Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:26])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:36]([O-:39])(=[O:38])C.[Li+].C(OC(=O)C)(=O)C>O.CN(C=O)C>[CH3:26][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH:8]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:36]([OH:39])=[O:38]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Reactant: CC(=O)[O-]
Agent: [Li+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)O)cc2C)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (racemate) (1.5 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.285 g), N,N-diisopropylethylamine (3.65 mL), lithium acetate 2 hydrate (2.85 g) and DMF (17 mL) was added acetic anhydride (1.977 mL), and the mixture was stirred at 120° C. overnight. To the reaction mixture was added water at room temperature, and the insoluble material was filtered off through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (725.6 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH:33]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:32][C:31]([CH2:43]Br)=[CH:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH:33]([CH2:34][OH:35])[CH2:32][C:31]([CH2:43][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:30]1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2=CC(CO)C(CO)C2)c(=O)[nH]c1=O
Yield: 19.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (53 mg).
Reaction SMILES: [OH-:1].[Li+].[F:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[N:11]=[N:12][CH:13]=[C:14]3[C:18]([CH:19]=[O:20])=[C:17]([CH3:21])[N:16]([CH2:22][C@H:23]4[CH2:25][C@@H:24]4[CH3:26])[C:15]=23)=[CH:6][CH:5]=1.Cl>O.C(O)C.[N+]([O-])([O-])=O.[Ag+]>[C:19]([C:18]1[C:14]2[C:15](=[C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:28][CH:27]=3)[N:11]=[N:12][CH:13]=2)[N:16]([CH2:22][C@H:23]2[CH2:25][C@@H:24]2[CH3:26])[C:17]=1[CH3:21])([OH:1])=[O:20]
Reactant: [OH-]
Reactant: Cc1c(C=O)c2cnnc(OCc3ccc(F)cc3)c2n1C[C@H]1C[C@@H]1C
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c2cnnc(OCc3ccc(F)cc3)c2n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a solution of silver nitrate (0.85 g, 5 mmol) in water (2.5 ml) was added an aqueous 2N lithium hydroxide solution (3 ml), followed by a solution of 7-(4-fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (0.177 g, 0.5 mmol) in ethanol (10 ml). The mixture was stirred at room temperature for 48 hours. To the reaction mixture was added 1N hydrochloric acid (3 ml) and the resulting mixture was filtered through celite (trade mark). The celite (trade mark) was washed with ethanol (30 ml). To the combined filtrates was added water and the resulting mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using chloroform/isopropanol=19/1 as the eluant to give the title compound (0.094 g, 51%) as pale yellow crystals.
Reaction SMILES: [Na].C(O[C:5](=[O:14])[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C.O>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[C:5]([OH:14])[N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[N:25]=1)=[O:9])[CH3:12]
Reactant: COc1cccc(NN)c1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(O)n(-c2cccc(OC)c2)n1
Temperature: 100 °C

Procedure:
To a solution of 1.2 g of 2-Oxo-succinic acid diethyl ester monosodium salt in 10 ml acetic acid, 900 mg of (3-Methoxy-phenyl)-hydrazine hydrochloride was added and the reaction mixture was heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure.
Reaction SMILES: FC1C=C(C=CC=1)C([N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[C:14]1[C:22](F)=[C:21]([C:24]([C:26]2C=C[CH:29]=[C:28]([F:32])[CH:27]=2)=C)C=CC=1C([O-])=O)=O.[OH2:36].[ClH:37]>>[ClH:37].[CH3:13][C:10]1[N:9]=[C:8]([CH2:14][C:22]([C:21]2[CH:24]=[CH:26][CH:27]=[C:28]([F:32])[CH:29]=2)=[O:36])[NH:7][C:11]=1[CH3:12]
Reactant: O
Reactant: C=C(c1cccc(F)c1)c1ccc(C(=O)[O-])c(-c2nc(C)c(C)n2C(=O)c2cccc(F)c2)c1F
Agent: Cl
Product: Cc1nc(CC(=O)c2cccc(F)c2)[nH]c1C
Yield: 23 %

