Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[N:19](COCC[Si](C)(C)C)[C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)[C:5]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C1COCC1>O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:11]=[CH:12][C:13]([O:14][C:15]4[NH:19][C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:32][CH:33]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(C3CCCn4ccnc43)cc2)nc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2[nH]c(Oc3ccc(C4CCCn5ccnc54)cc3)nc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
2-[4-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyridin-8-yl)phenoxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.19 g), 1.0 M tetrabutylammonium fluoride-THF solution (1.7 ml) and THF (3 ml) were stirred under microwave irradiation at 100° C. for 3 hr. The reaction mixture was stirred at 80° C. overnight, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from methanol/ethyl acetate to give the title compound (0.071 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][O:12][CH2:13][CH2:14][O:15]C(=O)C1C=CC=CC=1.[NH3:24]>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:24]
Reactant: N
Reactant: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Solvent: CO
Product: Nc1ncnc2c1ncn2COCCO
Yield: 70 %

Procedure:
A solution of 6-chloro-9-(2-benzoyloxyethoxymethyl) purine (50 g) and ammonia (31 g) in methanol (120 ml) was heated in a bomb at 95° C. for 18 hours. The reaction mixture was removed from the bomb and the solvent evaporated under reduced pressure at 50° C. The resulting solid was triturated first with water and then, after drying, with chloroform. The solid, 9-(2-hydroxyethoxymethyl)adenine, was retained, and the aqueous triturate was extracted several times with chloroform. The aqueous extracts were treated with a strongly basic ion exchange resin and then evaporated to dryness under reduced pressure. The remaining solid was combined with that from the trituration step, and recrystallized from isopropanol to give 22 g (70% of theoretical) of white 9-(2-hydroxyethoxymethyl) adenine, m.p. 199.5°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccnc1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccnc1
Yield: 75.3 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with nicotinaldehyde (1.13 mL, 11.9 mmol) (Aldrich) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-pyridin-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 2.3 g, 75%)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)N3CCOCC3)C2=O)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-(2-chloroacetyl)morpholine, to give the desired product as a white foam (10%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:40])[CH:6]([OH:39])[C@@H:7]([NH:11][C:12](=[O:38])[C@@H:13]([NH:25][C@@H:26]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:27]([F:30])([F:29])[F:28])[CH2:14][S:15]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:16])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5](=[O:40])[C:6](=[O:39])[C@@H:7]([NH:11][C:12](=[O:38])[C@@H:13]([NH:25][C@@H:26]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:27]([F:28])([F:29])[F:30])[CH2:14][S:15]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)[C@H](CS(=O)(=O)Cc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@H](CS(=O)(=O)Cc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxy-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionylamino}hexanoic acid cyclopropylamide (590 mg, 1 mmol) in methylene chloride, DMP was added slowly. The reaction mixture was stirred at room temperature for 30 min and then a 0.26 M Na2S2O3 in sat. NaHCO3 was added. The reaction mixture was stirred for 20 min. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over MgSO4, filtered and concentrated to give 2-oxo-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionylamino}hexanoic acid cyclopropylamide which was purified by flash column (2% MeOH—CH2Cl2) to give pure product as a yellow solid.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=O)[CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=[S:22])[CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CSc2ccccc2CN1
Solvent: Cc1ccccc1
Product: S=C1CSc2ccccc2CN1
Temperature: 100 °C

