Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:8]1([C:7]2[C:6]([CH2:5][C:4]([OH:3])=[O:23])=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:33]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: NNc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2Cl)c1-c1ccccc1
Yield: 36.9 %

Procedure:
8.0 grams 3,3-dibenzoyl-propionic acid-ethyl ester, 5.5 grams o-chlorophenylhydrazine hydrochloride, 2.5 grams sodium acetate and 4.0 grams glacial acetic acid were reacted and the reaction product recovered by a procedure analogous to the method set out in Example 21. 3.7 grams 3,5-diphenyl-1-(o-chlorophenyl)-pyrazol-4-acetic acid, melting at 191°-193° C., were obtained, representing a yield of 37%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:31]#[N:32])[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:20][CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:31]#[N:32])[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])=[CH:20][CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
In a 25 ml one necked round bottom flask, N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 0.00019 mol) was taken in CH2Cl2 (10 ml) followed by dropwise addition of TFA (2.0 ml) at 0°-5° C. and the reaction was allowed to stir at room temperature for 24 hr. After completion of the reaction, the pH of the solution was adjusted to neutral by the addition of saturated sodium bicarbonate solution and extracted with CH2Cl2 and the combined organic layer was dried over anhy. sodium sulphate and concentrated to obtain crude mixture which was dissolved in ethanol (10 ml). NaOAc.3H2O (0.242 g, 0.00178) was added and the reaction mixture was stirred at room temperature for 20 hr. Ethanol was distilled out and the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, concentrated to afford crude product which was purified using column purification by eluting the compound with 50% ethyl acetate in hexanes to yield 14.0 mg of N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Reaction SMILES: [Li]CCCC.[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].Br[CH2:22][CH2:23][CH2:24][Cl:25].[NH4+].[Cl-]>O.C1COCC1>[Cl:25][CH2:24][CH2:23][CH2:22][C:8]1([C:6]#[N:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
Charge 1780 g of THF and 86.6 g of diisopropylanmine to R1. Cool the mixture in R1 to −40° C.˜−60° C. Add drop-wise 210.5 g of n-BuLi (1.6 eq) into R1 and stir the mixture for 0.5-1 hour. Charge 890 g of THF then 100.0 g of tert-butyl 4-cyanopiperidine-1-carboxylate into R2. Add the solution of tert-butyl 4-cyanopiperidine-1-carboxylate in R2 drop-wise to R1, controling the temperature at −40° C.˜−60° C. Stir the mixture in R1 for 1˜2 hour. Charge 890 g of THF and 130.5 g of 1-bromo-3-chloro-propane into R2. Add the solution of 1-bromo-3-chloro-propane in R2 drop-wise to R1, control the temperature at −40˜−60° C. Stir the mixture in R1 for 3 hours at −40˜−60° C. then slowly warm the mixture to 20˜25° C. and stir for 13˜16 hours. Cool the mixture to 0˜5° C. Add drop-wise 525 g of NH4Cl (saturated aqueous solution) then 500 g of water into R1. Concentrate the mixture to total weight 1000˜1100 g below 40° C. then add 380 g of MTBE. Stir the mixture at 10˜20° C. for 20-40 minutes then allow to stand for 30˜60 mins Separate the aqueous layer and wash the organic layer with 2×500 g of H2O. Concentrate the mixture to 300 g total weight below 50° C. Add 136 g of n-heptane then concentrate the mixture to 300 g total weight below 50° C. Cool the mixture 0-5° C., then add drop-wise 340 g of n-heptane. Stir the mixture in for 5˜10 hours, then filter the suspension. Rinse the flask with 68.0 g of n-heptane, then wash the cake to provide of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate (118 g, 87.2% Assay, 75.4% yield): mass spectrum (m/z): 231 (M+H-tBu). Transfer the cake to a flask and add 610.0 g of Toluene. Concentrate mixture to 500 g total weight below 50° C. The product is stored as a toluene solution until required.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:18]I>CS(C)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:15])[N:11]([CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Oc1ncccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1cccc(OCc2ccccc2)c1=O
Yield: 94.4 %

