Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([O:33][C:34]([CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([O:33][C:34]([CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)C1CCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2C(=O)OCc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(benzyloxycarbonyl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.82 minutes; C29H26Cl2N4O4 (565.45); mass spectrum: (M−H)=564/566/568 (chlorine isotope).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[H][H].[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>[Pd].CO.NCC1C=CC=CN=1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][CH2:9][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: [H][H]
Reactant: NCc1ccccn1
Agent: [Pd]
Solvent: CO
Product: OCc1ccc(CNCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
Terephthaldicarboxaldehyde (40.75 g, 0.304 mol), methanol (250 mL), palladium on activated carbon, (10%, 4.24 g) and 2-(aminomethyl)pyridine (3.1 mL, 0.003 mol, 0.01 mol equiv) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 3.5 hours at 38 psi of hydrogen. The mixture was filtered through celite and the cake was washed with methanol. The solution was dried over Na2SO4, filtered, then reduced in volume to ˜200 mL under reduced pressure. To this stirred solution is then added a solution of 2-(aminomethyl)pyridine (28 mL, 0.272 mol, 0.9 mol. Equiv.) in methanol (50 mL) over 15 minutes. This was allowed to stir overnight at room temperature. The solution was transferred to a hydrogenation flask and palladium on activated carbon (10%, 2.60 g, 0.06) was added and the flask was shaken on a Parr hydrogenator for 4 hours at 39 psi of hydrogen. The mixture was filtered through celite and the cake was washed with methanol. The filtrates were then evaporated and the crude material was filtered through silica gel (180 g, 9:1 CH2Cl2:CH3OH) to provide the title compound (67.45 g, 93%) as a yellow oil. 1H NMR (CDCl3) δ 2.28 (br, 2H), 3.82 (s, 2H), 3.90 (s, 2H), 4.65 (s, 2H), 7.16 (br t, 1 H, J=6.0 Hz), 7.26–7.35 (m, 5H), 7.64 (td, 1H, J=7.7, 1.7 Hz), 8.54 (br d, 1H, J=4.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([C:25]([F:28])([F:27])[F:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[OH:30].O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34].BrBr>CO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([C:25]([F:27])([F:28])[F:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[O:30][C@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([OH:35])=[O:34]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(C(F)(F)F)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Solvent: CO
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(C(F)(F)F)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-trifluoromethyl-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenol (Example 61) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp 109-143° C.; [a]D25=+47.99° (10.002 mg/mL CH3OH); NMR (DMSO-d6); δ13.26 (s, 1 H), 8.30 - 8.27 (m, 1 H), 8.06 (d, J =7 Hz, 1 H), 7.87 - 7.81 (m, 3 H), 7.71 - 7.60 (m, 2 H), 7.52 (dd, J=8, 1 Hz, 1 H), 7.43 -7.24 (m, 6 H), 6.60 (d, J=8 Hz, 1 H), 5.33 (t, J=7 Hz, 1 H), 3.41 (d, J=7 Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 698 (8%), 700 (20%) 702 (15%); Anal. Calc. for C32H19Br2F3O3S: C, 54.88, H, 2.74, N, 0.00. Found: C, 55.29, H, 3.11, N, 0.10.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(F)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-fluorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.88-1.98 (m, 3H), 2.03 (s, 1H), 2.26-2.33 (m, 4H), 3.42 (s, 2H), 3.48-3.56 (m, 4H), 4.37 (s, 1 H), 7.27-7.32 (m, 1H), 7.44-7.53 (m, 1H), 7.55-7.62 (m, 1H), 7.66 (d, J=8 Hz, 1H); MS (APCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of 3,3,3-trifluoropropan-1-ol (500 mg, 4.38 mmol) in DCM (10 mL) was added TEA (1.22 mL, 8.77 mmol) followed by dropwise addition of methanesulfonyl chloride (0.51 mL, 6.58 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM and the organic phase washed with brine, dried and concentrated to give crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1) to give 3,3,3-trifluoropropyl methanesulfonate (490 mg, 58.2% yield) as light yellow oil. TLC (petroleum ether/ethyl acetate=3:1), Rf=0.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13](OC)=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:13][OH:14])([CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=CCc2ccccc2C1(CO)CCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of Example 178A (0.3 g, 1 mmol) in tetrahydrofuran (5 mL) was added a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (1.2 mL, 1.2 mmol) dropwise. The solution was stirred at room temperature for 1 h and then quenched carefully with a saturated solution of NH4Cl (5 mL). The mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) afforded product as a colorless oil (0.20 g, 74%). 1H NMR (300 MHz, CDCl3) δ ppm 0.79 (m, 8 H), 1.37 (m, 1 H), 1.55 (m, 1 H), 1.98 (m, 1 H), 3.53 (d, J=3.68 Hz, 2 H), 3.63 (s, 3 H), 3.71 (d, J=10.66 Hz, 1 H), 3.95 (m, 1 H), 5.09 (t, J=3.68 Hz, 1 H), 7.22 (m, 4 H); MS m/z 261.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1.CI.[C:13](OCC)(=O)C>CN(C)C=O>[CH3:13][N:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1
