alcohol obtaining 4 g of product with a yield equal to 32.7%.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:36]([OH:37])[C@@H:35]([CH3:38])[C@@H:34]([OH:39])[C@@H:33]([CH3:40])[C@H:32]([O:41][C:42]([CH3:44])=[O:43])[C@H:31]([CH3:45])[C@@H:30]([O:46][CH3:47])[CH:29]=[CH:28][O:27][C@:24]2([CH3:48])[C:25](=[O:26])[C:14]3[C:15]([O:23]2)=[C:16]([CH3:22])[C:17]([OH:21])=[C:18]2[C:19](=[O:20])[C:10](=[CH:11][C:12]4(OC(=O)CO4)[C:13]=32)[NH:9][C:7](=[O:8])[C:6]([CH3:54])=[CH:5][CH:4]=[CH:3]1.C(O)C.[NH2:58][C:59]1[CH:64]=[C:63]([CH3:65])[CH:62]=[CH:61][N:60]=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>Cl.O>[CH3:65][C:63]1[CH:62]=[CH:61][N:60]2[C:11]3[C:10]4[NH:9][C:7](=[O:8])[C:6]([CH3:54])=[CH:5][CH:4]=[CH:3][C@H:2]([CH3:1])[C@H:36]([OH:37])[C@@H:35]([CH3:38])[C@@H:34]([OH:39])[C@@H:33]([CH3:40])[C@H:32]([O:41][C:42]([CH3:44])=[O:43])[C@H:31]([CH3:45])[C@@H:30]([O:46][CH3:47])[CH:29]=[CH:28][O:27][C@:24]5([CH3:48])[C:25](=[O:26])[C:14]6=[C:15]([O:23]5)[C:16]([CH3:22])=[C:17]([OH:21])[C:18](=[C:13]6[C:12]=3[N:58]=[C:59]2[CH:64]=1)[C:19]=4[OH:20]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2(C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O)OCC(=O)O2
Reactant: Cc1ccnc(N)c1
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2(C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O)OCC(=O)O2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
Rifamycin O (50 g) and 76 ml of ethanol were stirred in a RBF at 20-30° C., for 15 minutes, DM water (100 ml) and 21.5 g of 2-Amino-4-picoline were added and stirred for 15 minutes at 25-30° C. The reaction mass was heated to 47° C. and stirred for 4-5 hours. Reaction mass was cooled to 20° C. and a solution of 1.32 g of ascorbic acid in 10 ml of concentrated HCl and 7.1 ml of DM water was added into it in 30 minutes. The reaction mixture was stirred for 30 minutes at 20° C.; ˜8.75 ml of concentrated HCl was added into it to adjust the pH to 1.5-2.0 and further stirred. The crude was isolated by filtration, washed with 100 ml of 1:1 Ethanol and water mixture. The Crude was pulped with DM water until the pH of filtrate is neutral, dried for 10-12 hours at 70° C. until the moisture content was <5.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
The reaction mixture of 1.0 g (6.4 mmoles) of 2-chloro-4-hydroxybenzaldehyde, 4.4 g (32 mmoles) of potassium carbonate, and 1.4 g (9.6 mmoles) of methyl iodide in 10 mL of N,N-dimethylformamide was stirred at 70° C. for 2 h and poured into ice water. The precipitate was filtered, washed with water, and dried at 40° C. in vacuum oven overnight to yield 750 mg (68%) of the title compound as a light pink solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[Cl:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([CH:29]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]>COCCOC.O.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>[Cl:18][C:19]1[C:20]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:21][CH:22]=[C:23]([CH:29]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCNC(=O)c1cnc(Cl)c(Cl)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)c1cnc(-c2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
2.44 g of Na2CO3 (23.0 mmol), 1.15 g of 4-formylphenylboronic acid (7.67 mmol), and 0.21 g of Pd(PPh3)4 were added to 1.68 g of 5,6-dichloro-N-ethyl-nicotinamide (5) (7.67 mmol) prepared in Example 2 dissolved in 30 mL of 1,2-dimethoxyethane and 30 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, concentrated about 50% under reduced pressure to extract the aqueous layer with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 5-chloro-N-ethyl-6-(4-formyl-phenyl)-nicotinamide 1.78 g (yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(Cl)c3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 50 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-chloro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (53 mg, 0.11 mmol) obtained in step 2 and ethanesulfonamide (58 mg,' 0.55 mmol), the title compound (32 mg, 50%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:26]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:31]([BH3-])#[N:32].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:26][NH:32][CH3:31])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1
Reactant: [BH3-]C#N
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
To a solution (12 mL) of 5-(4-fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (0.55 g) in methanol were added methylammonium chloride (1.11 g) and sodium cyanoborohydride (0.26 g), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as colorless crystals (yield 0.39 g, 68%).
Reaction SMILES: [Li+].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O-:26])=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:61]([C:64]1[CH:76]=[CH:75][C:67]([O:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[CH:66][C:65]=1[C:77]([F:80])([F:79])[F:78])([O-:63])=[O:62]>CN(C)C=O.ClCCl.O1CCCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([N:72]3[CH2:73][CH2:74][CH:69]([O:68][C:67]4[CH:75]=[CH:76][C:64]([N+:61]([O-:63])=[O:62])=[C:65]([C:77]([F:78])([F:79])[F:80])[CH:66]=4)[CH2:70][CH2:71]3)=[O:26])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1)N1CCC(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-propionic acid lithium salt (34 mg; 0.10 mmol, prepared in accordance with Example 22), diisopropylethyl amine (35 μL; 0.20 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (38 mg; 0.10 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 4-(4-nitro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (33 mg; 0.10 mmol, prepared in accordance with Example 44) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (19 mg; 0.03 mmol). The structure was confirmed using Protocol I-B. Calculated mass=613; observed mass=613; HPLC retention time=4.74 min.
Reaction SMILES: [O:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Yield: 62.1 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-phenoxymalonate (2.81 g), 4-benzyloxybenzyl chloride (2.59 g) and sodium hydride (55% suspension in oil, 530 mg) and the reaction mixture was treated to afford the desired compound (3.10 g) as a syrup.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=1>>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH:10]=1
Reactant: ClCc1cccnc1
Reactant: O=C1CCNCC1
Agent: Cl
Product: O=C1CCN(Cc2cccnc2)CC1