Procedure:
A stirred mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-one (1.79 g, prepared as example 1 of international patent application WO 92/21668) and Lawesson's reagent (2.22 g) in dry toluene (100 ml) was heated at 100° C. for three hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration, washed with toluene and dried to give 4,5-dihydro-1,4-benzothiazepin-3(2H)-thione. Yield 1.78 g (m.p. 215°-219° C.).
Reaction SMILES: C([Li])CCC.O1CCCC1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[N:26]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[N:25]=[C:24]([CH3:33])[C:22]=3[N:23]=2)=[C:14]([O:35][CH3:36])[CH:13]=1.[CH3:37][N:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1>O>[CH:27]1([N:26]2[C:21]3[C:20](=[O:34])[NH:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:41]5([OH:44])[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:13][C:14]=4[O:35][CH3:36])=[N:23][C:22]=3[C:24]([CH3:33])=[N:25]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C2(O)CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
In an atmosphere of argon, 0.95 ml of n-butyl lithium (1.59M/hexane solution, 1.51 mmol) was added dropwise at −78° C. to a 10 ml anhydrous tetrahydrofuran solution of 300 mg (0.72 mmol) of the compound obtained in Example 15. The mixture was stirred at −78° C. for 30 minutes, and then 133 μl (1.08 mmol) of 1-methyl-4-piperidone was added, followed by heating the mixture gradually to 0° C. over the course of 1 hour. Then, water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain 179 mg (55%) of the captioned compound.
Reaction SMILES: C[O:2][Si:3]([O:11]C)([O:9]C)[C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[C-:13]1([Si:18]([O:23]C)([O:21]C)[O:19]C)[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:25].C(O)(=O)C>CCOCC>[OH:2][Si:3]([OH:11])([OH:9])[C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[C-:13]1([Si:18]([OH:23])([OH:21])[OH:19])[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:25]
Reactant: CO[Si](OC)(OC)[c-]1cccc1
Agent: [Fe+2]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O[Si](O)(O)[c-]1cccc1

Procedure:
A solution of 1,1′ bis-(trimethoxysilyl)ferrocene (1.25 g, 2.93 mmol) in 3 ml of ether was stirred vigorously with 1.37 ml of 0.5% acetic acid solution for 75 days. The final orange suspension was filtered and the solid was washed three times with ethanol, acetone and ether.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:17][C:18]1[CH:19]=[C:20]([CH:54]=[CH:55][CH:56]=1)[C:21]([NH:23][C:24]1[S:25][C:26]2[CH2:53][CH2:52][CH2:51][CH2:50][C:27]=2[C:28]=1[C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)=[O:30])=[O:22])[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH2:17][C:18]1[CH:19]=[C:20]([CH:54]=[CH:55][CH:56]=1)[C:21]([NH:23][C:24]1[S:25][C:26]2[CH2:53][CH2:52][CH2:51][CH2:50][C:27]=2[C:28]=1[C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)=[O:30])=[O:22])[CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16]
Reactant: CCC(CC)N(CCNC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)N(CCN)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a mixture of 240 mg of methyl 4-(2-{4-[({2-[(3-{[{2-[(tert-butoxycarbonyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate and 5.0 mL of methylene chloride was added 3.0 mL of TFA under ice cooling, followed by stirring for 1 hour at the same temperature and then stirring for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, thereby obtaining 210 mg of methyl 4-(2-{4-[({2-[(3-{[(2-aminoethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].ClC1C=CC=CC=1Cl.[Br:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([NH:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:19][CH:18]=1>CO.S(=O)(=O)(O)O>[C:1]([N:33]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:20]1[C:21]2[C:22](=[O:32])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29](=[O:31])[C:30]=2[C:17]([Br:16])=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)ccc(Br)c21
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CC(=O)N(c1ccc(Br)c2c1C(=O)c1ccccc1C2=O)C1CCCCC1
Temperature: 110 °C
Reaction time: 6 h
Yield: 70.1 %

