Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.[CH2:18]([O:25][CH2:26][C:27](Cl)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([O:25][CH2:26][C:27]([NH:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)COCc2ccccc2)sc1C(=O)O
Temperature: 80 °C

Procedure:
300 mg (1.90 mmol) 2-Amino-4-methylthiazole-5-carboxylic acid and 0.67 mL (6.07 mmol) N-methylmorpholine are added to 20 mL DMF. After adding 0.32 mL (2.09 mmol) benzyloxyacetyl chloride the resulting mixture is stirred at 80° C. over night. Then the mixture is callowed to cool to r.t. and slightly acidified with aq. HCl solution (c=1 mol/L). The solvent is removed in vacuo, water is added and the suspension is stirred for 10 min before the precipitate is filtered off and dried.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:15][C@@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].O>CO>[C@@H:16]1([N:15]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:30])[CH:28]=[CH2:29])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC(=O)N(CCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.42 h

Procedure:
62.5 mmol (6.63 g) of sodium carbonate are added to 24 mmol (7 g) of N-octyl-β-D-glucopyranosylamine in 100 ml of methanol at 30° C.; 48 mmol (3.9 ml) of acryloyl chloride are run in at 0° C. over 5 minutes into the heterogeneous mixture. The reaction mixture is left at ambient temperature with stirring for 25 minutes. After addition of 100 ml of water and evaporation of the methanol the acrylamidosugar is extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3. dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(Br)cc1
Product: N#Cc1cc(Br)ccn1

Procedure:
The title compound was prepared from 4-bromopyridine-1-oxide (Rec. Trav. chim., 1951, 70, 581) and trimethylsilyl cyanide, using the procedure described in Chem. Pharm. Bull., 1985, 33, 565, and obtained as a solid (49% yield), m.p. 88°-93° C. Rf 0.53 (SS 11). Found: C,39.15; H,1.50; N,15.07. C6H3BrN2 requires C,39.37; E,1.65; N,15.30%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[C:6]([CH:7]=O)=[CH:5][N:4]=1.[NH3:17]>CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:9]([CH:10]=1)=[CH:11][CH:12]=[N:17][CH:7]=2
Reactant: N
Reactant: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Solvent: CO
Product: COc1cc2ccncc2cn1

Procedure:
6-Methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde (0.25 g, 1.1 mmol) and 7M ammonia in MeOH (5 mL) were stirred in a sealed vial at 80° C. overnight. The solution was concentrated, taken up in saturated sodium carbonate and extracted with ether. The organic phase was dried, filtered and concentrated to give 0.20 g of the title product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O.O>CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:9][N:10]([C:20]([NH2:19])=[O:21])[CH2:11]2)=[CH:12][CH:13]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of 9.6 g (0.025 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine 56.66% (contains diphenylmethane) in 50 ml of acetone was treated with 4.22 g (0.045 mole) of nitrourea and 5 ml of water. The mixture was heated on a hot plate until a clear solution was obtained then allowed to cool to ambient temperature during the next 4 hr. The reaction mixture was diluted with 200 ml of ice water and an oil separated (diphenylmethane) which was dissolved in 30/60 petroleum ether and separated. Upon standing, a fine white precipitate formed in the aqueous solution. Filtration yielded 3.6 g of fine white crystals, m.p. 176°-178° C. After drying under 0.5 mm Hg vacuum at 80° C., the product weight was reduced to 3.1 g (47.7%), m.p. 178°-179° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:11][CH:12]\1[OH:13].[C:33]([OH:36])(=[O:35])[CH3:34]>ClCCl>[C:33]([OH:36])(=[O:35])[CH3:34].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][NH:9][CH2:10][CH2:11][CH:12]\1[OH:13]
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccco1
Solvent: CC(=O)O
Solvent: ClCCl
Product: OC1CCNC/C1=C\c1ccco1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-3-[(furan-2-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (3.70 g) in dichloromethane (75 ml) was added acetic acid (10 ml) under ice-cooling, and the resulting mixture was stirred at 60° C. for 3 hours. After stirring, acetic acid (10 ml) was added to the reaction mixture, and the resulting mixture was furthermore stirred at 60° C. for 1.5 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:19 to 1:9) as the eluent to afford the title compound (2.81 g, yield: quantitative) as a pale brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]#[N:15]>CN(C)C=O.C(OCC)(=O)C>[N:1]1([CH2:13][C:14]#[N:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
A 0° C. solution of indole (7 g, 59.8 mmol) in 200 ml of dimethylformamide is treated with NaH (60% dispersion in mineral oil; 3.1 g, 77.7 mmol). After 20 minutes, bromoacetonitrile (4.2 ml, 59.8 mmol) is added, and the resulting mixture is allowed to slowly warm to ambient temperature and stir overnight. The reaction mixture is diluted with ethyl acetate (500 ml) and washed with H2O (3×200 ml). The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude residue is purified by flash chromatography (SiO2; 5% then 20% ethyl acetate in hexanes) to give 2.53 g of indol-1-yl-acetonitrile (27%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=O.[CH:12](=O)[CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:12]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:9]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)CCCCCBr
Product: CC(C)CC=CCCCCCO
Yield: 50 %

