Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)[CH:5]=[CH:6][CH:7]=1.[CH3:25][P:26](Cl)([CH3:28])=[O:27].[N:30]1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:4]1[CH:5]=[CH:6][C:7]([NH:30][P:26]([CH3:28])([CH3:25])=[O:27])=[CH:2][CH:3]=1)#[N:20]
Reactant: c1ccncc1
Reactant: CP(C)(=O)Cl
Reactant: CCn1c(C#Cc2cccc(N)c2)c(C#N)c2ccc(OC)cc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(C#Cc2ccc(NP(C)(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (300 μL) at 0° C. Dimethylphosphinic chloride (60 mg, 0.53 mmol) in THF (300 μL) is added. The reaction is stirred at room temperature for 2 hours. The reaction mixture is diluted in EtOAc, and is washed with aqueous HCl followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (acetone) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (65 mg, 52%), compound 227, as a pure white solid. The silica column is then flushed with 9/1 CH2Cl2/MeOH to yield 9 mg of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic) amide as a by-product.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@@H:6]([CH:8]2[CH2:10][N@@:9]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[O:5][C:4]1=[O:23])[CH3:2].[CH3:24][C:25]1([CH3:39])[CH2:30][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:28](=[O:38])[CH2:27][NH:26]1>C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:39])[CH2:30][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:28](=[O:38])[CH2:27][N:26]1[CH2:10][C@H:8]([NH:9][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C@@H:6]1[CH2:7][C@@H:3]([CH2:1][CH3:2])[C:4](=[O:23])[O:5]1
Reactant: CC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: Cc1ccccc1N1CC(C)(C)NCC1=O
Agent: CC[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3C)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 96.6 %

Procedure:
A solution of 770 mg of (3R,5S)-3-ethyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (106g) (2.26 mmol) and 593 mg of 5,5-dimethyl-1-(2-methylphenyl)piperazin-2-one obtained in Example (51d) (2.71 mmol) in toluene (23 ml) was stirred at 110° C. for five hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=4/1) to obtain 1.22 g of the title compound (yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].O>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([C:4](=[O:5])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[NH2:21]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: NN(C(=O)c1c(F)cccc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
71.7 g (0.37 mol) of 2-chloro-6-fluorobenzoyl chloride are slowly added dropwise to a solution, cooled to 5° C., of 65.4 g (0.37 mol) of o-trifluoromethylphenylhydrazine in 200 ml of pyridine in such a manner that the temperature of the reaction mixture does not exceed 5° C. The mixture is stirred at room temperature for a further 90 minutes and subsequently treated with 400 ml of water. The aqueous phase is extracted three times with 150 ml of diethyl ether each time and the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate and evaporated under reduced pressure, the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine. After recrystallization from methylene chloride/n-hexane there is obtained N1 -(α,α,α-trifluoro-o-tolyl)-2-chloro-6-fluorobenzhydrazide, m.p. 147°-148° C.; mass spectrum: 332(19), 157(100).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C[O:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[C:27](=[O:26])[NH:28][CH:29]=[CH:30][CH:31]=2)=[O:34])=[CH:11][C:12]=1[F:17]
Reactant: COc1ncccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: Cl
Product: O=C(NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1)c1ccc[nH]c1=O

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-methoxypyridine-3-carboxylic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH:18](OC)(OC)OC>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[CH:18][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:4](=[O:9])[O:3]1
Reactant: Nc1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Product: CC1(C)OC(=O)C(=CNc2ccncc2)C(=O)O1

