Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26](=[NH:34])[NH:27][O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:35]([O:37][C:38](OCC)(OCC)OCC)[CH3:36].C(O)(=O)C>O1CCOCC1>[CH2:35]([O:37][C:38]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26](=[NH:34])[NH:27][O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=1)[CH3:36]
Reactant: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(CNc2c(N)cccc2C(=O)OC)cc1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(Cn2c(OCC)nc3cccc(C(=O)OC)c32)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The pale brown syrup (8.58 g) obtained in Example (57a) was dissolved in dioxane (20 ml). To the solution were added tetraethoxymethane (8.64 g) and acetic acid (1.56 g). The mixture was stirred for 2 hours at 100° C. The reaction mixture was concentrated to dryness. The residue was crystallized from ethyl acetate (50 ml). Resulting crystalline precipitates were collected by filtration to obtain the title compound.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10](S(C3SC=CC=3)(=O)=O)[CH2:9][C:8]=2[CH:36]=1)#[N:3].[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1ccc(F)cc1)[C@H](Cc1ccccc1)CN2

Procedure:
The title compound was prepared from Compound A of Example 23 and 4-fluorophenylsulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([O-:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[Na+].C(C1(CC([O-])=O)CCCCC1)#N.[K+]>>[C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(CC(=O)[O-])CCCCC1
Agent: [K+]
Agent: [Na+]
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
sodium 1-cyanocyclohexaneacetate; and potassium 1-cyanocyclohexaneacetate;
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Cl[CH2:6][C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCCCCC.[Cu](C#N)C#N>[CH2:1]([OH:4])[C:2]#[C:3][CH2:6][C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCO
Reactant: CCCCCCCCC#CCC#CCCl
Agent: N#C[Cu]C#N
Solvent: CCCCCC
Product: CCCCCCCCC#CCC#CCC#CCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
In a second stage, the dianion of propargyl alcohol is formed by adding 19 g of propargyl alcohol, with stirring, to the above reaction mixture, cooled to 0° C. At the end of the addition, the mixture is stirred for another 1 h 30 min at ambient temperature. 0.5 g of copper cyanide is then added and stirring is continued for another 1 h 30 min, still at ambient temperature. 40.54 g of 1-chloro-2,5-tetradecadiyne are introduced dropwise into the mixture thus obtained, cooled to 0° C. The mixture is left to stand overnight at ambient temperature and it is then heated under reflux for 9 hours. The solvent is then removed by evaporation under vacuum and the residue obtained is extracted with methylene chloride. The organic phase is then washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The solid obtained is dissolved in 350 cm3 of boiling hexane. The expected alcohol crystallizes on cooling. It is filtered off and dried. 25 g of 2,5,8-heptadecatriyn-1-ol are obtained in the form of white crystals whose melting point is 48° C. Its 1H NMR spectrum is consistent with the expected structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[S:16][C@@H:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C@@H:18]([OH:22])[C:19](O)=[O:20].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(OCC)(=O)C.CO>CN(C=O)C>[CH2:9]([O:8][C:4]1[C:3]2[S:16][C@@H:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:18]([OH:22])[C:19](=[O:20])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc([C@H](Sc2c(N)cccc2OCc2ccccc2)[C@@H](O)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc([C@@H]2Sc3c(cccc3OCc3ccccc3)NC(=O)[C@@H]2O)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 2.11 g (4.96 mmol) of (+/−)-(2S,3S)-3-(2-amino-6-(benzyloxy)phenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoic acid in 25 mL of DMF was added 1.24 g (6.47 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 871 mg (6.45 mmol) of 1-hydroxybenzotriazole. The solution was stirred at 22° C. for 16 hours, and a solution of 7:3 ethyl acetate/methanol was added to the reaction. The organic layer was washed with 1 N HCl (2×) and then with a 1:1 mixture of satd. NaHCO3 and brine (2×). The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane then gradually increasing to 40% ethyl acetate/hexane to give (+/−)-(2S,3S)-9-(benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][C@H:10]([CH3:14])[C:11]([OH:13])=O.C([N:19](C(C)C)CC)(C)C.N[N:26]([CH:34]=[NH:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[NH:19]=[C:34]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[NH:35][C:11](=[O:13])[C@H:10]([O:9][C:2]1[C:1]([CH3:15])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C)c(O[C@H](C)C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(O[C@H](C)C(=O)NC(=N)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
