Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23]C3CCCCO3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30](O)=[O:31].[OH:34][N:35]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>ClCCl.CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[OH:34][NH:35][C:30]([CH:3]1[C:2]([CH3:33])([CH3:1])[S:7][CH2:6][CH2:5][N:4]1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][OH:23])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:31]
Reactant: On1nnc2ccccc21
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 207.7 %

Procedure:
To a solution of 0.33 g (0.663 mmol) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid (Step 5, Example 243) and 0.108 g (0.796 mmol) of 1-hydroxybenzotriazole in 3 mL of dichloromethane and 1 mL of DMF was added 0.169 g (0.88 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the reaction was stirred at room temperature for 1 h. Then 0.203 mL (3.31 mmol) of 50% aqueous hydroxylamine was added and the reaction was stirred for 18 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 10 mL of methanol and 0.028 g (0.11 mmol) of pyridinium p-toluenesulfonate was added and the reaction was heated to reflux for 18 h. The reaction was concentrated in vacuo and the residue was chromatographed on silica gel eluting with 2.5% MeOH/CH2Cl2 to provide 0.59 g (21%) of N-hydroxy-4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide as a white solid. Electrospray Mass Spec: 429.1 (M+H)+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.I[C:28]1[CH:29]=[CH:30][C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3.[C:41](#[N:44])[CH:42]=[CH2:43]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CCCCCC.O1CCOCC1>[C:41]([CH:42]=[CH:43][C:28]1[CH:29]=[CH:30][C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3)#[N:44]
Reactant: C=CC#N
Reactant: Ic1ccc2[nH]c3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#CC=Cc1ccc2[nH]c3ccccc3c2c1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 18.2 %

Procedure:
To a dioxane solution (10 mL) of triphenylphosphine (139 mg, 0.53 μmol), palladium acetate (40.0 mg, 0.18 μmol) and triethylamine (0.59 μL, 4.23 mmol) were added in this order. The mixture was stirred for 5 minutes at 75° C. A dioxane solution (15 mL) of the compound (1) (1.03 g, 3.52 mmol) and acrylonitrile (0.46 μL, 7.04 mmol) were added thereto, and the reaction solution was heated to reflux for 11.5 hours. Generation of a product was confirmed by TLC (HexH:AcOEt=4:1), and then palladium powder was removed by cotton filtration. The residue was purified by column chromatography (HexH:AcOEt=4:1), and compound (2) (0.14 g, 18%, trans:cis=97:3) was obtained as a white powder. Thus, compound (1) (0.37 g, recovery rate 37%) was recovered as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([F:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:1][C:2]2[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[C:23]([F:28])[CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 10 step (ii).
Reaction SMILES: [Cl-].[NH4+].C1O[C:6]2([C:14]3[C:9](=[CH:10][C:11]([N+:21]([O-])=O)=[C:12]([S:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)[CH:13]=3)[CH2:8][CH2:7]2)[O:5]C1>C(O)C.O.[Fe]>[NH2:21][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[S:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[C:6](=[O:5])[CH2:7][CH2:8]2
Reactant: O=[N+]([O-])c1cc2c(cc1Sc1nccs1)C1(CC2)OCCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc2c(cc1Sc1nccs1)C(=O)CC2
Yield: 69.7 %