Procedure:
9-methyl-6-decen-1-ol was prepared in the same manner according to Example 4 except that 111.56 g (0.5 mol) of ethyl 6-bromohexanoate was used in place of ethyl 5-bromovalerate and 43.07 g (0.5 mol) of isovaleraldehyde was used in place of 2-methyl valeraldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:41]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([OH:41])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(O)c3O2)cc1
Reaction time: 8 h
Yield: 41.4 %

Procedure:
A solution of {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-formyl-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.45 g, 8.95 mmole) in methylene chloride (50 mL) was added dropwise to a solution of m-chloroperoxybenzoic acid (6.45 g, 22.4 mmole) in methylene chloride (120 mL). The reaction was stirred under nitrogen overnight. After dilution to 300 mL in volume, it was washed with saturated sodium bicarbonate (2×200 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to dryness. A H1 NMR spectra was taken of the crude product and it was determined to be the formate ester. Cleavage was effected by stirring in methanol over basic alumina overnight. After filtration and evaporation, the product was purified by column chromatography on silica gel with hexane to remove the impurities, and the product eluted with methylene chloride to give the (R)-enantiomer of the title compound as a yellow oil (1.80 g, 40%). 1H (CDCl3) doublet 7.8 δ (2H); multiplet 7.2-7.4 δ (7H); broad singlet 7.0 δ (1H); doublet 6.4 δ (1H); singlet 5.2 δ (2H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1H); singlet 2.4 6 (3H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28](=[O:41])[N:29]([CH3:40])[C:30](Cl)=[N:31][C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:24]=[CH:25][CH:26]=1>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28](=[O:41])[N:29]([CH3:40])[C:30]([N:7]3[CH2:8][CH2:9][CH2:10][CH:6]3[CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[N:31][C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)NC[C@H]1CCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.78 g, 3.6 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 2.1 mL diisopropylethylamine (12 mmol) was added drop wise, and stirred for 10 min. 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.13 g, 3 mmol) was added in one portion. The mixture was stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was yielded in 1.3 g as pale yellow solid. MS (ES+): 482 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[OH:10][C@@H:11]([CH3:15])[C:12](O)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([C@@H:11]([OH:10])[CH3:15])=[N:9][N:8]=2)[N:3]=1
Reactant: C[C@H](O)C(=O)O
Reactant: NNc1ccc(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](O)c1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), (S)-2-hydroxypropanoic acid (1.06 g, 10 mmol, i.e. L-lactic acid, 85% in water) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was poured off, and the oil residue was suspended in water (10 mL), then basified with 3 N aq. NaOH to pH=10. This aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded the title compound as an off-white solid. MS (ES+): 199/201 (3/1) [MH+]. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=6.8 Hz, 3H), 2.94 (d, J=6.6 Hz, 1H, —OH), 5.51 (m, 1H), 7.15 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([NH:7][C:8](=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])SC)#[N:6]>C(#N)C>[CH2:1]([NH:4][C:8]([NH:7][C:5]#[N:6])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CC#N
Product: C=CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Reaction of allylamine and N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea by the procedure of Example 11 afforded the title compound, m.p. 113°-114° C. (from acetonitrile)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@H]2[C@@H](O)C[N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C@@H:19]([OH:27])[CH2:20][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine 1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.39–7.25, 5.18, 4.99, 4.89, 4.71, 4.55, 4.04, 3.75–3.58, 3.36, 2.69, 2.49, 1.30, 1.15; HRMS (FAB) calcd for C26H28Cl2N4O3+H 515.1616, found 515.1641.
Reaction SMILES: [C:1](=[O:6])(OC)OC.C[O-].[Na+].[NH2:10][C:11]1[C:16]([CH2:17][NH:18][CH3:19])=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>CO.O>[Br:20][C:14]1[CH:13]=[N:12][C:11]2[NH:10][C:1](=[O:6])[N:18]([CH3:19])[CH2:17][C:16]=2[CH:15]=1
Reactant: COC(=O)OC
Reactant: CNCc1cc(Br)cnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1Cc2cc(Br)cnc2NC1=O
Temperature: 50 °C
Yield: 67.1 %