Procedure:
1-(3-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 3-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[CH2:14]([O:16][C:17](=[O:31])/[C:18](=[N:23]\[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])/[C:19]([F:22])([F:21])[F:20])[CH3:15]>C1COCC1>[CH2:14]([O:16][C:17](=[O:31])[C:18]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]([F:22])([F:21])[F:20])[CH3:15]
Reactant: CCOC(=O)/C(=N\C(=O)OC(C)(C)C)C(F)(F)F
Reactant: Brc1cccc(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.66 g (20 mmol) 1-bromo-3-iodo-benzene in 25 ml THF was stirred at −20° C. A 1.82 M solution of isopropylmagnesium chloride (12.1 ml, 22.0 mmol) in THF was added and the mixture was stirred 1 h at 0° C. The mixture was cooled to −78° C. and a solution of 5.38 g (20 mmol) 2-[(E)-tert-butoxycarbonylimino]-3,3,3-trifluoro-propionic acid ethyl ester in 50 ml of THF was added over a period of 2 h. After 20 min the mixture was quenched with 5% aqueous NH4Cl. The mixture was extracted with TBME. The organic phase was dried with Na2SO4, filtered and evaporated. Purification via chromatography on silica gel (c-hexane/0-14% EtOAc) gave the desired product as a colorless resin.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>O>[Br:1][C:2]1[N:10]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reaction time: 3 h

Procedure:
50 g of 8-bromo-3-methyl-3,7-dihydropurine-2,6-dione are introduced into 900 ml of DMF, and 14.1 g of potassium carbonate are added. The suspension is heated to an internal temperature of 60° C., and 31.7 g of 1-bromo-3-methyl-2-butene are slowly 10 added. The mixture is stirred at this temperature for 3 hours and then 1.2 1 of water are added. The solid is filtered off with suction, thoroughly washed with water and dried in vacuo at 45° C.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:23])C1C=CC=CC=1>C(O)C.Cl.[Pd]>[ClH:23].[Cl:23][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: COc1ccc(Cl)c(N=C2NCCN2OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Cl)c(N=C2NCCN2O)c1