Reactant: c1cc2[nH]ccn2n1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 62% sodium hydride (0.36 g) in N,N-dimethylformamide (6 ml) was added 1H-imidazo[1,2-b]-pyrazole (1 g) under ice-cooling Then, thereto was added dropwise methyl iodide (0.58 ml) at the same temperature After the mixture was stirred at room temperature for 4 hours, ethyl acetate was added thereto The precipitate was filtered off, and the organic solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 1-methyl-1H-imidazo-[1,2-b]pyrazole (0.9 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:44][C:41]3[CH:42]=[CH:43][N:38]=[CH:39][N:40]=3)(=[O:24])=[O:25])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB, 46.12 mg, 0.084 mmol), pyrimidin-4-amine (11.95 mg, 0.126 mmol), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (176 μL, 0.176 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the flask was lowered into an ice bath for 1 h. Glacial acetic acid (2 drops) was added, and the mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (25.2 mg, 0.055 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (br. s., 1 H), 8.65 (s, 1 H), 8.42-8.35 (m, 2 H), 8.09 (dd, J=2.0, 8.8 Hz, 1 H), 7.74 (d, J=8.6 Hz, 1 H), 7.38 (d, J=2.1 Hz, 1 H), 7.31 (dd, J=2.2, 8.6 Hz, 1 H), 7.04 (d, J=6.0 Hz, 1 H), 6.80 (d, J=8.6 Hz, 1 H), 4.38-4.32 (m, 2 H), 3.89-3.84 (m, 2 H). m/z (ESI) 462.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].CCCCCC.C([Li])CCC.Cl[Si:20]([CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]([C:3]1[CH:7]=[CH:6][CH:5]([Si:20]([CH:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)([CH3:22])[CH3:21])[CH:4]=1)[CH3:2]
Reactant: C[Si](C)(Cl)C1C=CC=C1
Reactant: CCC1=CC=CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1=CC([Si](C)(C)C2C=CC=C2)C=C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ethylcyclopentadiene in an amount of 7.52 g (80 mmol) was dissolved in 100 ml of THF, and the solution was cooled to −78° C. A 1.58 M hexane solution of n-butyllithium in a volume of 56 ml (92 mmol) was added thereto dropwise. The mixture was stirred at room temperature for 2 hours and was added dropwise to 50 ml of THF containing 110 mmol of the chloro(cyclopentadienyl)dimethylsilane at −78° C. The temperature was gradually increased, and the mixture was stirred at room temperature for 24 hours and was concentrated under reduced pressure. Insolubles were removed by filtration. The filtrate was washed with hexane and was distilled under reduced pressure. The distillate was subjected to silica gel column chromatography, and 0.86 g of (3-ethylcyclopentadienyl)(cyclopentadienyl)dimethylsilane was obtained. The compound was identified by GC-MS. GC-MS: 216 (MS).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([F:17])[F:16])=[N:12][CH:13]=1)=[CH2:7])CCC.[Br:18]N1C(=O)CCC1=O>C1COCC1.O.O>[Br:18][CH2:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: C=C(OCCCC)c1ccc(OC(F)F)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(OC(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A solution of 100 mg (0.41 mmol) of 5-(1-butoxyvinyl)-2-difluoromethoxypyridine in 4 mL of THF/H2O (3/1: v/v) is cooled to 0° C. 74 mg (0.41 mmol) of N-bromosuccinimide are then added in a single portion. The yellow solution is stirred at 0° C. for 1 hour and then taken up in water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaHCO3 solution and then with saturated NaCl solution, dried over magnesium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 20/80 EtOAc/heptane to 40/60 EtOAc/heptane over 15 minutes) to give 82 mg of 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.Br>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: BrBr
Reactant: Oc1c(F)cccc1F
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: S=C=S
Product: Oc1c(F)cc(Br)cc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of bromine (1.6 g) in dry carbon disulphide (10 cm3) was added over 5 minutes to a solution of 2,6-difluorophenol (1.3 g) in dry carbon disulphide (10 cm3). To the stirred reaction mixture was added 5 drops of 48% hydrogen bromide solution. The mixture was heated for 2 hours at the reflux temperature, then allowed to stand at the ambient temperature (ca 22° C.) for 16 hours. After a further period of heating (4 hours) the mixture was allowed to stand for 24 hours before being poured onto water (20 cm3). To the mixture was added saturated sodium metabisulphite solution (30 cm3). The layers were separated, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3). The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure to given an oil which solidified. The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca. 20 mmHg). The distillate crystallised to give 4-bromo-2,6-difluorophenol as a white solid (0.48 g).