Procedure:
To a solution of 3-(benzyloxy)pyridin-2-ol (25 g, 123.00 mmol) and potassium hydroxide (10 g, 178.22 mmol, 1.45 equiv) in dimethylsulfoxide (250 mL) maintained under nitrogen atmosphere was added methyl iodide (27 g, 190.14 mmol) dropwise with stirring. The resulting solution was stirred overnight at room temperature then concentrated under vacuum. The residue was diluted with water (500 mL) then extracted with dichloromethane (2×400 mL). The combined organic layer was washed with water (3×500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (25 g, 93%) as a light brown oil: 1H NMR (400 MHz, DMSO) delta 7.44-7.32 (m, 5H), 7.29-7.27 (m, 1H), 6.91-6.88 (m, 1H), 6.12-6.09 (m, 1H), 5.02 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([CH:5]2[CH2:9][CH2:8][CH2:7][N:6]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:17]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1csc(N)n1

Procedure:
An ethanol (20 mL) solution of tert-butyl 2-(2-chloroacetyl)pyrrolidine-1-carboxylate (1.08 g, 4.4 mol) and thiourea (334 mg, 4.4 mmol) was stirred at 55 C for 70 hours. Upon completion of the condensation, the solution was evaporated. The solid was dissolved in CH2Cl2 (100 mL). It was washed with dilute NaHCO3 solution, dried and evaporated. Recrystallization from CH2Cl2/hexane afforded tert-butyl 2-(2-aminothiazol-4-yl)pyrrolidine-1-carboxylate. 1H NMR (400 MHz, CDCl3): mixture of rotamers: δ 8.81 (s, 2H, br), 6.22 and 6.15 (2s, 1H), 4.84 and 4.78 (2s, 1H), 3.62 and 3.44 (2m, 2H), 2.4-1.8 (m, 4H), 1.46 and 1.36 (2s, 9H). MS (ES+): M/Z 270 (M+H)+, 170 (M−C5H8O2)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][NH2:10])[CH:7]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][N:10]=[CH:13][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(F)cc1CCN
Solvent: CCO
Product: COC(=O)c1ccc(C=NCCc2cc(F)ccc2OC)cc1

Procedure:
9.00 g (53 mmol) of 2-(5-fluoro-2-methoxyphenyl)ethylamine and 8.73 g (53 mmol) of methyl 4-formylbenzoate are dissolved in 450 ml of ethanol, the mixture is heated at reflux for 2 hours and the solvents are then evaporated under reduced pressure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:4]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:28]2[CH2:29][CH2:30][C:25]([OH:31])([CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH2:26][CH2:27]2)=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: OC1(Cc2ccccn2)CCNCC1
Reactant: O=C(O)c1ccc(F)cc1-c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1-c1ccncc1)N1CCC(O)(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A suspension of 4-fluoro-2-(pyridin-4-yl)benzoic acid hydrochloride (0.15 g), 4-(pyridin-2-ylmethyl)piperidin-4-ol (0.17 g), HATU (0.34 g) and triethylamine (0.41 mL) in DMF (2.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.16 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCSCc1cccnn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCSCc1cccnn1)N[N+](=O)[O-]

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]-pyridazine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyridazinylmethylthio)ethyl]guanidine. Similarly, by the procedure of Example 2(iii), there is obtained N-methyl-N'-Nitro-N"-[2-(3-pyridazinylmethylthio)ethyl]-guanidine.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:5][O:6][CH:7]([CH2:9][O:10][CH:11]([CH2:13][OH:14])[CH3:12])[CH3:8])[CH3:4].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=O)([O-])[O-].[Zn+2].C1(C)C=CC=CC=1>[C:15]([O:14][CH2:13][CH:11]([CH3:12])[O:10][CH2:9][CH:7]([CH3:8])[O:6][CH2:5][CH:3]([O:2][CH3:1])[CH3:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(C)COC(C)COC(C)CO
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COC(C)COC(C)COC(C)COC(=O)c1ccccc1
Yield: 110.5 %

