Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:47])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:46])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:45])[C@H:22]([CH2:30][CH2:31][CH2:32][CH:33](C(OCC1C=CC=CC=1)=O)[NH2:34])[NH:23][P:24]([CH2:28][CH3:29])([CH2:26][CH3:27])=[O:25])C1C=CC=CC=1.[OH-].[Ca+2:49].[OH-]>CO.O.[C].[Pd]>[Ca+2:49].[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([O-:47])=[O:8])=[O:46])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH2:28][CH3:29])=[O:25])[CH3:27].[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([O-:47])=[O:8])=[O:46])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH2:28][CH3:29])=[O:25])[CH3:27]
Reactant: CCP(=O)(CC)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCP(=O)(CC)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]
Yield: 94.9 %

Procedure:
Diethylphosphoryl-ε-carbobenzoxy-L-lysyl-L-prolyl-L-proline benzyl ester (2.48 g, 3.5 mmole) was dissolved in methanol (25 ml), and calcium hydroxide (0.133 g) suspended in water (10 ml) was added thereto. The catalytic reduction reaction was carried out in the presence of 5% palladium-carbon as catalyst. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The thus obtained milk-white and candy-like residue was dissolved in water. After removal of insoluble matter by filtration, the solution was freeze-dried to obtain diethylphosphoryl-L-lysyl-L-prolyl-L-proline calcium salt (1.54 g, yield: 87.8%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].P(Cl)(Cl)(Cl)=O.CN(C=O)C.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2)=[O:24]>ClCCCl>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[C:30]2[CH:8]=[O:9])=[O:24]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2cc[nH]c12
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirred mixture of phosphorus oxychloride-dimethylformamide in anhydrous 1,2-dichloroethane (prepared by the slow addition of phosphorus oxychloride (0.43 ml, 4.6 mmol) to anhydrous DMF (0.35 ml, 4.6 mmol) in anhydrous 1,2-dichloroethane (6 ml) cooled below 5° C.) a solution of 7-methoxycarbonylindole (0.69 g, 4 mmol) in anhydrous 1,2-dichloroethane (6 ml) was dropwise below 5° C. The mixture was stirred at room temperature for 2 h and then was heated at 50° C. for 30 minutes. After cooling, the precipitate was filtered off and washed with 1,2-dichloroethane. This precipitate was suspended in aq Na2CO3 10% (30 ml) and stirred at room temperature for 20 minutes; dichloromethane was added and stirring was continued 10 minutes more. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to yield 0.75 g (93%) of the entitled product. Mp: 153–4° C.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:13]([O:21][CH3:22])=[CH:12][C:4]=1[O:5][CH2:6][C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:10][N:9]([CH3:11])[C:7]([CH2:6][O:5][C:4]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:3]=1/[CH:1]=[CH:24]/[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:25])=[O:8]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OCC(=O)N(C)C)c(C=O)cc1-c1cccs1
Product: COc1cc(OCC(=O)N(C)C)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 75 %

Procedure:
The title compound was prepared by condensing 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl-acetamide (Ex-67A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 228–229° C., 75% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (d, 2H, J=9.3 Hz), 8.22 (d, 2H, J=13.3 Hz), 8.08 (d, 2H, J=9.3 Hz), 7.95 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 2.7 Hz), 6.85 (s, 1H), 5.11 (s, 2H), 3.99 (s, 3H), 3.06 (s, 3H), 2.93 (s, 3H). MS (EI) m/z=465 ([M]+, 100%). HRMS (EI) Calcd. for C25H23NO6S: 465.1246. Found: 465.1246.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.O.[C].[Pd]>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)NC1CCNC1
Yield: 97.9 %

Procedure:
To a solution of the above 3-acetylamino-1-benzylpyrrolidine (4.0 g) in ethanol (30 ml) was added 10% palladium-carbon (0.8 g) in water (1 ml). The mixture was shaken at room temperature for 22 hours under hydrogen pressure of 55 p.s.i. using Parr hydrogenator. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and dried over anydrous magnesium sulfate, followed by distilling off the solvent to give 3-acetylaminopyrrolidine (2.3 g) as oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][C:14]([OH:21])=[O:15])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:18])[CH3:17]
Reactant: CCCc1c(OCCCO)ccc(C(C)=O)c1O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCc1c(OCCC(=O)O)ccc(C(C)=O)c1O
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A solution of 2.00 g of 1-[2-hydroxy-4-(3-hydroxypropoxy)-3-propylphenyl]ethanone in 30 ml of acetone was added dropwise over 45 minutes to a stirred, ice cooled solution of 4.0 ml of Jones reagent in 10 ml of acetone. After 15 additional minutes, the cooling bath was removed and the reaction mixture was stirred at 23° for 15 minutes. Jones reagent (0.5 ml) was added and stirring was continued for 15 minutes. The reaction mixture was concentrated in vacuo and the residue was treated with water and extracted with ether. The ether extract was washed with three portions of 1N sodium hydroxide and the aqueous layers were combined and acidified. The product was extracted with ether and the dried (over magnesium sulfate) extract was concentrated in vacuo to a solid (1.48 g). Recrystallization from ether-hexane gave 1.21 g, mp 142°-146°, (57% yield) of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propanoic acid, the titled compound.
Reaction SMILES: Br[C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:4]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:5](=[O:20])[N:6]([CH2:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:7]=1.[NH2:36][NH2:37]>N1C=CC=CC=1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:3]2[C:2]([NH:36][NH2:37])=[N:7][N:6]([CH2:8][C:9]3[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[C:5](=[O:20])[C:4]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)=[CH:30][CH:31]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(Br)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Reactant: NN
Solvent: c1ccncc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 200 °C
Reaction time: 1.5 h

