Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([CH3:30])=O)=[CH:23][CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]([C:6]1[N:2]2[N:1]=[C:28]([CH3:30])[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:3]2=[CH:4][CH:5]=1)[CH3:8]
Reactant: CCc1ccc(C(=O)c2ccc(C#N)cc2)n1N
Reactant: COc1ccc(CC(C)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc2c(-c3ccc(C#N)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Temperature: 80 °C
Yield: 20.2 %

Procedure:
To a solution of 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (100 mg) in toluene (1 mL) were added 1-(4-methoxyphenyl)acetone (103 mg) and p-toluene-sulfonic acid monohydrate (16 mg) at ambient temperature. The reaction mixture was heated at 80° C. for 3 hours. The mixture was evaporated in vacuo. The residue was purified by flash silica gel column chromatography eluting with hexane-ethyl acetate=20-1 and 15-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (31 mg, 20.2%) as an yellow solid.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[O:18]=[C:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:29][C:30]([O:32][CH3:33])=[O:31].O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1>>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([C:27]2([OH:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:19]2=[O:18])=[C:47]([OH:51])[CH:46]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)CN1C(=O)C(=O)c2ccccc21
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: COC(=O)CN1C(=O)C(O)(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with methyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 3-chlorophenol, the title compound was obtained (29%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.48 (d, 1H), 7.38 (t, 1H), 7.19 (t, 1H), 7.01 (br, 1H), 6.80-6.64 (m, 3H), 5.28 (br s, 1H), 4.51 (d, 1H), 4.44 (d, 1H), 3.75 (s, 3H); MS (ES+) m/z 370.5 (M+23), 372.4 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26]Cl)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH2:26][C:25]([C:24]3[CH:29]=[CH:30][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=3)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Product: CC(C)(C)c1ccc(C(=O)CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 4-tert-butyl-phenacyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:11]#[N:12])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)c(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(Cl)c(C#N)cn1
Temperature: 120 °C
Yield: 54 %

Procedure:
A suspension of 4-chloro-5-iodo-2-methoxy-pyridine (30.5 g, 0.11 mol), zinc (II) cyanide (7.97 g, 68 mmol), Pd(PPh3)4 (6.56 g, 5.66 mmol) and DMF (450 mL) was degassed and then heated at 120° C. for 1 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM, the organic extract dried (MgSO4), filtered, then concentrated in vacuo. The resultant residue was crystallized from DCM to give the title compound (10.1 g, 54%). The mother liquors were concentrated in vacuo and the residue subjected to flash chromatography (SiO2 gradient 0 to 100% ethyl acetate in cyclohexane) then crystallization from cyclohexane to give the further title compound (5.16 g, 28%, 82% total). 1H NMR 400 MHz (CDCl3) δ: 8.45 (1H, s), 6.90 (1H, s), 4.01 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2>C(O)(=O)C.C(O)C.[Fe]>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ncccc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(Br)c2ncccc12
Reaction time: 0.75 h

Procedure:
At reflux, 10.0 g of 8-bromo-5-nitroquinoline in 68 ml of glacial acetic acid and 34 ml of ethanol were added dropwise to a mixture of 7.75 g of iron powder, 18 ml of glacial acetic acid and 9 ml of ethanol. After stirring for 45 minutes at reflux, the mixture was cooled and filtered through diatomaceous earth. The filtrate was concentrated, taken up in methylene chloride, washed with sodium carbonate solution, dried and concentrated.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:22])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([C:16]2[C:20](=C)[CH:19]=[CH:18][CH:17]=2)[CH2:9]1.[NH4+].[Cl-].Cl>O1CCCC1.O>[CH:16]1([CH:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]([CH3:22])([CH3:7])[CH2:9]2)[CH:17]=[CH:18][CH:19]=[CH:20]1
Reactant: C=C1C=CC=C1C1CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(C2C=CC=C2)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 17 h
Yield: 98.8 %

