Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:33])[C@@H:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:48][CH2:49][CH2:50][C:51](=O)[CH2:52][CH2:53][CH3:54].CC(O)=O>C(Cl)Cl>[CH2:5]([C@H:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:15]=1)[C@H:3]([OH:33])[CH2:2][NH:1][CH:51]([CH2:52][CH2:53][CH3:54])[CH2:50][CH2:49][CH3:48])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCC(=O)CCC
Reactant: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN)cc(N2CCCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(CCC)CCC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 92 h
Yield: 11.5 %

Procedure:
To a solution of N-((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (E182) (30 mg, 0.066 mmol, 1 equiv) in (CH2Cl)2 (5 ml) were added sodium triacetoxyborohydride (20 mg, 0.094 mmol, 1.4 equiv), 4-heptanone (10 μl, 0.070 mmol, 1.1 equiv) and CH3COOH (4 μl, 0.070 mmol, 1,1 equiv). The resulting mixture was stirred at room temperature for 92 hours, diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/ethyl acetate: 3/2) gave N-[(1S,2R)-1-benzyl-2-hydroxy-3-(1-propyl-butylamino)-propyl]-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (4.2 mg, 11%) as a colourless oil. [M+H]+=552.2, RT=2.98 min
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH3:26])[C:12]([C:15]2([OH:25])[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.[OH-].[Na+]>O>[Br:8][C:9]1[CH:10]=[C:11]([CH3:26])[C:12]([C:15]2([OH:25])[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]2)=[N:13][CH:14]=1
Reactant: Cc1cc(Br)cnc1C1(O)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(Br)cnc1C1(O)CCC(=O)CC1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
Trifluoroacetic acid (11 ml) and water (1 ml) were added to 8-(5-bromo-3-methylpyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (7.45 g) described in Reference Example 105(1) and stirred at room temperature. After completion of the reaction, water was added and neutralized by the addition of 1N aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxy-cyclohexanone (2.69 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH:16][NH2:17])=[O:15].C(=O)(O)[O-].[Na+].C(=O)=O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][NH:13][C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NNC(=O)NN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Product: NNC(=O)NNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
211 (1.0 mole) p-chlorobenzenesulfonyl chloride was added to a suspension of 45 g (0.5 mole) carbohydrazide and 100 g sodium bicarbonate in 1000 ml ethanol in a 3 liter reaction flask. The mixture was stirred and heated gradually to gentle reflux (80° C) as carbon dioxide was evolved. Heating was continued until CO2 no longer evolved (3hours). The mix was cooled to 20 C and filtered. The mixture of product and sodium chloride was dried at 60° C. Yield = 227 g. The solid mixture was suspended in 2000 ml water, stirred to dissolve the sodium chloride, and then the insoluble product was filtered, washed and dried. Yield = 129 g, m.p. 239-240° C (dec.)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13](F)[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C-:26]#[N:27].[Na+]>CS(C)=O>[C:1]([C:5]1[CH:14]=[C:13]([C:26]#[N:27])[C:12]2[C:11](=[O:16])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[CH2:24][OH:25])[N:9]=[CH:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C#N)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a 100 mL round-bottomed flask were added 6-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-fluorophthalazin-1(2H)-one (671 mg, 1.86 mmol, prepared according to US2010/0222325), sodium cyanide (365 mg, 7.44 mmol) and DMSO (10 mL) to give a light yellow suspension. The mixture was stirred at 80° C. for 16 hrs. Additional sodium cyanide (182 mg, 3.72 mmol) was added and the mixture was further stirred at 80° C. for 60 hrs. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. Solvents were evaporated and the residue was purified through flash column chromatography (220 g silica gel, 0% to 40% acetone in heptane) to give 7-tert-butyl-3-[3-chloro-2-(hydroxymethyl)phenyl]-4-oxo-3,4-dihydrophthalazine-5-carbonitrile as a yellow solid (390 mg, 57% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CN(C)CCOC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 28.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), N,N-dimethyl-2-(piperidin-4-yloxy)ethanamine (85) (0.116 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.087 g, 28.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.62-1.51 (1H, m), 1.84-1.66 (3H, m), 1.95-1.89 (1H, m), 2.28 (6H, s), 2.52 (2H, t), 3.15-3.01 (1H, m), 3.48-3.40 (1H, m), 3.62-3.51 (3H, m), 4.07-3.98 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.32-7.25 (2H, m), 7.77-7.70 (3H, m), 8.47-8.45 (1H, m), 10.62 (1H, s); m/z (LC-MS, ESI+), RT=1.67 (M+H 452).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.CC1(C)C(C)(C)OB([C:28]2[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:11][N:10]1[C:9](=[O:12])[CH2:8][O:7][C:6]2[N:13]=[C:2]([C:28]3[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:30][CH:29]=3)[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:5]1=2