Procedure:
To a microwave flask was added 4-(6-bromo-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (105 mg, 0.187 mmol), pyridine (10 ml) and anhydrous hydrazine (60 mg, 1.87 mmol). The reaction was subjected to microwaves with heating to 200° C. and the conditions were continued at that temperature for 1.5 hr. After this time, the reaction was cooled to rt and the solvent was removed to give product as yellow solid. The product was used in the next reaction without further purification.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(Br)cc1)S(C)(=O)=O
Reaction time: 24 h
Yield: 83.2 %

Procedure:
Methyl iodide (2.38 g, 0.0382M) was added to a mixture of N-(4-bromophenyl)methanesulfonamide (6.37 g, 0.0255M) and potassium carbonate (5.21 g, 0.0382M) in dimethylformamide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for a further 24 hrs after which time it was partitioned between diethylether (100 ml) and water (100 ml). The aqueous was extracted further with diethyl ether (2×100 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a white solid (5.6 g). 1H NMR (CDCl3): 2.94 (s, 3H), 3.04 (s, 3H), 6.89 (d, J=2.56 Hz, 2H), 7.30 (d, J=2.56 Hz, 2H),).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>O=S(Cl)Cl.CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Reactant: Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (0.5 g, 1.99 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) and a few drops of DMF (0.05 mL) was heated with stirring at 90° C. for 3 hours. The solvents were then evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then 3-chloroaniline (0.25 g, 1.99 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:2:0.05) as eluent to give the desired (3-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 0.4 g, 56%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[CH:2]=[N:19][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Brc1ccc(-c2cnc3ccccc3n2)cc1
Yield: 40.9 %

Procedure:
Ten grams (36 mmol) of 2,4′-dibromo acetophenone and 4.0 g (37 mmol) of 1,2-phenylenediamine were refluxed under heating among 20 milliliter of ethanol for 3.5 hours. After completion of the reaction, resultant crystals were separated with filtration, washed with ethanol, thereby obtaining 4.2 g of 2-(4-bromo-phenyl)-quinoxaline (yield: 41%).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([N:25]([CH3:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH:62]2[CH2:64][O:63]2)=[CH:56][CH:55]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:25]([CH3:33])[C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:64][C@H:62]([OH:63])[CH2:61][O:60][C:57]4[CH:58]=[CH:59][C:54]([OH:53])=[CH:55][CH:56]=4)=[CH:35][CH:34]=3)[CH2:17][CH2:16]2)=[O:19])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1)c1ccc(Cl)cc1
Solvent: O=CO
Product: CN(C(=O)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)c1ccc(Cl)cc1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-{3-[4-chloro(methyl)anilino]-3-oxopropyl}-1-piperidinecarboxamide formate (0.78 g, 1.55 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to provide the title compound (0.27 g, 0.3 mmol)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2](Cl)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:2]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)([C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: COc1cccc(C(Cl)(Cl)c2cccc(OC)c2)c1
Product: CCOC(=O)c1ccc2c(c1)OC(c1cccc(OC)c1)(c1cccc(OC)c1)O2

Procedure:
This compound was prepared from dichloro-bis-(3-methoxyphenyl)-methane and ethyl 3,4-dihydroxybenzoate according to Example 269d; the crude product was used for the next step.
Reaction SMILES: C(OC([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[NH:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: c1nc(N2CCCC3(CCN3)C2)c2cc[nH]c2n1
Reaction time: 5 h
Yield: 94.3 %

Procedure:
To a solution of an optically-active compound of 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (2.55 g) in methanol/tetrahydrofuran (51 ml/51 ml) was added 20% palladium carbon (510 mg), and the mixture was hydrogenated under 4 atmospheres for 5 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was slurry-washed with diisopropyl ether (30 ml) to give the titled compound (1.55 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15](C(=O)C)[CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)N1CCC(c2csc3c(C(F)(F)F)cccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)c1cccc2c(C3CCNCC3)csc12
Temperature: 80 °C
Yield: 94.1 %

Procedure:
A mixture of 1-[4-(7-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-yl]-ethanone (2.95 g, 9.01 mmol), concentrated HCl (30 mL), and ethanol was heated at 80° C. for 18 h. After cooling to room temperature, the reaction was basified with 20% aqueous potassium carbonate (150 mL) and the mixture extracted with DCM (2×100 mL). The organics were washed with water (100 mL), dried over potassium carbonate, filtered, and concentrated to give 2.42 g (94%) the desired product as an amber waxy solid.
Reaction SMILES: [Cl:1]Cl.[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26](SC(C)(C)C)[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26]([Cl:1])[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CN=[N+]=[N-]
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CN=[N+]=[N-])C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: -60 °C
Reaction time: 2 h