Procedure:
Tripropylene glycol monomethyl ether (841.6 grams; 3.39 mol), benzoic acid (501.7 grams; 3.46 mol), zinc carbonate 13.5 grams) and toluene (100 ml) were placed into a two liter, three-necked round bottom flask equipped with stirrer, 10" Vigreux column, Dean Stark trap, condenser, heating mantle and thermometer. The reaction temperature was 173° .C at the beginning of the reaction and 235° C. after six hours and 48 minutes. During that time, water (70 ml) was removed. The reaction was continued the next day at 214° C. for an additional three hours and 45 minutes removing additional water (35 ml). Toluene was removed at 65° C. @ 45 mm Hg. The product was washed first with sodium carbonate (170 ml; 15%) at 95°-100° C. for 30 minutes, then with sodium carbonate (22 ml; 15%) and sodium hypochlorite (50 ml), then with sodium carbonate (22 ml; 15%) and sodium hypochlorite (25 ml) with water (300 ml) and finally a second time with water (300 ml). It was dried at 135° C. and filtered to give the desired product (1162.9 grams; 93.6% yield). The product assayed with the following properties:
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])#[CH:15].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Br
Reactant: C#Cc1ccccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C#Cc1cc(Cl)ccc1OCC(=O)O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of (2-bromo-4-chlorophenoxy)acetic acid (200 mg; 0.75 mmol, Intermediate 4) and 2-ethynylanisole (Aldrich, 107 μL; 0.83 mmol) in anhydrous, degassed ACN (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol) followed after 5 minutes by copper iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.3 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvents were removed under vacuum, the residue was then taken up in EtOAc and washed with HCl (1N aqueous solution), the organic phase was washed with water (750 mL) then with brine (750 mL), dried over MgSO4, filtered and concentrated under vacuum to give a brown oily residue which was purified by preparative HPLC to afford the title compound as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCCCCC.CC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 690 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (1-a)) is dissolved in a mixture of 5 ml of n-hexane and 5 ml of acetone and reduced at room temperature and atmospheric pressure with addition of 3.2 g of a Lindlar catalyst. The catalyst is filtered off from the reaction mixture, and the solvent distilled off. The residue is purified by a silica gel column and distilled in a vacuum, giving 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (1-b), R1 =t-Bu, R2 =CH3) in a yield of 99.8%, b.p. 81°-84° C./0.005 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.FC(F)(F)S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: FC(F)(F)Cn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.1 %

Procedure:
A 250 mL RB flask was charged with 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.35 ml, 17.0 mmol), cesium carbonate (8.87 g, 27.2 mmol), and 1,4-dioxane (40.0 ml, 468 mmol), capped, and stirred at room temperature for 20 hours. The reaction mixture was filtered and the solid washed with dioxane; the filtrate was then concentrated to give 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.402 g, 77.1% yield) as a crude oil.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:6][NH2:7])=[O:5])#[N:2].[CH3:14][CH2:15][C:16](=O)[CH2:17][C:18](=O)[CH2:19][CH3:20]>>[CH2:15]([C:16]1[CH:17]=[C:18]([CH2:19][CH3:20])[N:7]2[N:6]=[C:4]([OH:5])[C:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:1]2[N:2]=1)[CH3:14]
Reactant: N#CC(C(=O)NN)c1ccccc1
Reactant: CCC(=O)CC(=O)CC
Product: CCc1cc(CC)n2nc(O)c(-c3ccccc3)c2n1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 36.1 %

Procedure:
2-Cyano-2-phenylacetohydrazide [Int-1A] (8.40 g, 43.2 mmol, 1.0 eq) and heptane-3,5-dione (5.85 mL, 43.2 mmol, 1.0 eq) were dissolved in 140 mL acidic acid and stirred for 4.5 h at 60° C. The resulting suspension was cooled to rt and the precipitate was isolated by filtration. The solid was washed with hexane and dried to give 4.17 g (29% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][CH:15]=[N:14][C:13]=2[CH3:17])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[O:16][C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[N:4])=[CH:11][CH:10]=2)=[C:13]([CH3:17])[N:14]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(C(C)(C)C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.9 %