Reactant: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 71.8 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (50 mg, 0.150 mmol) in 1,4-dioxane (2 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.5 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (40 mg, 72% yield). 1H-NMR (500 MHz, CDCl3) δ 7.27-7.32 (5H, m), 7.25 (1H, s), 7.16-7.20 (2H, m), 7.10 (2H, d), 4.89 (2H, s), 4.81 (1H, br s), 4.26 (2H, br s), 3.39 (3H, s), 1.23 (9H, br s). LCMS (Method D): RT=1.40 min, M+H+=446.20.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)C1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 73.6 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 43(a)) (200 mg) and 4-piperidinecarboxylic acid, ethyl ester (470 mg) to afford the sub-titled compound as a solid (200 mg).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].Br[C:14](Br)([F:16])[F:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C)C(=O)C.[Zn]>[F:15][C:14]([F:16])=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCCCCCCCC=O
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
Under an argon atmosphere, a stirred mixture of 101.0 grams (0.60 mole) of 10-undecenal and 251.9 grams (1.20 moles) of dibromodifluoromethane was cooled to 0° to -5° C., and a solution of 314.9 grams (1.20 moles) of triphenylphosphine in 1100 ml of N,N-dimethylacetamide was added dropwise during a five to ten minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for two hours. After this time a small portion from 70.5 grams (1.20 mole) of zinc powder was added to the reaction mixture. The reaction mixture was warmed to approximately 34° C. with an external heat source to initiate further reaction. Upon commencement of the reaction, the reaction mixture temperature rose to 44° C. The remainder of the 70.5 grams of zinc powder was added portionwise during a ten to twenty minute period. Upon completion of addition, the reaction mixture was warmed to 85°-90° C. where it stirred vigorously for two hours. After this time the reaction mixture was cooled to ambient temperature, and 400 ml of water was added. The reaction mixture was stirred for 30 minutes and then was allowed to stand for 18 hours. After this time the reaction mixture was subjected to a steam distillation using pentane as the extraction solvent. The pentane distillate was concentrated under reduced pressure to a residual oil. The residual oil was heated at 94° C. to remove any N,N-dimethylacetamide. The remaining oil was distilled under reduced pressure, yielding 24.3 grams of 1,1-difluoro-1,11-dodecadiene; b.p. 133° C./66 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: COC(C)(C)C.[CH3:7][CH:8]([CH3:20])[C:9]([O:11][CH:12]([O:16][C:17]([CH3:19])=[S:18])[CH:13]([CH3:15])[CH3:14])=[O:10]>O>[CH3:7][CH:8]([CH3:20])[C:9]([O:11][C@@H:12]([O:16][C:17]([CH3:19])=[S:18])[CH:13]([CH3:14])[CH3:15])=[O:10]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: CC(=S)O[C@H](OC(=O)C(C)C)C(C)C
Yield: 70 %

Procedure:
A mixture of 990 mL methyl-tert-butylether (MTBE) and 10 mL water was stirred until a clear solution was obtained (ca. 5 hrs). To this solution was added 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (50 g) and PLE/MPEG (50 mg/1 g, 7.5 g). The resulting suspension was stirred at room temperature. The reaction was monitored by 1H-NMR using a chiral solvating agent. After 1H-NMR showed only one enantiomer remained in the reaction mixture (ca. 48 hrs), the reaction was quenched by filtration through a pad of CELITE® 545. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) and brine, and dried over anhydrous sodium sulfate (Na2SO4). After rotary evaporation, the title compound (12) was obtained with 70% yield. The enantiomeric excess of the S-enantiomer was 100% e.e. as determined by chiral HPLC. 1H-NMR (CDCl3): δ 0.96 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (septet, J=7.2 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H) ppm. 1H-NMR with chiral solvating agent (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: δ 0.98 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 1.19 (d, J=7.2 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=7.2 Hz, 1.5H), 2.01-2.09 (m, 1H), 2.34 1(s, 1.5H), 2.44 (s, 1.5H), 2.59 (septet, J=7.2 Hz, 0.5H), 2.59 (septet, J=6.8 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.70 (d, J=5.2 Hz, 0.5H) ppm.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([OH:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N+:2]=[N-:3].Cl[C:16]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]([CH2:4][CH2:5][CH:6]([O:14][C:16]1[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:7]([F:12])([F:13])[C:8]([F:10])([F:11])[F:9])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCC(O)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)nc1OC(CCN=[N+]=[N-])C(F)(F)C(F)(F)F
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 5-azido-1,1,1,2,2-pentafluoro-3-pentanol (500 mg, 2.28 mmol) in dimethylformamide (10 ml) was added 2-chloro-6-(trifluoromethyl)nicotinonitrile (565 mg, 2.74 mmol) followed by caesium carbonate (2.20 g, 6.75 mmol). The reaction mixture turned brown. After 2 h, the reaction mixture was added to water (10 ml) and extracted with diethyl ether (2×15 ml). The combined organics were washed with brine (20 ml) and dried over anhydrous sodium sulfate. Removal of the solvents yielded a brown liquid. Purification by silica gel chromatography using hexanes/ethyl acetate (10:1 then 1:1) gave the title compound as a yellow liquid (780 mg, 88%).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[C:7]([CH2:8][NH2:9])[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: NCc1cc(-c2ccc(Cl)cc2)cnc1Br
Product: C[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1CN

Procedure:
The product was prepared analogously to Example 7.1c starting from [2-bromo-5-(4-chlorophenyl)pyridin-3-yl]methylamine and trimethylsilylacetylene. Yield: 0.23 g (91% of theoretical); C17H19ClN2Si (M=314.884); calc.: molpeak (M+H)+:315/317 (Cl); found: molpeak (M+H)+:315/317 (Cl).