Procedure:
286 μl of a solution containing 1.14 g/10 ml of chlorine in carbon tetrachloride are added to a solution of 110 mg of p-nitrobenzyl 5-azido-2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 9 ml of methylene chloride at -60° C., and the mixture is subsequently stirred for 2 hours at -60° C. The reaction solution is evaporated in a rotary evaporator to give 119 mg of a yellow oil. IR spectrum in CH2Cl2 : 2930, 2860, 2105, 1780, 1755, 1720, 1610, 1530, 1350, 1190 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[CH:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:22]([C:29]1[CH:30]=[CH:31][C:32](=[O:35])[NH:33][N:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][N:33]2[C:32](=[O:35])[CH:31]=[CH:30][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:34]2)=[N:6][CH:7]=1
Reactant: ClCc1cccc(-c2ncc(Br)cn2)c1
Reactant: O=c1ccc(Oc2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Oc2ccccc2)nn1Cc1cccc(-c2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.3 2.59 g (9.14 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and 2.84 g (8.70 mmol) of caesium carbonate are added to a suspension of 1.64 g (8.70 mmol) of 6-phenoxy-2H-pyridazin-3-one in 17.5 ml of DMF, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one as colourless crystals; ESI 435, 437.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][N:25]1[C:29](=[O:30])[CH2:28][NH:27][C:26]1=[O:31]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:28][C:29](=[O:30])[N:25]([CH3:24])[C:26]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CN1C(=O)CNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3)CC2)c(C)c1
Yield: 30.6 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (169 mg) described in Preparation Example 113 and 3-methylimidazolidine-2,4-dione (46 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (50 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])=[CH:6][CH:7]=1.NC(N)=[S:18].C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2](=[S:18])[NH:3][N:4]=1
Reactant: Cc1ccc(-c2ccc(Cl)nn2)c(C)c1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(=S)[nH]n2)c(C)c1
Yield: 83.5 %

Procedure:
3-chloro-6-(2,4-dimethylphenyl)pyridazine (example 13b) (1.36 g) was refluxed with thiourea (473 mg, 6.2 mmol) in EtOH (25 mL) for 5 hrs. The mixture was evaporated, and water (45 mL) was added to the residue, followed by Na2CO3 (318 mg, 3 mmol). The precipitate that formed was collected by filtration, washed with diethylether and dried to give 6-(2,4-Dimethylphenyl)pyridazine-3(2H)-thione (1.12 g, 52%). 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.32 (s, 3H), 7.12-7.30 (m, 2H), 7.29-7.31 (d, 1H), 7.46-7.49 (d, 1H), 7.65-7.68 (dd, 1H); MS (M+H, 217).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:8][CH:7]=1.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[N:13]=[C:14]([NH2:17])[S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:22][CH2:23]2)=[N:25]1
Reactant: Nc1nc(-c2ccc(CCCCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.22 g (3.52 mmol) (4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole, 0.90 g (3.52 mmol) 3-piperazinyl-benzisothiazole, 1.84 ml (10.57 mmol) diisopropylethylamine, 0.75 g (7.04 mmol) sodium carbonate, 2 mg sodium iodide, and 35 ml methylisobutylketone. The reaction mixture was refluxed 6 days, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions dissolved in methylene chloride/methanol and precipitated by addition of methylene chloride saturated with HCl. The precipitate was filtered and dried to give a solid, 242 mg (13%), m.p. 258-261° C. NMR (DMSO-d6): 1.6-1.8 (m, 4H), 2.7 (t, 2H), 3.2-3.6 (m, 8H), 4.1 (m, 2H), 7.20 (s, 1H), 7.3-8.2 (m, 8H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]2[C:17](=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:16]=[CH:15][CH:14]=[CH:13]2>C1C=CC=CC=1>[Br:1][CH2:9][C:10]1[N:11]=[C:12]2[C:17](=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2c2ccccc12
Solvent: c1ccccc1
Product: BrCc1nc2ccccc2c2ccccc12
Reaction time: 0.75 h
Yield: 87 %

Procedure:
N-bromosuccinimide (557 mg, 3.13 mmol) was added to a solution of the phenanthridine 5 (403 mg, 2.09 mmol) in benzene (20 mL) and the reaction mixture was stirred while lit with a tungsten lamp (150 W) for 45 minutes. The reaction crude, including precipitated succinimide, was deposited onto silica and purified by flash chromatography eluting with CH2Cl2. Evaporation of the solvent under reduced pressure yielded the bromo 6 as a white solid (495 mg, 87.1%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])=[CH:9][CH:10]=1
Reactant: C#CCCCO
Reactant: COc1ccc(I)cc1
Product: COc1ccc(C#CCCCO)cc1

Procedure:
5-(4'-methoxyphenyl)-4-pentyn-1-ol was prepared from 4-pentyn-1-ol and 4-iodoanisole using the same method as in Example 15 to give 1.55 g (70% of theory) of product.