Procedure:
To a solution of dimethyl carbonate (2.14 g, 23.7 mmole) and sodium methoxide (1.0 mL, 4.5 mmole, 25% wt in CH3OH) in CH3OH (25 mL) was added 2-amino-5-bromo-3-(methylaminomethyl)pyridine (I 0.0 g, 4.62 mmole). The reaction was heated at 50° C. overnight, diluted with H2O (1 mL) and concentrated. Toluene was added to the reaction residue and the contents were heated to reflux for 12 hr under a Dean-Stark apparatus. The reaction was cooled to RT, diluted with EtOAc, and washed with H2O. Purification on silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (0.75 g, 67%) as an off-white solid: MS (ES) m/e 243 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.Cl.[OH-:28].[Na+]>>[NH2:3][S:2]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:6]=1[N:5]1[CH2:23][CH2:24][CH2:25][C:4]1=[O:28])[O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=[O:17])(=[O:26])=[O:1]
Reactant: [OH-]
Reactant: COC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Agent: Cl
Agent: [Na+]
Product: NS(=O)(=O)c1cc(Oc2cccc(C(=O)O)c2)ccc1N1CCCC1=O
Temperature: 95 °C

Procedure:
A suspension of the product obtained in Step A (1.1 g, 2.55 mmol) in 18 ml of 1N NaOH is heated at 95° C. until a solution is obtained. The solution is allowed to return to ambient temperature, is acidified with 1N HCl and extracted (CH2Cl2). The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated. The residue is triturated in Et2O; the title product precipitates out and is recovered by filtration.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[CH2:20]([N:27]([CH2:33]O)[CH2:28][Si](C)(C)C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([N:27]1[CH2:33][C@@H:4]([CH2:3][C:2]([F:11])([F:12])[F:1])[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)/C=C/CC(F)(F)F
Reactant: C[Si](C)(C)CN(CO)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CC(F)(F)F
Yield: 98 %

Procedure:
To a stirred solution of ethyl (2E)-5,5,5-trifluoropent-2-enoate (3.0 g, 16.5 mmol) and TFA (0.38 g, 3.3 mmol) in DCM (40 mL) was added dropwise {benzyl[(trimethylsilyl)methyl]amino}methanol (7.8 g, 33 mmol) at 0° C. over a period of 30 min. After the addition, the mixture was refluxed overnight. TLC (petroleum ether:EtOAc 10:1) indicated ethyl (2E)-5,5,5-trifluoropent-2-enoate was consumed. The reaction mixture was washed with sat. NaHCO3 (40 mL), brine (40 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:EtOAc=100:1 to 10:1) to give the title compound (5.1 g, 98% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:11](OC(=O)C)=[O:12]>>[C:7]([C:6]1[N:5]([CH3:9])[N:4]=[C:3]([CH3:10])[C:2]=1[NH:1][CH:11]=[O:12])#[N:8]
Reactant: Cc1nn(C)c(C#N)c1N
Reactant: CC(=O)OC=O
Product: Cc1nn(C)c(C#N)c1NC=O
Reaction time: 8 h
Yield: 74 %

Procedure:
The starting material is obtained by treating 16 g (0.12 mol) of 4-amino-5-cyano-1,3-dimethyl pyrazole [U.S. Pat. No. 3,121,092: CA 60 2030 (1964)] with acetic-formic anhydride (prepared by adding 45 ml of acetic anhydride to 20 ml of 98% formic acid at 50° C.). After standing at room temperature overnight, the solution is evaporated in vacuo. The residue is stirred in ether to give 14.5 g (74%) of N-(5-cyano-1,3-dimethylpyrazol-4-yl) formamide, mp 135° C.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC(=O)OCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Dinitroethane (12 g, 0.10 mol) and potassium hydroxide (6 g, 0.11 mol) were dissolved in 100 mL of water to form a first solution. 500 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Butyl acrylate (36 mL, 0.25 mol) was mixed with 300 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 3 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid butyl 4,4-dinitropentanoate (21.5 g, yield: 87%).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([S-:15])(=[S:14])OCC.[Na+]>CN(C=O)C.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:10]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h
Yield: 112.6 %

Procedure:
A mixture of 2-fluoro-4-iodoaniline (2.4 g, 10 mmol) and sodium O-ethyl carbonodithioate (3.2 g, 20 mmol) in DMF (8 mL) was stirred at 95° C. for 5 h. The reaction mixture was cooled to rt then diluted with water (25 mL) and 1 N aqueous HCl (20 mL). The mixture was stirred at room temperature for 1 h. The resulting precipitate was collected by filtration and washed with water. The solid was dried to afford 6-iodobenzo[d]thiazole-2-thiol as a light yellow solid (3.3 g, 100%). 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J=1.2 Hz, 1H), 7.67 (dd, J=1.8, 8.7 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H). LCMS (ESI) m/z 294 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>ClCCl>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Oc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Oc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenoxy)-2,4-dimethylquinolin-5-ol (0.16 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.20 g) and bromoacetic acid methyl ester (0.88 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 5:1 by volume) gave title compound as an off-white solid, 0.20 g.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:22])([O:14][C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 60.