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[ClH:44].[CH3:45][N:46]([CH3:51])[CH2:47][C:48]([Cl:50])=[O:49].Cl>C(Cl)Cl>[ClH:50].[ClH:44].[Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:48](=[O:49])[CH2:47][N:46]([CH3:51])[CH3:45])[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)CN(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol), triethylamine (0.028 mL, 0.20 mmol), and CH2Cl2 (2 mL). 2-(Dimethylamino)acetyl chloride hydrochloride (12.9 mg, 0.0817 mmol) was added and stirred at room temperature for 10 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (15% MeOH in EtOAc with 0.3% ammonia) to afford 1 the title compound (35.6 mg, 70.1% yield) after HCl salt formation. 1H NMR (d6-DMSO) δ 11.15 (bs, 1H), 9.60 (bs, 1H), 8.17 (d, 1H), 7.75 (m, 1H), 7.32 (m, 2H), 7.21 (t, 1H), 6.94 (d, 1H), 6.79 (m, 1H), 6.75 (s, 1H), 6.71 (m, 2H), 4.42 (d, 1H), 4.31 (qd, 2H), 3.69 (s, 3H), 3.19 (t, 1H), 2.93 (m, 1H), 2.82 (m, 6H), 2.04 (d, 2H), 1.64 (m, 1H), 1.52 (m, 1H). Mass spectrum (apci) m/z=674.3 (M+H-2HCl).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:17])[C:7]=2[CH:18]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:5]1[C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:17])[C:7]=2[CH:18]=[C:3]([CH:2]=[O:1])[CH:4]=1
Reactant: O=S1c2ccccc2C=Cc2ccc(CO)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)S(=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 512 mg (2 mmole) of 3-hydroxymethyldibenzo[b,f]thiepin 5-oxide in 50 ml of methylene chloride and add 648 mg (3 mmole) of pyridinium chlorochromate. Stir at room temperature for 1.5 hours and then filter the mix through a bed of Florisil. Wash the Florisil with dichloromethane; and to the combined filtrate add 4 g of silica gel. Evaporate the suspension to dryness, and place the solid on top of a column of 50 g of silica and elute the title compound with a 1:9 mixture of ethyl acetate and toluene. The compound has a m.p. of 188°-190° C.
Reaction SMILES: C([O:3][C:4](=[O:10])[CH:5](Cl)[C:6]([CH3:8])=O)C.[CH:11]([NH2:13])=[O:12].[OH-].[Na+]>CCOC(C)=O>[CH3:8][C:6]1[N:13]=[CH:11][O:12][C:5]=1[C:4]([OH:3])=[O:10]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ncoc1C(=O)O
Temperature: 120 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120° C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separate. The organic layer was discarded while the aqueous was acidified with conc. (32%) aqueous HCl to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40° C. over night under reduced pressure to give 4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[Cl:17][C:18]([Cl:28])=[CH:19][CH:20]1[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25]([OH:27])=[O:26]>>[Cl:17][C:18]([Cl:28])=[CH:19][CH:20]1[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25]([O:27][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[O:26]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: [Na]
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
In a similar manner, 3-phenoxybenzylchloride is reacted with the sodium salt of 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid, prepared by the process of this invention, to yield 3-phenoxybenzyl 2-(2,2-dichlorovinyl)3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][Cl:6])[CH3:2].Cl.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14][Cl:15])[CH3:11].[OH:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:32])=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[ClH:6].[ClH:15].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][O:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[CH2:16][CH3:17])=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1)[CH3:2]
Reactant: Oc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc2c(c1)Cc1cc(OCCN(CC)CC)ccc1-2
Reaction time: 3 h

Procedure:
A solution of 2-diethylaminoethyl chloride [obtained from 12.9 g (0.075 mole) of 2-diethylaminoethyl chloride hydrochloride] in 100 ml of toluene (dried over molecular sieves) is added to a mixture of 4.9 g (0.025 mole) of 2,7-dihydroxyfluorene and 2.7 g (0.05 mole) of sodium methoxide in 200 ml of toluene (dried over molecular sieves). This mixture is refluxed with stirring for three hours. Upon cooling the mixture is filtered to remove the precipitated sodium chloride. The toluene solution is washed three times with water, then once with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. This mixture is filtered and the filtrate acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, dissolved in butanone with enough methanol added to effect solution, decolorized with charcoal, and the product obtained at 80°C under vacuum, 2,7-bis(2-diethylaminoethoxy)fluorene dihydrochloride. M.P. 213°-216°C.