Procedure:
A mixture of 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid) (8.4 g, 59 mmol) and trimethyl orthoformate (50 mL) was heated to reflux for 2 hours. 4-Aminopyridine (5 g, 53 mmol) was added and the mixture heated for a further 0.25 hour. The resulting solid was washed with a small amount of cold ethanol and dried in vacuo (7.3 g, 55%).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][O:7][CH2:8][C@@H:9]([C:21]([OH:23])=O)[NH:10]C(OCC1C=CC=CC=1)=O)=[NH:3].[CH3:24][S:25]([Cl:28])(=[O:27])=[O:26].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[NH:3]=[C:2]([NH:4][CH2:5][CH2:6][O:7][CH2:8][C@@H:9]([C:21]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:23])[NH2:10])[NH:1][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: N=C(N)NCCOC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Reactant: C1CCNC1
Product: CS(=O)(=O)NC(=N)NCCOC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-3-(2-{[amino-(imino)-methyl]-amino}-ethoxy)-N-(benzyloxycarbonyl)-alanine, methanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](CN)[CH:5]=[CH:6][CH:7]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11].O.C(OCC)(=O)C.[CH3:28][N:29](C)C=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>[CH3:28][NH:29][C:4]1[CH:5]=[C:6]([C:15]2[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=2)[CH:7]=[CH:2][CH:3]=1
Reactant: CN(C)C=O
Reactant: NCc1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cccc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
5 g (26.8 mmol) of 3-bromophenylmethylamine and 4 g (26.8 mmol) of commercial 4-formylbenzeneboronic acid are dissolved in 50 mL of an aqueous 6/1 mixture of dimethylformamide/aqueous 2 M potassium phosphate. 1.5 g (1.3 mmol, 5 mol %) of tetrakis(triphenylphosphine)palladium are added. The mixture is stirred for 2 hours at 90° C. The reaction is worked up by addition of 50 mL of water and extraction with ethyl acetate. The organic phases are washed with sodium chloride solution and dried over magnesium sulfate. The solvents are evaporated off, and the residue is then purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 4.3 g (76%) of 3′-methylaminobiphenyl-4-carbaldehyde are obtained.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)([O-:10])=[O:9].[NH3:19]>C(O)(C)C>[CH3:5][C:3]1[NH:19][C:3]([CH3:5])=[C:2]([C:1]([OH:7])=[O:6])[CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N+:8]([O-:10])=[O:9])[C:2]=1[C:1]([OH:7])=[O:6]
Reactant: CC(=O)CC(=O)[O-]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: N
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2ccccc2[N+](=O)[O-])C(C(=O)O)=C(C)N1

Procedure:
In 30 ml of isopropyl alcohol were dissolved 2 g of 3-nitratopropyl acetoacetate and 0.74 g of 2-nitrobenzaldehyde. To the solution was added 4 ml of isopropyl alcohol saturated with an ammonia gas at 10° C. The mixture was treated in the manner described in Example 1 to obtain a residue, which was then subjected to column chromatography on silica gel (eluted with n-hexane-acetone=5:3) and recrystallized from ether to obtain 1.11 g of 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid bis(3-nitratopropyl) ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)(O)[O-].[Na+].[S:17](Cl)(Cl)(=[O:19])=[O:18].Cl>>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:1][S:17]([CH3:12])(=[O:19])=[O:18])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(Br)cc(C(=O)O)c1
Reactant: O=C([O-])O
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)Nc1cc(Br)cc(C(=O)O)c1

Procedure:
3-Amino-5-bromobenzoic acid (1 g, 4.63 mmol, prepared according to EP 2394998 A1 20111214) was suspended in a saturated solution of sodium bicarbonate (6.4 ml). Sulfonyl chloride (0.54 ml, 6.94 mmol) was added dropwise at 0° C. After 2 h of stirring at this temperature, concentrated HCl was added dropwise to the reaction mixture until pH=7 and the resultant dissolution was directly purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%), to obtain 360 mg of the final compound as a white solid. Purity: 99%
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4C(=O)C5=CC=CC=C5C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.NN.O.[ClH:35]>CO.C(O)C>[ClH:35].[ClH:35].[NH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCO
Product: NCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propyl]phthalimide (8.5 g, 21 mmol), hydrazine monohydrate (1.5 g, 30 mmol) in methanol (60 ml) was heated at reflux for 2 hours. At the end of the reaction, methanol was removed to leave a crude solid. To this was added water (60 ml), then the mixture was acidified with HCl to pH 1. The insolubles were filtered with the aid of a pad of Celite. The aqueous solution was basified with 50% NaOH, (pH 13), then extracted with dichloromethane. The combined dichloromethane solution was washed with brine, then dried to a colorless oil (4.5 g). The analytical sample (1.5 g) was prepared by treating the oil with HCl in ethanol at 0° C. The 1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride was obtained as white crystals, 2.03 g, m.p.=231°-234° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][C:23]([CH2:25][CH3:26])=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:27]=[C:28]([O:31][Si](C(C)(C)C)(C)C)[CH:29]=[CH:30][C:15]3=4)[C:11](=[O:39])[NH:10][C:9]2=[O:40])[CH:5]=[CH:4][N:3]=1.[C:41]([CH:44]1[CH2:47][NH:46][CH2:45]1)([OH:43])=[O:42].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH2:25]([C:23]1[CH:24]=[CH:19][C:20]2[CH:14]([C:12]3[C:11](=[O:39])[NH:10][C:9](=[O:40])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:46]5[CH2:47][CH:44]([C:41]([OH:43])=[O:42])[CH2:45]5)[N:7]=4)[CH:13]=3)[C:15]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:16]=3[CH:17]=[CH:18][C:21]=2[CH:22]=1)[CH3:26]
Reactant: CCc1ccc2c(c1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: O=C(O)C1CNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc2c(c1)C=Cc1cc(O)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O
Temperature: 90 °C