Procedure:
Iron powder (265 mg, 4.7 mmol), ammonium chloride (35 mg, 0.65 mmol) and the nitroindane from Step 7 (275 mg, 0.82 mmol) were mixed together in ethanol (5 ml) and water (2.5 mL). The mixture was refluxed for l h and then filtered through celite, washing the cake with EtOAc. The volatile, s were removed in vacuo and the residue was dissolved in EtOAc:CH2Cl2 (3:1), washed with brine and dried over MgSO4. Evaporation of the solvent left a residue that was purified by flash chromatography on silica gel (EtOAc:toluene:CH2Cl2 from 30:50:20 to 1:1:1 ) to give 150 mg of the title compound.
Reaction SMILES: N1C=CC=CC=1.[Br:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:9](Cl)=[O:10].[CH3:19][C:20]([NH:29][CH2:30][C:31]([CH3:33])=[CH2:32])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21].O>ClCCl>[CH3:21][C:20]([N:29]([CH2:30][C:31]([CH3:33])=[CH2:32])[C:9](=[O:10])[CH:8]([Br:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:19]
Reactant: C=C(C)CNC(C)(C)c1cccc(Cl)c1
Reactant: O=C(Cl)C(Br)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)CN(C(=O)C(Br)c1ccccc1F)C(C)(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
In 30 ml of dichloromethane containing 2.8 g of pyridine, 4.0 g of 2-bromo-2-(2-fluorophenyl)acetyl chloride were added dropwise to 2.5 g of N-[1-methyl-1-(3-chlorophenyl)ethyl]-2-methyl-2-propenylamine at 10° to 15° C. After stirring at room temperature for 1 hour, the solution was poured into water, and extraction was then made with dichloromethane. The resultant extract was washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. After concentration, column chromatography was done to obtain 2.0 g of the desired N-[1-methyl-1-(3-chlorophenyl)ethyl]-N-(2-methyl-2-propenyl)-2-bromo-2-(2-fluorophenyl)acetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].C(Cl)(Cl)[Cl:14]>>[Cl:14][C:7](=[N:8][OH:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Reactant: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Yield: 93.7 %

Procedure:
32.9 g (0.2 mol) of 3-nitrobenzaldoxime was suspended in 150 g of chloroform and chlorine gas was bubbled into the suspension while maintaining the reaction mixture at a temperature of from 5° to 10° C. 3-Nitrobenzaldoxime went into solution showing a green color upon reaction with chlorine to give a reaction mixture having a deep green color. The reaction mixture turned a pale yellowish-brown upon standing; chloroform was then removed from the reaction mixture under reduced pressure to give 37.6 g of pale yellow crystals having a melting point of 98°-101° C. Yield, 94%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[F-].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[C:9]([CH3:10])=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1ccc(C#N)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(C#N)ccc2C)c1
Reaction time: 12 h
Yield: 98.1 %

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (3.30 g, 20 mmol), 3-methoxyphenylboronic acid (4.56 g, 30 mmol), palladium acetate (89.8 mg, 0.4 mmol), 2-dicyclohexylphosphanyl-2′-dimethylaminobiphenyl (0.236 g, 0.6 mmol), and CsF (9.11 g, 60 mmol) in dioxane (60 mL) at room temperature was stirred for 12 hours, and concentrated. The concentrate was dissolved in ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexane to provide 4.38 g (98%) of the desired product. MS (DCI/NH3) m/z 241 (M+NH4)+; 1H NMR (CDCl3) δ 7.55-7.52 (m, 2H), 7.38-7.33 (m, 2H), 6.94 (m, 1H), 6.86 (m, 1H), 6.80 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:9][CH:8]=1
Reactant: Oc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of imidazole (2.3 g, 34 mmole) and 4-bromonaphthol (13, 5.0 g, 22 mmole) in DMF (10 mL) at 0° C. was added t-butyldimethylsilyl chloride (3.7 g, 24.6 mmole) in several portions. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was partitioned between Et2O (500 mL) and water (300 mL) and the aqueous layer was back-extracted with Et2O (300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to afford (4-bromonaphthalen-1-yloxy)(tert-butyl)dimethylsilane (14, 6.4 g, 85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.21-8.14 (m, 2H), 7.61-7.49 (m, 3H), 6.74 (d, J=8.2 Hz, 1H), 1.10 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:25]1OC(O)C[O:27][CH:26]1O.CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH2:25][CH2:26][OH:27]
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: OC1COC(O)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCO)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 56.2 %