(2R)-2-(Mesityloxy)propionic acid (11.6 g; 55 mmol), diisopropylethylamine (35.6 g; 275 mmol), tert-butyl amino(imino)methylcarbamate (8.8 g; 55 mmol), and 1-hydroxybenzotriazole monohydrate (8.4 g; 55 mmol) were dissolved in N,N-dimethylformamide (150 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (20.9 g; 55 mmol) was added thereto, and the mixture was stirred for 18 hours at room temperature. To the reaction solution, ethyl acetate (400 mL) was added, and the mixture was washed sequentially with 10% aqueous citric acid solution, brine, and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting oily substance was crystallized from diisopropyl ether, collected by filtration and dried to give 14.1 g of the title compound (yield 73%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:16])[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(-c2ccco2)cc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in N,N-dimethylformamide (2.5 mL) were added potassium carbonate (139 mg) and methyl iodide (0.25 mL) and the mixture was stirred at room temperature for 8 hrs. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→0:1) to give the title compound (94 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])S[C:7]=1[NH2:13])=[O:5])C.CO[C:16]1[NH:17][CH2:18][CH2:19][CH:20]=1.P(Cl)(Cl)(Cl)=O>[Ni]>[CH3:11][CH:10]([C:6]1[C:4](=[O:5])[N:17]2[CH2:18][CH2:19][CH2:20][C:16]2=[N:13][CH:7]=1)[CH2:9][CH3:12]
Reactant: COC1=CCCN1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Agent: [Ni]
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)c1cnc2n(c1=O)CCC2
Yield: 36.5 %

Procedure:
According to Khim. Geterosikl. Soedin, 6, 765, 1975, ethyl-2-amino-4,5-dimethyl-thiophene-3-carboxylate is reacted with 2-methoxy-pyrroline in the presence of phosphoryl chloride and the obtained 2,3-dimethyl-4-oxo-5,6-tetramethylene-4H-thieno[2,3-d]pyrimidine is desulphurated in an alcoholic solution with Raney-nickel and thus 3-(1-methyl-propyl)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine is obtained. In the complicated two-step synthesis the pyrrolo-pyrimidine derivative is obtained with a yield of 36.5%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=[O:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=O)C>CO>[CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:27])=[O:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
N-Benzyl 2-(3-carboxyphenoxy)nicotinamide (1.00 gram, 2.87 mmol) is slurried in 12 ml of methanol in a 125 ml round bottom flask equipped with magnetic stir bar and nitrogen source and chilled to 0° C. Acetyl chloride (0.57 ml) is added to the flask and the reaction allowed to slowly warm to room temperature. After 18 hours the reaction is quenched by adding 50 ml of 2N sodium hydroxide solution. It is then extracted (2×50 ml) with ethyl acetate, the combined extracts washed with (2×100 ml) 2N sodium hydroxide and dried over anhydrous magnesium sulfate. Filtration and concentration of the extract in vacuo yield a pasty solid which is purified by trituration with diethyl ether to yield 0.38 grams (36.5%) of the title product as a white crystalline solid.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[N:15]=1.N1([CH2:35][OH:36])C2C=CC=CC=2N=N1>C1COCC1>[Br:13][C:14]1[N:15]=[C:16]([CH:20]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1
Reactant: OCn1nnc2ccccc21
Reactant: Brc1cccc(Cn2ccnn2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCC(c1cccc(Br)n1)n1ccnn1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of i-Pr2NH (370 μL, 2.59 mmol) in THF (3.0 mL) was cooled to −20° C., and n-butyllithium (970 μL, 2.43 mmol) was added dropwise. After stirring for 15 minutes at −20° C., the colorless solution was cooled to −78° C. before adding 2-bromo-6-(1H-1,2,3-triazol-1-ylmethyl)pyridine (200 mg, 0.84 mmol) in THF (2.0 mL) dropwise over 30 minutes. After stirring for an additional 30 minutes at −78° C., 1H-benzotriazole-1-methanol (250 mg, 1.67 mmol) in THF (5.0 mL) was added dropwise over 25 minutes. The solution was stirred at −78° C. for 2 h. The reaction was quenched (while cold) with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (50-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:15][N:14]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(OCC2CC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cccc(OCC4CC4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-cyclopropylmethoxy-phenyl)acetohydroximoyl chloride (150 mg, 0.626 mmol) described in Manufacturing Example 66-1-4 and 3-ethynyl-pyridin-2,6-diamine (53.2 mg, 0.399 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (218 μL, 1.57 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (117 mg, 56%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+:42]>C(O)C.O>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@H:11]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O-:33])=[O:32])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[Na+:42]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)[O-])CC2)cc1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
To a microwave vial was added (R)-1-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxylic acid (100 mg, 218 μmol), hydroxylamine hydrochloride (45.5 mg, 654 μmol) and sodium hydrogencarbonate (91.6 mg, 1.09 mmol) in ethanol (2 mL) and water (0.2 mL). The vial was capped and heated at 120° C. for 15 min, then hydroxylamine hydrochloride (45.5 mg, 654 μmol) and sodium hydrogencarbonate (91.6 mg, 1.09 mmol) were added again. The vial was capped and heated at 120° C. for 10 min, then the reaction mixture was evaporated. The residue was washed with dichloromethane, then suspended in dichloromethane/methanol 9:1 and filtered. The filtrate was concentrated and purified by chromatography (SiO2; gradient dichloromethane/methanol 19:1 to dichloro-methane/methanol 4:1) to afford the title compound (66 mg, 61%). Light brown solid, MS (ESI−): m/z=472.4 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[Cl:11].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:19])=[CH:6][C:5]=1[Cl:11]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OC)cc1Cl