Procedure:
12.97 g crude compound of Example VII are refluxed 1.5 h in 200 ml concentrated hydrochloric acid. The mixture is cooled to rT and 200 mL water are added. The solution is extracted twice with toluene and the aqueous phase is concentrated under vacuum. The residue is stirred with ethanol, filtered, washed once with ethyl acetate and once with petrol ether and dried to yield 1.7 g (23% of th.) 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-fluorophenyl)ethanone hydrochloride.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(Cl)(Cl)Cl.[C:17]([O:20][CH:21]([CH2:26][CH2:27][OH:28])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])[CH3:18]>O>[C:17]([O:20][CH:21]([CH2:26][CH2:27][O:28][S:9]([CH3:8])(=[O:11])=[O:10])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(CCO)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)C(CCOS(C)(=O)=O)OC(C)=O
Reaction time: 0.5 h

Procedure:
In an ice bath, 6.1 ml of triethylamine and 2.3 ml of methanesulfonyl chloride were added to a chloroform (15 ml) solution of 2.59 g of methyl 2-(acetyloxy)-4-hydroxybutanoate, and stirred for 30 minutes. Saturated saline water was added to the reaction liquid, extracted with chloroform, and the organic layer was dried. The solvent was evaporated away under reduced pressure to obtain 2.54 g of methyl 2-(acetyloxy)-4-[(methylsulfonyl)oxy]butanoate as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].O.N>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.CO>[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][O:10][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:12])[CH3:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)(CO)c1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)nc1
Reaction time: 2 h

Procedure:
1.9 g (10.2 mmol) of 2-(6-chloro-pyrid-3-yl)-2-methylpropanol are dissolved in 15 ml of toluene, 2.7 g (10.3 mmol) of 3-phenoxy-benzyl bromide are added and a solution of 0.6 g (1.8 mmol) of tetra-n-butylammonium hydrogen sulfate in 5 g of 50% strength sodium hydroxide solution is added. The mixture is stirred at 70°-80° C. for 2 hours, mixed with a mixture of 2 ml of methanol and 2 ml of concentrated ammonia water and finally all distributed between water and toluene. The organic phase is washed with ammonium chloride solution, the solvent is removed and the crude product is purified through a silica gel column. 2.4 g (62.9% of theory) of a weakly yellowish oil are thus obtained. The oil is distilled in the bulb tube at 0.03 mbar and 230°-240° C. apparatus temperature.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]([C:18](=[O:36])[C@H:19]([CH3:35])[NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:38]>C(O)(=O)C>[BrH:38].[CH2:33]([O:32][C:30]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:37])=[O:5])=[O:36])[CH3:35])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.17 h