Reaction SMILES: [NH3:1].[Cl-].[NH4+].[CH3:4][C:5](=[O:11])[CH2:6][C:7]([CH3:10])(O)[CH3:8].[CH3:12][C:13]([CH3:15])=O>CO>[CH3:8][C:7]1([CH3:10])[CH2:6][C:5](=[O:11])[CH2:4][C:13]([CH3:15])([CH3:12])[NH:1]1
Reactant: CC(=O)CC(C)(C)O
Reactant: CC(C)=O
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
40 g of ammonia gas is introduced in the course of about 4 hours at 13°-15°C into a mixture consisting of 126 g of acetone, 22.5 g of methanol and 4.7 g of ammonium chloride. The reaction mixture is subsequently stirred for a further 30 minutes at the same temperature. An addition is then made to the reaction mixture of 220 g of diacetone alcohol and 110 g of acetone; the whole is heated within 1 hour to 55°C and held at this temperature for 12 hours. Processing by fractional distillation yields 125 g of 2,2,6,6-tetramethyl-4-oxopiperidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[O:15][CH3:16].O.[OH-].[Li+]>C1COCC1.CO.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[O:15][CH3:16]
Reactant: C=Cc1nc(C(=O)OC)c(OC)c(N)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=Cc1nc(C(=O)O)c(OC)c(N)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
To a solution of methyl 4-amino-5-fluoro-3-methoxy-6-vinylpicolinate (140.0 mg, 0.619 mmol) in THF (1.2 mL), MeOH (1.200 mL), Water (0.600 mL), lithium hydroxide hydrate (78 mg, 1.857 mmol) was charged as a solid. The reaction was allowed to stir at room temperature for 18 hrs. The reaction was concentrated to dryness. The resulting residue was diluted with 2 N HCl and MeOH. The product was purified (C18 10-80% ACN in H2O 12 CV) to yield 4-amino-5-fluoro-3-methoxy-6-vinylpicolinic acid (79 mg, 0.372 mmol, 60.2% yield). ESIMS for m/z 213 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 5.50 (dd, J=11.0, 2.2 Hz, 1H), 6.20 (dd, J=17.3, 2.2 Hz, 1H), 6.35 (s, 2H), 6.83 (ddd, J=17.3, 10.9, 1.7 Hz, 1H), 12.98 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −145.09.
Reaction SMILES: Br[CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH:17]=[CH:16][C:14]=1[O:15][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])[CH:8]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCC(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(CC)Oc1ccc(C=O)cc1OC
Yield: 47 %

Procedure:
3-Bromopentane (1.2 mL, 9.9 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol), potassium carbonate (2.7 g, 20 mmol) in EtOH (10 mL) and treated according to Procedure 3. The crude product was purified by flash chromatography with 10% EtOAc/petrol as eluent to give 3-methoxy-4-(pent-3-yloxy)benzaldehyde (0.69 g, 47%) as a pale yellow oil; δH (400 MHz, CDCl3) 0.96 (t, J=7.2 Hz, 6H, CH3), 1.73 (m, 4H, CH2), 3.88 (s, 3H, OCH3), 4.23 (m, 1H, OCH), 6.94 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (s, 1H, H2), 7.41 (d, J5,6=8.0 Hz, 1H, H6), 9.81 (s, 1H, CHO); δC (100 MHz, CDCl3) 9.6, 26.1, 56.0, 81.9, 109.8, 113.1, 126.5, 129.7, 150.5, 154.0, 190.7; vmax 1133, 1263, 1504, 1582, 1682, 2967 cm−1.