Procedure:
A solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (350 mg, 1.05 mmol), glycolaldehyde dimer (130 mg, 1.05 mmol) and AcOH (0.15 ml, 2.1 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. Saturated aqueous sodium carbonate (10 ml) and DCM (10 ml) were added and the mixture was shaken and partitioned. The aqueous phase was extracted with DCM (2×10 ml) and the combined organics dried (K2CO3), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (223 mg, 0.59 mmol, 56%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.90 (m, 6H), 1.96 (s, 3H), 2.00 (quintet, 2H), 2.14 (m, 2H), 2.37 (t, 2H), 2.40-2.60 (m, 6H), 2.65 (t, 2H), 3.35 (t, 2H), 3.50 (m, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.89 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 377.2796 [MH]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.O>O1CCCC1>[C:18]([O:17][C:15]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(CCN)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mL tetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC2O. The mixture was stirred for about 16 h at 22° C. and 100 mL of water was added. The mixture was extracted with ethyl acetate (2×100 mL) and the organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 20% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was further converted to 2d in a manner analogous to Method B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCCN(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of bromobenzene (0.82 mL, 0.0078 mol), (3S)-piperidine-3-carboxylic acid hydrochloride (6.5 mmol, 0.0065 mol), sodium tert-butoxide (1.2 g, 0.013 mol), palladium acetate (40 mg, 0.0002 mol) and 2-(di-tert-butylphosphino)biphenyl (60 mg, 0.0002 mol) was degassed under vacuum and charged with nitrogen. To the mixture was added 1,4-dioxane (20 mL, 0.2 mol) and the resulting mixture was refluxed overnight. After cooling the reaction mixture to ambient temperature, the mixture was filtered and the filtrate was adjusted with TFA to pH=3.0 and extracted with EtOAc. The crude product was used in the following step without further purification.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([CH3:23])([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:23][C:4]1([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH:3]=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(O)c2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)C=Cc2ccccc2O1
Yield: 84.8 %

Procedure:
A mixture of 1 g of 4-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 2), 70 mg of p-toluenesulfonic acid monohydrate and 10 ml of benzene was heated under reflux for 45 minutes. At the end of this time, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 20:1 by volume mixture of hexane and ethyl acetate, to afford 800 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][CH:6]([C:8](O)=[O:9])[CH2:5]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8]([CH:6]1[CH2:7][CH:4]([CH2:3][C:2]([CH3:12])([CH3:11])[CH3:1])[CH2:5]1)=[O:9]
Reactant: CNOC
Reactant: CC(C)(C)CC1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(CC(C)(C)C)C1
Yield: 101 %

Procedure:
3-(2,2-Dimethylpropyl)cyclobutanecarboxylic acid (75.2 g) and DMF (600 mL) were mixed. After an addition of N,O-dimethylhydroxylamine hydrochloride (51.7 g), triethylamine (92.4 mL), HOBt.H2O (81.2 g) and WSC.HCl (101.6 g) to the mixture, the mixture was stirred at RT overnight. Water was poured into the reaction and the mixture was extracted with ethyl acetate/hexane=1/1. The organic layer was washed with 1 N hydrochloric acid, water, aqueous 10 w/v % sodium carbonate and water, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (95.2 g) as a crude product.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][C:21]#[CH:22].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH2:22]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: C#CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 0.83 g of 1-bromo-2-propyne were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 2-(2-propynyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (76)).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13]Br>CO>[Br:11][CH2:12][CH2:13][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
To a solution of hydroquinone (1.0 g, 9 mmol) in MeOH (15 mL), KOH (1.02 g, 9 mmol) was added and stirred at room temperature for 30 minutes under argon. 1,2-dibromoethane (0.98 mL, 11.3 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was refluxed for 12 hours. The reaction mixture was concentrated and was then quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layer was washed with water, brine, and dried over Na2SO4. The solvent was evaporated to give a colorless oil, which was purified by column chromatography to isolate the intermediate 5a as a white solid (0.39 g, 1.79 mmol, 20% yield). 1H NMR (CDCl3, 400 MHz) δ 6.78-6.85 (m, 4H), 4.53 (s, 1H), 4.26 (t, J=6.4 Hz, 2H), 3.63 (t, J=6.4 Hz, 2H).
Reaction SMILES: C(C1SC(C2SC(NC(=O)C)=C(C)N=2)=CC=1)=O.[CH:18]([C:20]1[S:24][C:23]([C:25]2[S:29][C:28]([NH:30][C:31](=[O:33])[CH3:32])=[N:27][C:26]=2[CH3:34])=[CH:22][CH:21]=1)=O.Cl.[NH2:36][OH:37].N1C=CC=CC=1>C1COCC1.C(O)C>[OH:37][N:36]=[CH:18][C:20]1[S:24][C:23]([C:25]2[S:29][C:28]([NH:30][C:31](=[O:33])[CH3:32])=[N:27][C:26]=2[CH3:34])=[CH:22][CH:21]=1
Reactant: NO
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Agent: CC(=O)Nc1sc(-c2ccc(C=O)s2)nc1C
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(C=NO)s2)s1
Temperature: 70 °C