Procedure:
A mixture of the product from step (viii) (0.5 g), 3-carboxyazetidine (0.13 g) and N,N-diisopropylethylamine (0.52 ml) in 1-methyl-2-pyrrolidinone (10 ml) was heated at 90° C. for 6 hours and partitioned between ethyl acetate and 1M HCl. The organic phase was washed with water, dried (MgSO4) and concentrated in vacuo to 10 ml. Isohexane (5 ml) was added and the product was collected by filtration. Yield 0.25 g.
Reaction SMILES: BrC1C=CC([N:8]([C:15]2[C:24]3[C:19](=CC=CC=3)[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)=CC=1.C([Li])CCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C.O>C1COCC1.C(Cl)(Cl)Cl>[CH3:41][C:36]1([CH3:42])[C:37]([CH3:40])([CH3:39])[O:38][B:34]([C:18]2[CH:17]=[CH:16][C:15]([NH2:8])=[CH:24][CH:19]=2)[O:35]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 24 h

Procedure:
3.7 g (10 mmol) of (4-bromophenyl)naphthalen-1-yl-phenylamine was dissolved in 100 ml of THF and cooled to −78° C. 4.8 ml (12 mmol) of 2.5M n-butyllithium was added slowly to the THF solution and maintained at the same temperature as above for an hour to allow reaction. 2.2 g (12 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the reactant solution, maintained at the same temperature as above for an hour to allow reaction, heated to room temperature (RT) and stirred for 24 hours. Water was added to end the reaction, and 300 ml of chloroform was added. The resulting organic layer was washed with 200 ml of water and dried with anhydride magnesium sulfate. 3.4 g of Naphthalen-1-yl-phenyl[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (intermediate A) was obtained through silica chromatography with a yield of 81%.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:15][CH2:16]Br)([CH3:14])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2].[CH3:22][NH:23][CH3:24].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:15][CH2:16][N:23]([CH3:24])[CH3:22])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCBr)O2
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCN(C)C)O2
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 3.55 g (0.01 mol) of 3,4-dihydro-2-(2-bromoethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-yl acetate and 2.0 g of liquid dimethylamine in 50 ml of dimethylformamide is stirred at room temperature for 40 hours. Water is added and the product is extracted with ethyl acetate and ethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil crystallizes from a mixture of ethyl ether and pentane to give 2.05 g of 3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-yl acetate as the free base.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[O:30]([NH2:32])[CH3:31]>C(O)C>[CH3:31][O:30][N:32]=[C:21]([C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[CH:20][CH:19]=1)[CH3:22]
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C(C)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared as a ca. 9.5:0.5 mixture of two isomers by using a procedure similar to the one described for example 216 from example 208 (0.070 g, 0.230 mmol), ethanol (1.5 ml), sodium acetate (0.018 g, 0.230 mmol) and methoxylamine hydrochloride (0.019 g, 0.230 mmol). Off-white solid (0.020 g, 26%). M.P.: 155-157° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (d, J=2.6 Hz, 1H), 8.61 (d, J=8.8 Hz, 0.05H), 8.55 (d, J=8.8 Hz, 0.95H), 8.36 (d, J=8.4 Hz, 1H), 8.02 (m, 3H), 7.81 (dd, J=8.8, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.16 (s, 2H), 4.01 (s, 2.85H), 3.79 (s, 0.15H), 2.32 (s, 2.85H), 2.24 (s, 0.15H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)=[O:13])[N:6]=1)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([NH:22][NH2:23])=[O:2])[N:6]=2)=[O:13])[CH:19]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 92 %

Procedure:
The crude 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester from the previous step (25.3 g, 87.8 mmol) was suspended in ethanol (200 mL), and hydrazine hydrate (21.3 mL, 439 mmol) was added. The reaction mixture was refluxed for 4 hours, solvent removed under reduced pressure, and the residue suspended in acetonitrile and collected by filtration. The solids were washed with acetonitrile (2×100 mL) and diethylether (2×100 mL), and dried under reduced pressure to afford 25.3 g (92% yield) of 4-chloro-N-(6-(hydrazinecarbonyl)pyridin-2-yl)picolinamide as a white solid.
Reaction SMILES: CN1CCCC1=O.[CH2:8]([N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1Cl)[C:9]#[C:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O>[CH2:8]([N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[N:33]1[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34]1)[C:9]#[C:10][CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(Cl)nc2cnn(C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 130 °C
Yield: 99.2 %