Reaction SMILES: [C:1]1([C:3](=[CH:5][C:6](=[CH:8][CH:9]=1)[CH3:7])[CH3:4])C.[F:10][C:11]([F:24])([F:23])[CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[CH3:21].[OH-:25].[Na+].[OH2:27]>>[OH-:22].[C:21]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:7]1[C:18]2[C:17]([O+:22]=[C:8]3[C:6]=1[CH:5]=[C:3]([CH3:4])[C:1]([NH:14][CH2:13][CH2:12][C:11]([F:10])([F:24])[F:23])=[CH:9]3)=[CH:16][C:15]([NH:14][CH2:13][CH2:12][C:11]([F:23])([F:24])[F:10])=[C:20]([CH3:21])[CH:19]=2)([OH:27])=[O:25]
Reactant: Cc1ccc(C)c(C)c1
Reactant: O
Reactant: Cc1ccc(O)cc1NCCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(-c3ccccc3C(=O)O)c3cc(C)c(NCCC(F)(F)F)cc3[o+]c2cc1NCCC(F)(F)F
Temperature: 100 °C

Procedure:
The pseudocumene layer from alkylation, containing 0.35-0.38 mole of 3-trifluoropropylamino-4-methylphenol was refluxed in a 1 L 3-necked flask fitted with thermometer, stirrer and Dean-Stark trap in order to remove water as the azeotrope. To the dry solution was added 30 g of phthalic anhydride. Condensation was effected by heating at reflux for 20 hours while removing water generated by reaction as the pseudocumene-water azeotrope. The solution turned red. When condensation was complete the solution was cooled to 100° C., 300 ml water and 25 g 50% sodium hydroxide added, and the pseudocumene removed by azeotropic distillation. The red dye which had crystallized out was separated by filtration and washed with 400 ml water (142 g wet paste). This filtercake was reslurried in 400 ml water and 10 g 50% sodium hydroxide, heated 30 minutes at 100° C., filtered again and washed with 400 ml water. Upon drying at 100° C., 40 g of dye zwitterion was obtained which melted at 258°-260° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11]C(=O)OC(C)(C)C)[N:7]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)nn1-c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(CN)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
In 3 mL of dichloromethane, tert-butyl (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methylcarbamate (232 mg, 0.668 mmol, 1 equiv.) was dissolved and trifluoroacetic acid (0.496 mg, 0.331 ml, 6.5 equiv.) was added. The reaction mixture was stirred overnight at room temperature, extracted with aqueous sodium carbonate (c=1 mol/L), dried over magnesium sulfate and evaporated to give (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (127 mg) which was used without further purification.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][OH:23])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].CCOCC>ClCCl>[Si:12]([O:19][CH2:20][CH2:21][CH:22]=[O:23])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
To a suspension of pyridinium chlorochromate (8.50 g, 39.4 mmol) in dichloromethane (53 ml), stirred at room temperature under dry nitrogen, was added 3-(t-butyldimethylsilyloxy)propan-1-ol (5.00 g, 26.3 mmol). After 1.5 hr, dry ether (50 ml) was added and the supernatant liquid decanted from a black gum. The residual gum was washed with ether (3×50 ml) and the combined organic portions passed through a column of Florisil. The resulting brown solution was evaporated then the residue taken up in dichloromethane and passed through fresh Florisil to give a yellow solution from which the solvent was removed to leave a brown liquid (2.75 g). This material was shown by 1Hnmr analysis to be approximately 40% pure and was used without further purification; δH (CDCl3) 0.10 (6H, s, CH3), 0.93 (9H, s, C(CH3)3), 0.63 (2H, dt, J 2 HZ and 6 Hz respectively, CH2), 4.03 (2H, t, J 6 Hz, CH2O ), 9.97 (1H, d, J 2 Hz, CHO).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].OO>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
Into a 100-mL three neck round-bottom flask, was placed a solution of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (compound 244.1, 3.47 g, 12.2 mmol) in tetrahydrofuran (35 mL). Sodium hydroxide (980 mg, 24.5 mmol) was added and then the mixture was cooled to 0° C. Hydrogen peroxide (2.51 mL, 24.4 mmol) was carefully added drop-wise and the resulting mixture was stirred for 2 h at room temperature. The reaction was carefully quenched with aqueous Na2S2O3(sat.) (20 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with brine (2×150 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish the title compound as a white solid (1.64 g, 77%).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].C(Cl)/C=C/C>>[CH3:10][O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:11]/[CH:12]=[CH:13]/[CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: [Li]CCCC
Agent: C/C=C/CCl
Agent: [H-]
Agent: [Na+]
Product: C/C=C/CCC(=O)CC(=O)OC

Procedure:
In accordance with the process of Reference 1, sodium hydride (1.20 g; 50 m mol), methyl acetoacetate (5.70 g; 50 m mol), n-butyl lithium (50 m mol) and trans-crotyl chloride (4.43 g; 50 m mol) were used to obtain 3.60 g of (E)-3-oxo-6-octenoic acid methyl ester.