Procedure:
A 500 mL flask was charged with LiAlH4 (2.50 g, 65.9 mmol) and 200 mL tetrahydrofuran. An addition funnel containing 3,3,5,5-tetramethylcyclohexylfulvene (11.89 g, 58.8 mmol) dissolved in 50 mL tetrahydrofuran was attached. The vessel was cooled to 0° C. before dropwise addition over 25 minutes. After 17 hours of stirring at room temperature, the vessel was cooled to 0° C. and 20 mL of water were added dropwise. Then, aqueous NH4Cl (100 mL) and water (200 mL) were added before the organic layer was isolated. 15 mL of concentrated aqueous HCl were added to the aqueous layer and it was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and rotavapped to provide 11.87 grams of product (98.8%) as a light orange oil. MS (GC-MS) m/z 204.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28](O)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:28][OH:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(-c3ccco3)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a solution of 1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylic acid (0.1 g, 0.235 mmol) in THF (2 mL) at 0° C. was added dropwise 1M borane-THF complex (0.7 mL). The mixture was stirred at room temperature for 3 hours. The solution was added water (1 mL) and ethyl acetate (20 mL), and the mixture was washed with 1N HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (1/1) to give the title compound (0.051 g, 52.6% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[N:14]=[CH:15][N:16]3[CH:20]=[CH:19][S:18][C:17]=23)[CH2:10][C@@H:9](O)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:53]([OH:61])(=[S:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[N:14]=[CH:15][N:16]3[CH:20]=[CH:19][S:18][C:17]=23)[CH2:10][C@H:9]([S:60][C:53](=[O:61])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ncn2ccsc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1ncn2ccsc12
Reaction time: 1.5 h

Procedure:
A solution of 134 mg of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-7-yl)methylpyrrolidine in 8 ml of THF is ice-cooled. Triphenylphosphine (228 mg) and 0.139 ml of diethyl azodicarboxylate are added in an argon atmosphere. The mixture is stirred at that temperature for 1.5 hr, 0.104 ml of thiobenzoic acid is added thereto, and the mixture is stirred at that temperature for 20 min and then at room temperature for 3 hr. The reaction solution is diluted with 30 ml of ethyl acetate, saline is added thereto, the mixture is adjusted to pH 9 by addition of a saturated aqueous sodium hydrogencarbonate solution, and the organic layer is separated. The organic layer is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on silica gel (toluene:ethyl acetate=1:1→chloroform:ethyl acetate 2:1) to give 147 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)(=[O:3])[CH3:2]>C(O)C.C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)NCC1CNCCO1
Temperature: 60 °C
Reaction time: 22 h
Yield: 122.4 %