Procedure:
5 g of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester obtained in Example 3 is dissolved in 5 ml of acetic acid, 20 ml of 25% hydrobromic acid in acetic acid is added to the solution, and the mixture is shaken for 10 minutes. The crystals which precipitate on addition of 300 ml of ethyl ether are collected by filtration to give 5 g of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrobromide as colorless crystals melting at 180°-183° C.
Reaction SMILES: C12BC(CCC1)CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl[C:44]1[CH:49]=[C:48]([Cl:50])[N:47]=[C:46]([S:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:54]=2[F:60])[N:45]=1.[CH3:61][C:62]1([CH3:69])[O:67][CH2:66][C:65](=[CH2:68])[CH2:64][O:63]1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:50][C:48]1[CH:49]=[C:44]([CH2:68][CH:65]2[CH2:66][O:67][C:62]([CH3:69])([CH3:61])[O:63][CH2:64]2)[N:45]=[C:46]([S:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:54]=2[F:60])[N:47]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C=C1COC(C)(C)OC1
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC1(C)OCC(Cc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A solution of 0.5M 9-borabicyclo[3.3.1]nonane (9-BBN) in tetrahydrofuran (17.12 ml) and 2,2-dimethyl-5-methylene-1,3-dioxane. (Tet. Lett. (1988) 29 (4S) 5703-5706) (1.3 g) was heated at 45° C. for 18 h. The solution was cooled and added to mixture of palladium(II) acetate, potassium phosphate (1.16 g), (biphenyl-2-yl)dicyclohexyl-phosphine (0.14 g) and 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (1.5 g) stirred under nitrogen. The mixture was heated in a microwave at 70° C., 250 W for a total of 1.5 h, then 70° C. on a hot-plate for 2 days. The reaction mixture was adsorbed onto silica-gel, the solvent evaporated under reduced pressure and the residue purified by flash silica-gel chromatography eluting with 20% ethyl acetate in iso-hexane to give a yellow oil. The oil was further purified by flash silica-gel chromatography eluting with dichloromethane to give the sub-title product as a viscous oil.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OCC)C>C1COCC1>[N:22]1([CH2:6][C@@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CN1CCOCC1)c1ccccc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
The mixture of 25 g (0.0792 mol) of (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate and morpholine (69.37 mL, 0.792 mol) in 250 mL of dry THF under inert atmosphere was refluxed for 8 hours. The reaction was then cooled to room temperature, treated with diethylether and the solid filtered. The solution was evaporated affording the crude as a yellow oil that was purified through silica gel chromatography (eluant hexane/ethylacetate 6/4). 11.59 g of the title product were isolated (48% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH:27]([CH3:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9]C.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:28][CH:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]1[S:11]([C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1OC
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A stirred suspension of 5-[(3,4-dimethoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (988 mg, 2.5 mmol) and cyclohexene (4.11 g, 50 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (15 mL, 15 mmol). After stirring for approximately two hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous, sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude residue (1.0 g). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless solid. Crystallization of the colorless solid from a mixture of ethyl acetate-diethyl ether-hexane yielded the title compound (0.523 g, 1.42 mmol, 57%) as a colorless, amorphous solid, m.p. 163-165° C.;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(O)(=O)C.[O-:16][C:17]#[N:18].[K+]>O>[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH:5][C:17]([NH2:18])=[O:16]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cl)c(NC(N)=O)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
2-Chloro-5-methoxyaniline hydrochloride (26 g, 134 mmol) was added to acetic acid (117 ml) and water (13 ml). The slurry was warmed to 30° C. A solution of potassium cyanate (13 g, 161 mmol) in water (104 ml) was added dropwise. After 1 hour at 40° C., the reaction was cooled to 20° C., filtered and washed with water (78 ml). The product was dried overnight in vacuo at 60° C. to yield the title compound as a white solid (21.8 g, 81%).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.C([N:20](CC1C=CC=CC=1)[C:21]1[C:26]([NH2:27])=[C:25]([NH:28][CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH:24]=[C:23]([C:37]2[O:38][CH:39]=[CH:40][N:41]=2)[N:22]=1)C1C=CC=CC=1>C1COCC1>[NH2:20][C:21]1[C:26]2[NH:27][C:6](=[O:7])[N:28]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:25]=2[CH:24]=[C:23]([C:37]2[O:38][CH:39]=[CH:40][N:41]=2)[N:22]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(CNc2cc(-c3ncco3)nc(N(Cc3ccccc3)Cc3ccccc3)c2N)cn1
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(=O)[nH]c3c(N)nc(-c4ncco4)cc32)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
CDI (272 mg) was added to a solution of N2,N2-dibenzyl-N4-(6-methyl-pyridin-3-ylmethyl)-6-oxazol-2-yl-pyridine-2,3,4-triamine (400 mg) in THF (10 ml). The solution was left to stir under N2 at 60° C. for 5 h. A further 3 equivalents of CDI (408 mg) were added and the reaction heated at reflux for 16 h. The reaction mixture was allowed to cool then concentrated in vacuo. The crude mixture was then dissolved in concentrated H2SO4 (5 ml) and left for 30 minutes at RT. The dark brown solution was added drop-wise onto crushed ice. The pH was adjusted to ˜8 by addition of a saturated solution of K2CO3 then the mixture was filtered. The solid obtained was washed with EtOAc (50 ml) then the organic and aqueous filtrates were transferred to a separating funnel. The layers were separated and the aqueous was re-extracted with EtOAc (50 ml). The organics were combined, dried (MgSO4) and evaporated to provide a gummy solid. This was triturated with Et2O and the solid collected by filtration and washed with Et2O, giving the title compound as an off-white solid (30 mg). 1H NMR (CDCl3, 400 MHz) □ 2.45 (s, 3H), 5.09 (s, 2H), 7.21-7.28 (m, 2H), 7.30 (s, 1H), 7.70 (dd, 1H), 7.95 (s, 1H), 8.42 (d, 1H). LCMS rt=2.29 m/z 323 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:25])[OH:14]
Reactant: Oc1ccc(Br)cc1C(O)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccccc1C(O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of 5-bromo-2-hydroxy-α-(2-pyridyl)-benzyl alcohol (3.18 g) in chloroform (60 ml) was added at 0° C. 70% m-chloroperbenzoic acid (3.30 g). The mixture was stirred for 10 minutes at the same temperature, then for further 3.5 hours while warming up to room temperature. The reaction mixture was poured into an aqueous solution of sodium sulfite, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous solution of sodium carbonate and a saturated aqueous saline solution, successively, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-2, α-dihydroxybenzyl)pyridine N-oxide (2.50 g, m.p.188°-189° C.), whose spectrum data are shown below.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Reaction time: 0.07 h
Yield: 82.8 %