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
To a solution of compound of example 163 (2.8 g, 15 mmol) in dry dioxane (50 mL) was added NaH (50%, 1.44 g, 30 mmol) and dimethyl sulfate (3.78 g, 30 mmol). It was stirred at 60-65° C. for 1 h. It was poured into ice water and extracted with EtOAc (2×100 mL). The organic extract was washed with brine, dried (anhydrous Na2SO4) and concentrated to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
To a mixture of commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-fluoro-phenylboronic acid (0.3 g, 2.17 mmol) in 1,2-dimethoxyethane (14 ml), 2M sodium carbonate solution (2.71 ml, 5.42 mmol) was added, and the reaction mixture was purged with argon for 5 min in an ultrasonic bath. Afterwards tetrakis(triphenylphosphine)palladium(0) (125 mg, 108 μmol) was added, and the stirred reaction mixture was heated under reflux conditions for 17 h. The reaction mixture was cooled to room temperature, poured into water (30 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude material (0.74 g) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 98:2) and trituration (diethyl ether) to yield the title compound as a light yellow solid (0.3 g, 48%), MS (ISP) m/z=291.3 [(M+H)+], mp 102° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CC#N>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12]([O:14][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCC2
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.10 g, 3.74 mmol), NaI (841 mg, 5.61 mmol) and triethylamine (1.56 mL, 11.22 mmol) in CH3CN (15 mL), is added trimethylsilyl chloride (0.707 mL, 5.61 mmol) via syringe. The reaction mixture is stirred at room temperature for 15 h., 30 mL of ethyl acetate/hexanes (1:1 with a few drops of triethylamine) is added to dilute the solution. Saturated sodium bicarbonate solution (20 mL) is added. The layers are separated and the aqueous phase is extracted with ethyl acetate/hexanes (1:1) (3×10 mL). The combined organic layers are dried (Na2SO4) and evaporated to provide 4-trimethylsilanyloxy-6,7-dihydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.3 g, 100%) as a viscous red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([OH:16])=[O:15])=[N:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[C:17](=O)([O-])O.[Na+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2c(C(=O)O)n[nH]c(=O)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1n[nH]c(=O)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A mixture of 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid (10.0 g.), sodium hydrogen carbonate (15.0 g.) and methyl iodide (15.0 ml.) in dry dimethylformamide (200 ml.) was stirred at room temperature for 16 hours. The mixture was then poured into water (600 ml.). The precipitated solid was separated, washed first with water then cold methanol, and then recrystallised from methanol to give methyl 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate (8.6 g.), m.p. 222°-225° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([C:15]1[N:20]=[CH:19][C:18]([C:21](=[C:39]([CH3:41])[CH3:40])[C:22]([O:24][CH2:25][C:26]2[C:31]([F:32])=[C:30]([F:33])[C:29]([CH2:34][O:35][CH3:36])=[C:28]([F:37])[C:27]=2[F:38])=[O:23])=[CH:17][N:16]=1)([CH3:14])[CH3:13].C(O)(=O)C>O1CCCC1>[CH3:14][C:12]([C:15]1[N:16]=[CH:17][C:18]([CH:21]([C:39]([CH3:41])=[CH2:40])[C:22]([O:24][CH2:25][C:26]2[C:31]([F:32])=[C:30]([F:33])[C:29]([CH2:34][O:35][CH3:36])=[C:28]([F:37])[C:27]=2[F:38])=[O:23])=[CH:19][N:20]=1)([CH3:11])[CH3:13]
Reactant: COCc1c(F)c(F)c(COC(=O)C(=C(C)C)c2cnc(C(C)(C)C)nc2)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=C(C)C(C(=O)OCc1c(F)c(F)c(COC)c(F)c1F)c1cnc(C(C)(C)C)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A 1 molar solution of lithium hexamethyldisilazide (0.125 cm3) in dry tetrahydrofuran was added to a stirred solution of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.05 g) in dry tetrahydrofuran (1 cm3) whilst the reaction temperature was maintained at -78° C. After 30 minutes, acetic acid (0.01 g) was added in one portion, and the stirred reaction mixture was allowed to warm to the ambient temperature, and quenched with water. Extraction into ethyl acetate, and concentration by removal of the solvent under reduced pressure gave 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl)-3-methylbut-3-enoate (0.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH2:13][CH2:12]1>C(OCC)C.ClCCl>[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)C1=CCCN(C)C1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1CN(C)CCC1c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (3.5 ml, 1.4 molar equivalents) was stirred at −5 to −10° C. under nitrogen, and a solution of arecoline (0.78 g) in dichloromethane (4.0 ml) added over 15 minutes at −5° C. The clear solution was stirred at −5° C. for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans 1 ethyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 965 mg (77 %).