Procedure:
5 ml of 1-methyl-2-pyrrolidone was added to a mixture consisting of 1.183 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, 0.829 g of potassium carbonate, and 1.395 g of t-butyl piperazine-1-carboxylate under a nitrogen atmosphere. The resulting mixture was heated at 130° C. for 6 hours. The reaction mixture was cooled, and 50 ml of water was added thereto. Then, the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed twice with 50 ml of water and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. Thus, 1.916 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: BrBr.[OH-:3].[Na+].[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C>OS([O-])=O.[Na+]>[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:3]
Reactant: COc1ccc(C(C)=O)c(Br)c1
Reactant: [OH-]
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Br)c1
Temperature: 36 °C
Reaction time: 17 h
Yield: 68 %

Procedure:
Br2 (8.5 mL, 165.89 mmol) is added dropwise to 20% NaOH (97 mL) at 0-10° C. in a 15-min period. The resulting solution is warmed to room temperature before 1-(2-bromo-4-methoxyphenyl)ethanone (2) (9.50 g, 41.47 mmol) is added. The mixture is stirred at 36° C. for 29 h and at room temperature for 17 h, diluted with 0.5 M NaHSO3 (25 mL), and extracted with ether (100 mL and 70 mL). The aqueous layer is acidified with conc. HCl (30 mL) to give 6.56 g (68%) of 3 as a white solid, mp 195-197° C. IR 2997, 1686, 1596, 1290 cm−1; 1H NMR (CDCl3) δ 3.80 (s, 3H, CH3O), 6.83 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.15 (d, J=2.0 Hz, 1H, 3PhrH), 7.90 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[CH2:27]([C:31]1[CH:35]=[CH:34][S:33][CH:32]=1)[CH2:28][CH2:29][CH3:30].C[O:37][B:38](OC)[O:39]C.C(O)CCO>C(OCC)C>[CH2:27]([C:31]1[CH:35]=[C:34]([B:38]2[O:39][CH2:6][CH2:5][CH2:7][O:37]2)[S:33][CH:32]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COB(OC)OC
Reactant: CCCCc1ccsc1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: OCCCO
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCc1csc(B2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (21.6 ml, 154.0 mmol) in 200 ml of anhydrous diethyl ether was added 2.5 M n-BuLi in hexane (49.3 ml, 123.3 mmol) at room temperature. After stirring at room temperature for 30 min, the resulting lithium di-isopropylamide (LDA) solution was cooled to −76° C. A solution of 3-butylthiophene (18.0 g, 123.3 mmol) in 100 ml of ether was cooled to −76° C. and added to the above LDA solution. The temperature was allowed to rise slowly to −40° C., whereupon it was stirred for 1 h. The solution was then recooled to −76° C. and trimethylborate (20.6 ml, 185.0 mmol) was added slowly. The mixture was allowed to warm to room temperature and stirred for 2 h. After quenching with 10% HCl (180 ml) the organic layer was separated and the aqueous layer was extracted with ether (2×). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was added to 1,3-propanediol (8.9 ml, 123.3 mmol) and refluxed for 2 h. The mixture was then placed directly on a silica column and eluted first with hexane, then chloroform to give the product, 8.46 g, 31%. 1H NMR (CDCl3-d3, 500 MHz): δ 7.36 ppm (s, 1 H), 7.12 ppm (s, 1 H), 4.14-4.12 ppm (t, 4 H, J=8.6 Hz), 2.60-2.63 ppm (t, 2 H, J=8.6 Hz), 2.04 ppm (m, 2 H), 1.35 ppm (m, 2 H), 1.32 ppm (m, 2 H), 0.89 ppm (t, 3 H, J=7.5 Hz); 13C-NMR (CDCl3, 500 MHz): δ 144.4, 136.8, 126.5 126.4, 62.1, 32.85, 29.73, 27.46, 22.45, 13.90 ppm. EI, MS m/z (%): 224 (100, M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@@H:18]1[CH2:24][CH2:23][C@H:22]2[C@H:20]([O:21]2)[CH2:19]1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[Si:16]([O:17][C@@H:18]1[CH2:24][CH2:23][C@H:22]([OH:21])[C@@H:20]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H]2O[C@@H]2C1
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Yield: 68.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-methylpyrazole (500 mg, 6.09 mmol), n-butyl lithium (2.69 M solution in hexane, 2.37 mL, 6.37 mmol), tert-butyl(dimethyl)[(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]hept-3-yloxy]silane (J. Pharm. Pharmacol., 49, 835-842, 1997; 1.32 g, 5.78 mmol) and THF (30 mL), to yield the title compound (1.23 g, 69%) as a colorless solid.