Procedure:
102 g of acetic anhydride was placed in a 20 g 1,2-dichlorobenzene solution of 76.9 g of 4-bromo-1-cyclohexylaminoanthraquinone, and 1 g of concentrated sulfuric acid was placed to the solution. The solution was stirred at 110° C. for 6 hours. After the reaction was completed, the solution was diluted with 1000 g of methanol and filtered to obtain 59.8 g of 1-(acetylcyclohexylamino)-4-bromoanthraquinone (yield of 70.1%). Further, a solution of 12 g of sodium hydroxide/150 g of water was dropped to a 150 g isobutanol solution of 1-(acetylcyclohexylamino)-4-bromoanthraquinone, and the obtained solution was stirred at 90° C. for 6 hours. After the reaction was completed, the solution was cooled, the obtained solid was filtered to obtain 28.7 g of 4-bromo1,9-N-cyclohexylanthrapyridone (70.4%). Next, 19.3 g of 4-methylanilinehexylamine, 8.6 g of sodium carbonate, and 6.8 g of copper powder were placed in a 40 g 1,3-dimethyl-2-imidazolidine solution of 20.4 g of 4-bromo1,9-N-cyclohexylanthrapyridone, and the reaction was made at 190° C. for 4 hours. After the reaction was completed, the solution was cooled, diluted with ethyl acetate, and filtered. Column chromatography refining (toluene/THF) was performed to obtain 17.6 g of a compound (15) (yield of 85.0%).
Reaction SMILES: [F:1][C:2]1[C:7](I)=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(CC)CC)C.CN(C)C=O>[Cu]I.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>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([F:9])[C:7]=1[C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(OC)c(F)c(I)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(F)c(C#C[Si](C)(C)C)c1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (740 mg, 2.47 mmol), (trimethylsilyl)acetylene (0.697 mL, 4.93 mmol), copper(I) iodide (38 mg, 0.20 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (DMF) (4 mL, 50 mmol), bis(triphenylphosphine)palladium(II) chloride (86 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 70 hours. The reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (630 mg, 94%).
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])[CH2:6]1)(=O)C.[ClH:30].C(O)C>>[ClH:30].[NH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22]3)=[CH:12][C:11]=2[F:29])[CH2:6]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(C3CCC(NC(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: NC1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A mixture of 20.0 g (50 mmol) of 7-[3-(acetylamino) cyclopentyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, ethyl ester was heated in a mixture of 6.0 M hydrochloric acid/ethanol (20 ml/150 ml) at reflux for 8 hours. The solvent was removed in vacuo and the residue slurried in 200 ml of water and filtered. The filtrate was evaporated in vacuo and the residue triturated in ethanol and filtered. The precipitate was washed with ethanol, ether, and dried in vacuo to give 13.6 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-:10].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: [Cl-]
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(CCl)c1ccccc1
Temperature: 80 °C
Yield: 55 %

Procedure:
Acetophenone (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 6 h. The product was purified by column chromatography to give α-chloroacetophenone (55%).
Reaction SMILES: [N:1]([CH:4]([CH:12]([OH:26])[CH:13]([OH:25])[CH:14]([N:22]=[N+]=[N-])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH:4]([CH:12]([OH:26])[CH:13]([OH:25])[CH:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: NC(Cc1ccccc1)C(O)C(O)C(N)Cc1ccccc1
Yield: 78.8 %

Procedure:
A solution of 67 mg (0.19 mmol) of 6 in 4 mL of methanol was stirred with 30 mg of 10% palladium on carbon under 1 atmospheric hydrogen pressure for 18 hours at room temperature. The mixture was filtered through a 0.45 micron Millipore filter and the residue washed with methanol. The filtrate and the washings were concentrated to provide 45 mg (79% yield) of 7. This material showed NMR (CDCl3): d 2.64 (m, 8H), 7.283 (m, 10H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([C:14]2[CH:23]=[C:22]([CH3:24])[C:17]3[NH:18][C:19](=[O:21])[O:20][C:16]=3[CH:15]=2)=[O:13])[CH:11]=1)[C:7]#[N:8].I[CH3:26]>CN(C=O)C>[CH3:26][N:18]1[C:17]2[C:22]([CH3:24])=[CH:23][C:14]([C:12]([C:10]3[CH:9]=[C:6]([CH:5]=[C:4]([F:3])[CH:11]=3)[C:7]#[N:8])=[O:13])=[CH:15][C:16]=2[O:20][C:19]1=[O:21]
Reactant: CI
Reactant: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.161 g (3.70 mmol) sodium hydride (55%, suspension in mineral oil) were added to 1.00 g (3.38 mmol) 3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitrile in 5 mL DMF at RT and stirred for 30 min at RT. Then 0.317 mL (5.00 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then a further 0.1 mL iodomethane were added and stirring was continued at RT. After dilution with ice water the aqueous phase was extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and dried i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][N+:3]=1[O-:12].[CH3:13][NH2:14].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:14][CH3:13])=[CH:4][N+:3]=1[O-:12]
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]