Procedure:
In a solution of 2-(N-acetylaminomethyl)-4-benzylmorpholine (20 g, 80.7 mmol) in ethanol-acetic acid (20/1, 210 ml) was suspended 2.0 g of 10% palladium-carbon and the mixture was stirred at 60° C. under hydrogen stream for 22 hours. The reaction mixture was filtered with Celite, the solvent was distilled off from the filtrate under reduced pressure to give crude 2-(N-acetylaminomethyl)morpholine (15.62 g). Yield=100%. This compound was used for the subsequent reaction without purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](S)C1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 130 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 1.93 g, 5.69 mmol), (S)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (STEP C, 7.42 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (165 mg, 0.285 mmol), tris(dibenzylideneacetone)dipalladium(0) (130 mg, 0.142 mmol) and N,N-diisopropylethylamine (1.10 g, 8.54 mmol) in 1,4-dioxane (25 mL) was stirred at 130° C. for 18 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (pre-treatment with triethylamine, hexane-ethyl acetate, gradient) to give the title compound (1.83 g, 70%) as a brown oil.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Br[CH:22]1[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[S:23]1>C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]([CH:22]2[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)[S:23]2)[C:2](=[O:3])[N:4]=1
Reactant: Cc1ccc(COC[C@H]2SC(Br)[C@@H](F)[C@@H]2OCc2ccc(C)cc2)cc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: Cc1ccc(COC[C@H]2SC(n3ccc(N)nc3=O)[C@@H](F)[C@@H]2OCc2ccc(C)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To another reaction vessel, 0.10 g of cytosine and 0.58 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80° C. for 1.5 hours. After cooling in air, the methylene chloride solution containing (3S,4S,5R)-2-bromo-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)meth yl)thiolane was added to the reaction mixture, and the obtained mixture was then stirred at 60° C. for 2.5 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was washed with a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10), so as to obtain 72 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolane in the form of a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:68])/[C:30](=[N:56]\[O:57][C:58]([C:61]([O:63]C(C)(C)C)=[O:62])([CH3:60])[CH3:59])/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)[C:26](=[O:69])[N:17]2[C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])[CH3:9]>C1(OC)C=CC=CC=1>[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:68])/[C:30](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:56]\[O:57][C:58]([C:61]([OH:63])=[O:62])([CH3:60])[CH3:59])[C:26](=[O:69])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Trifluoroacetic acid (18 ml) was added to a solution of the product of Stage (a) (2.4 g) in anisole (18 ml) at 0°. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The pH of the aqueous extracts was adjusted to 6, and the solution washed with ethyl acetate. The aqueous phase was acidified to pH 1.5 under ethyl acetate, saturated with sodium chloride, and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated. The residue was dissolved in warm 50% aqueous formic acid (20 ml) and allowed to stand for 2 hours. The mixture was diluted with water (50 ml). and filtered. The filtrate was concentrated. The residue was taken up in water (50 ml), refiltered, and lyophilized to give the title compound (920 mg), λmax (pH 6 buffer) 236 nm (E1 cm1% 250), λinf 255 nm (E1 cm1% 235), 296 nm (E1 cm1% 103); [α]D20 +20.0° (c 1.0, DMSO).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14][OH:15])=[CH:9][C:8]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:34]=[C:33]([C:35]([C:37]([F:40])([F:39])[F:38])=[CH2:36])[CH:32]=[C:31]([Cl:41])[C:28]=1[C:29]#[N:30].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:36][C:35]([C:33]3[CH:32]=[C:31]([Cl:41])[C:28]([C:29]#[N:30])=[C:27]([Cl:26])[CH:34]=3)([C:37]([F:38])([F:40])[F:39])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C=NO)ccc1C(=O)OC(C)(C)C
Reactant: C=C(c1cc(Cl)c(C#N)c(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)c(C#N)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 4-(hydroxyimino-methyl)-2-methyl-benzoic acid tert-butyl ester (1.47 g) in N, N-dimethylformamide (13 ml) was added N-chlorosuccinimide (“NCS”) (832 mg). The reaction mixture was stirred at ambient temperature for 2 hours. More N-chlorosuccinimide (“NCS”) (850 mg) was added and the reaction mixture was stirred at ambient temperature for 1 hour. A solution of 2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g) and triethylamine (0.72 ml) in N,N-dimethylformamide (13 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for 17 hours. Water and ethyl acetate were added and the phases were separated. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel to give 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (0.902 g). 19F-NMR (CDCl3, 75 MHz): −78.93 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1>C1COCC1.[Cl-].[NH4+].O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[O:2][CH3:1])[C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC)nccc3c2)c(OC)c1
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (117 mg, 0.466 mmol) and THF (1944 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (466 μl, 0.466 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 200.53 mg, 0.389 mmol) in THF (1 mL with a 0.5 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min, the mixture was diluted with saturated aq ammonium chloride and water, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 25-micron column, 25-75% EtOAc/Heptane) to give 1-(4-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (217 mg, 0.372 mmol, 96% yield) as a white foam. m/z (ESI) 583.0 (M+H)+.
Reaction SMILES: [CH2:1](/[C:3](/[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)=[CH:4]\[C:5]#[CH:6])[CH3:2].[H-].[Na+].[C:16]([O:24][CH2:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[CH2:34][O:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:16]([O:24][CH2:25][C:26]1[CH:31]=[C:30]([CH2:32][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7](/[C:3](/[CH2:1][CH3:2])=[CH:4]/[C:5]#[CH:6])[CH:8]=2)[CH:29]=[CH:28][C:27]=1[CH2:34][O:35][C:36](=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#C/C=C(\CC)c1cccc(O)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#C/C=C(\CC)c1cccc(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
610 mg (3.5 mmol) of 3-((E)-1-ethylbut-1-en-3-ynyl)phenol are dissolved in 80 ml of DMF. 150 mg (3.7 mmol) of sodium hydride are added, and the mixture is stirred at ambient temperature. 1.5 g (6.2 mmol) of 2-benzoyloxymethyl-5-bromomethylbenzyl benzoate are then added, and the medium is stirred for 2 hours. After the usual treatment and purification by chromatography on a silica gel column, a colorless oil is obtained (m=1.66 g; Y=88%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=C=O.C[N:23]([CH:25]=[O:26])C>>[CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].[CH2:15]([C:25]([NH2:23])=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CN(C)C=O
Reactant: CCCCCCCN=C=O
Agent: CCCCN1CC(=O)NC1=O
Product: CCCCCCCC(N)=O

Procedure:
1-Butylimidazolidine-2,4-dione (100 mg, 0.64 mmol) and 1-isocyanatoheptane (108.5 mg, 0.768 mmol) were reacted in DMF in analogy to example 1. Yield: 15 mg (8%), M+H+: 298.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:26]([F:29])([F:28])[F:27])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:26]([F:27])([F:29])[F:28])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
After adding 3.00 g of toluene to 1.00 g (2.19 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, 0.52 g (4.39 mmol) of thionyl chloride and 0.35 g (4.39 mmol) of pyridine were added at 80° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.18 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.92 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 99.4%).