Procedure:
N-[2-(5-Formyl-thiophen-2-yl)-4-methyl-thiazol-5-yl]-acetamide, Compound (1) (104 mg; 0.39 mmol; 1 eq.), is dissolved in a THF/Ethanol 1:1 mixture (10 ml) at room temperature. Hydroxylamine hydrochloride (275 mg; 3.9 mmol; 10 eq.) and pyridine (310 μl; 3.9 mmol; 10.0 eq.) are added and reaction mixture is heated at 70° C. for 30 minutes. Reaction mixture is cooled down to room temperature and solvents are evaporated. The crude material is dissolved in dichloromethane and filtrated through a small silica cartridge, affording Compound (14) as mixture of oxime isomers, a yellow solid (55 mg; 55%). 1H NMR (MeOH-d4, 300 MHz) δ 2.25 (s, 3H), 2.50 (s, 3H), 6.65 (s, 1H), 7.12 (d, J=6 Hz, 1H), 7.40 (d, J=6 Hz, 1H), 7.72 (s, 1H). M−(ESI): 280.36; M+(ESI): 282.40. HPLC, Rt: 2.64 min (purity: 87.8%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.CCCCCC.C(=O)(O)[O-].[Na+]>C1COCC1>[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]#[CH:2])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of the compound of step 1b above (27.1 g, 76.3 mmol) and THF (550 mL) was cooled to -75° C. Under a nitrogen atmosphere, a 2.5 M solution of n-butyllithium in hexane (62.6 mL, 156 mmol) was added dropwise over a 15 minute period. After stirring for 1 hour, saturated aqueous sodium bicarbonate was added dropwise to the reaction flask. The dry ice bath was removed and an additional portion of saturated aqueous sodium bicarbonate was added. The mixture was extracted with EtOAc (3×) and the combined organic phases dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with Et2O/hexane (1:6 to 1:5) to give 11.5 g (77% yield) of the title compound (1c) as an oil: [α]D≤ -92.1 (c 2.20, MeC)H); 1H NMR (CDCl3, 300 MHz) δ 4.45 (m, 1H), 3.53-3.24 (m, 2H), 2.25-1.85 (m, 5H), 1.48 (s, 9H); MS (CI) m/e 196 (M+H)+.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][NH:2]1.CN(C)CCCN.[C:14]([N:22]1[C:26]2[N:27]=[CH:28][C:29]3[C:30](OC4C=CC=CC=4)=[N:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[C:34]=3[C:25]=2[CH:24]=[N:23]1)(=O)[C:15]1C=CC=CC=1>>[CH2:14]([N:22]1[C:26]2[N:27]=[CH:28][C:29]3[C:30]([N:1]4[CH:6]=[CH:5][CH2:4][CH2:3][NH:2]4)=[N:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[C:34]=3[C:25]=2[CH:24]=[N:23]1)[CH3:15]
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Reactant: C1=CNNC=C1
Agent: CN(C)CCCN
Product: CCn1ncc2c1ncc1c(N3C=CCCN3)nc3ncnn3c12

Procedure:
By substituting dihydropyridazine for the 3-(dimethylamino)propylamine in the procedure of Example 1 (c), 8-ethyl-5-(dihydropyridazin-1-yl)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[C:5]=2[N:6]=1>CCS>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:5]=2[N:6]=1
Reactant: COc1cccc2sc(N)nc12
Solvent: CCS
Product: Nc1nc2c(O)cccc2s1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of AICl3 (5 mmole) in EtSH (10 mL) was cooled to 0° C. and treated with 2-amino-4-methoxybenzothiazole (1 mmole). The mixture was stirred at 0-5° C. for 2 h. Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as white solid.