Procedure:
To a solution of Example 35C (2.35 g, 10.4 mmol) in THF (50 mL) at −78° C. was added LiHMDS (1.0 M in THF, 11.4 ml, 11.4 mmol) slowly via syringe. The solution was stirred 45 min, and then solid hexachloroethane (3.69 g, 15.6 mmol) was added in one portion. The reaction was allowed to proceed for 16 hr, gradually warming to ambient temperature. The reaction was quenched with half-saturated aq NH4Cl solution, and the product was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 0% to 20% EtOAc/hexanes eluant; SF40-150 g column) yielded 2.52 g (93%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.66 (s, 4H), 2.36 (s, 3H), 1.71 (s, 6H). MS (DCI+) m/z 261 (M+H).
Reaction SMILES: [Li+].C[CH:3]([N-:5]C(C)C)C.CCCCCCC.C1COCC1.[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]1[C:44](O)=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CI>C1COCC1>[C:3]([C:32]1([CH3:44])[CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:35][CH2:36][N:31]1[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:30])#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C#N)C1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a cooled (−75° C.) solution of LDA 2M in heptane/THF (1.5 eq) in THF, a solution of 1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Bigge et al, Tetrahedron Lett. 1989, 30: 5193) in THF was added dropwise at −75° C. After being stirred for 1 hour at −75° C., MeI (1.5 eq) was added. After 2 hours at −75° C. the reaction mixture was left warming to r.t., evaporated, diluted with AcOEt, washed with NaHCO3, water, brine and dried over Na2SO4. The crude was purified by flash chromatography on silica gel (petroleum ether/AcOEt, 85:15) to obtain the title compound (C-41).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:31][NH:32][O:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:32]([O:33][CH3:34])[CH3:31])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CNOC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(Br)cc1Cl
Reaction time: 72 h
Yield: 90.3 %

Procedure:
A solution of 4-bromo-2-chloro-benzoic acid (3.30 g, 14 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (2.44 g, 14 mmol) and N-methylmorpholine in tetrahydrofuran were stirred for 2 hours at room temperature. N,O-Dimethylhydroxyamine hydrochloride (1.37 g, 14 mmol) and triethylamine (2 mL, 14 mmol) were added and the resulting mixture was stirred for 3 days. The reaction mixture was evaporated and ethyl acetate was added. The mixture was washed with 1N aqueous hydrochloric acid, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-2-chloro-N-methoxy-N-methyl-benzamide (3.52 g, 91%).
Reaction SMILES: C(O/[CH:4]=[C:5](\[CH3:12])/[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>CCO>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: NN
Reactant: CCO/C=C(\C)C(=O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: Cc1c[nH]nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed (E)-4-ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one (compound 261.1, 2.6 g, 14.3 mmol) in EtOH (20 mL). Hydrazine hydrate (1.8 mL, 38 mmol) was added and the resulting solution was stirred for 2 h at 80° C. The reaction was concentrated under reduced pressure to obtain the title compound as a yellow oil (2 g, crude).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2cccc3c2OCO3)c(F)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(F)c(-c2cccc3c2OCO3)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a reaction vessel containing methyl 4-amino-6-(benzo[d][1,3]dioxol-4-yl)-3-chloro-5-fluoropicolinate (0.150 g, 0.462 mmol) was added methanol (9.24 mL) and 2 N sodium hydroxide (0.924 mL, 1.848 mmol). The reaction mixture was stirred overnight at room temperature, neutralized to pH 3 with 2 N HCl, and concentrated under a stream of nitrogen. The precipitate that formed was filtered off, washed with water, and dried to provide the title compound as a white solid (0.107 g, 74.6%): mp 171-173° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.08-7.00 (m, 2H), 6.99-6.93 (m, 2H), 6.93 (br s, 2H), 6.06 (s, 2H); ESIMS m/z 311.2 ([M+H]+), 309.1 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:29]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cc(OC2CCCCO2)ccc1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (1.43 g, 7.94 mmol), [2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methanol (2.37 g, 7.94 mmol) and tributylphosphine (2.97 mL, 11.9 mmol) in toluene (120 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (3.00 g, 11.9 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (60 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (3.05 g, yield 83%).