Procedure:
A solution of 1.84 g of 1-(benzyloxy)-2-[(2-chloro-5-methoxyphenyl)imino]imidazolidine in 10 ml of ethanol and 0.65 ml of 25 percent hydrochloric acid is hydrogenated over palladium/carbon. The catalyst is subsequently removed by filtration and the solution obtained is evaporated in vacuo. There is obtained 2-[(2-chloro-5-methoxyphenyl)imino]-1-hydroxyimidazolidine hydrochloride of melting point 182°-184° (acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7].[NH2:18][C:19]1[C:27]([Br:28])=[CH:26][C:25]([Br:29])=[CH:24][C:20]=1[C:21](O)=[O:22].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:29][C:25]1[CH:26]=[C:27]([Br:28])[C:19]2[N:18]=[C:15]([C:4]3[N:5]([C:8]4[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=4)[C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=3)[O:17][C:21](=[O:22])[C:20]=2[CH:24]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: O=C(O)c1cc(Cl)c(Cl)n1-c1ncccc1Cl
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Cl)c(Cl)n2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4,5-dichloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4,5-dichloro-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([C:11](=O)[CH3:12])[C:6](OCC)=[O:7].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(O)C>[NH2:21][C:19]1[N:20]=[C:6]([OH:7])[C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:11]([CH3:12])[N:18]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(CCOC)C(C)=O
Agent: O=C(O)O
Solvent: CCO
Product: COCCc1c(C)nc(N)nc1O
Yield: 41.5 %

Procedure:
A mixture of ethyl 2-(2-methoxyethyl)-3-oxobutanoate (4 g, 21 mmol), guanidine carbonate (2.27 g, 16.3 mmol) and ethanol (16 ml) was refluxed for 9 hours. After cooling, the precipitate was filtered and washed with water, ethanol and ether in order, to give the object compound (1.24 g, 31.9%)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([CH2:13]O)[CH2:10][CH2:11]O>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]=[CH:9][CH:10]=[CH2:11]
Reactant: OCCCCO
Solvent: C=Cc1ccccc1
Product: C=CC=C

Procedure:
A 2 gallon reactor was initially flushed with nitrogen before being charged with a solution prepared from 540 g (5.19 moles) of styrene, 81.0 g (˜0.27 moles) of N,N-dimethyloctadecylamine and 4.77 g (˜0.0123 moles) of BHDTTC and stirred at 200 rpm. To this mixture was then added an aqueous solution prepared from 3510 g of RO water, 12.6 g (0.0466 moles) of potassium persulfate and 33.66 g of conc. Hydrochloric acid (˜0.34 moles). The reactor was again flushed with nitrogen before adding 1260 g (˜23.33 moles) of distilled butadiene. The stirred reactor was then heated to 65° C. with “solids” being taken every 2 hours to follow the progress of the polymerization. The reaction was shortstopped at ˜23 percent solids (˜65 percent conversion) with 45 g of a 2 percent aq. solution of 4-hydroxy TEMPO after 10.5 hours. The latex was then cooled and vacuumed stripped of residual monomers to yield a final latex with 24.1 percent solids, pH 1.53, viscosity of 352 cps, mechanical stability of 221 mg and an alcohol Mooney (ML4) of 37. NMR analysis indicates 23.3 percent styrene, 62.3 percent 1,4-BD and 14.4 percent 1,2-BD.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C>[OH:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:18]=1[CH3:19]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCCCO)ccnc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCCCO)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
80 ml of ethanol was added to a mixture comprising 1.39 g (9.27 mmol) of 2-mercaptobenzimidazole, 2.0 g (9.27 mmol) of 2-chloromethyl-4-(3-hydroxypropoxy)-3-methylpyridine and 0.44 g (11.1 mmol) of sodium hydroxide. The obtained mixture was stirred at 50° C. for one hour. After the completion of the reaction, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1.7 g of the title compound (56%).