Procedure:
2-Bromo-5-fluoro-4-nitropyridine 1-oxide (11.2 g, 47 mmol) and 2 N methylamine (solution in THF) (48 mL, 96 mmol) in 150 mL THF was stirred for 5 min at ambient temperature. Water was poured into the mixture and THF was removed i.vac. The solid was filtered, washed with water and dried at 50° C. i. vac.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C.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>[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:20][C:15]=3[CH3:14])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Reactant: Cc1cc(OC(F)(F)F)ccc1B(O)O
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)(F)F)ccc1-c1ccc2nnc(C(C)C)n2n1

Procedure:
To a microwave reaction tube was added 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine prepared as described in Step 1 above (1.28 mmole), 2-methyl-4-(trifluoromethoxy)phenylboronic acid (1.40 mmole), tetrakis(triphenylphosphine)palladium (0.064 mmole), 2M Na2CO3 (1 mL), and DMF (3 mL). The resulting reaction mixture was heated in the microwave at 130 C for 10 min. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by preparative HPLC to afford 3-isopropyl-6-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:12]>>[CH:1]1([CH2:6][CH2:7][C:8]#[N:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: [NH4+]
Agent: [OH-]
Product: N#CCCC1CCCC1
Reaction time: 8 h

Procedure:
3-Cyclopentylpropionitrile is prepared in this example. 3-Cyclopentylpropionyl chloride (57.7 g, 0.36 mole) is added dropwise to a large excess of concentrated ammonium hydroxide (400 ml) cooled in an ice/salt bath. The heavy suspension of white solid is stirred overnight, collected by filtration, washed with cold water, and recrystallized from about 2 liters of boiling water. The lustrous white plates of the amide are dried in vacuo over P2O5 ; yield 31.6 g (62.3%); mp 122° C.
Reaction SMILES: [C:1](/[C:4](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)/[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].S(O)(O)(=O)=O.[CH3:22][O:23][C:24](=[NH:26])[NH2:25].C([O-])(O)=O.[Na+]>C(O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[NH:26][C:24]([O:23][CH3:22])=[N:25][C:1]([CH3:2])=[C:4]2[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=1
Reactant: COC(=O)/C(=C\c1ccc(F)cc1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl (2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate (0.220 mole, 48.8 g), O-methyl isourea hydrogensulfate (53.40 g, 0.310 mol, 1.5 eq.), NaHCO3 (61.74 g, 0.74 mole, 3.5 equiv.) and ethanol (1.2 L) was refluxed for 24 h, cooled to room temperature, and filtered. The solid was washed with ethanol (200 mL) and the combined filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, hexanes/EtOAc/Et3N 50:50:0.1) to yield a mixture of tautomers (4:1, 33.0 g, 53.9%). 1H NMR (CDCl3) δ 7.32-7.24 (m, 2H), 7.04-6.95 (m, 2H), 5.81 (s, 1H), 5.38 (d, 1H, J=2.9 Hz), 4.00 (s, 3H), 3.63 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: ClC1C=CC2SC=C(C[N:10]3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[Cl-].[NH4+]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH2:10])=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(N)=O
Yield: 43 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with ammonium chloride, the title compound was obtained as a colorless solid in 43% yield: mp 201-203° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.38-7.31 (m, 4H), 7.23-7.17 (m, 2H), 4.42 (s, 2H), 3.99 (t, J=9.0 Hz, 2H), 3.45 (t, J=9.0 Hz, 2H), 2.46 (s, 3H): MS (ES+) m/z 33.51 (M+1).