Procedure:
Add trimethylsilylacetylene (3.4 mL, 24.0 mmol) to a mixture of bis(triphenylphosphine)palladium (II) dichloride (766 mg, 1.1 mmol), copper (I) iodide (418 mg, 2.2 mmol) and 3-iodobenzonitrile (5 g, 21.8 mmol) in triethylamine (20 mL). Upon addition of the trimethylsilylacetylene an exothermic reaction occurs and after about 4 min the reaction mixture solidifies. Cool the reaction mixture for about 15 min, dilute with ethyl acetate (100 mL), filter through fluted filter paper using ethyl acetate and concentrate. Dissolve the residue in ethyl acetate (200 mL) and wash sequentially with an aqueous solution of 0.1 N hydrochloric acid and a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes, to give the title compound as a tan solid (3.6 g, 83%).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)#[N:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([O:10][CH2:11][C@H:12]([OH:21])[CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
Prepared according to the method described in Example 26e) from (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.281 g), sodium hydride (60% dispersion in mineral oil, 0.056 g) and 4'-cyanobiphenyl-4-ol (0.269 g) in N,N-dimethylformamide (5 ml). The adduct was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride (0.522 g) was added. The reaction was stirred at room temperature for 1 hour and then poured into brine and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a solid (0.081 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[C:20](=O)[NH:19][C@H:18]([CH3:22])[C:17](=O)[N:14]3[C:15]=2[CH:16]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2].Cl>CCOCC.O>[ClH:7].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17][N:14]3[C:15]=2[CH:16]=1
Reactant: C[C@H]1NC(=O)[C@@H]2Cc3ccc(Cl)cc3N2C1=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CN2c3cc(Cl)ccc3C[C@H]2CN1
Temperature: 25 °C
Yield: 119.3 %

Procedure:
To a stirred suspension of lithium aluminum hydride (95%; 55 mg, 1.4 mmol) in anhydrous ether (15 mL) under Ar was added (3R,10aS)-7-chloro-1,2,3,4,10,10a-hexahydro-3-methylpyrazino[1,2-a]indole-1,4-dione (82 mg, 0.33 mmol). The mixture was heated at reflux for 18 h, then allowed to cool to ambient temperature. Water (0.06 mL) was added, followed by aqueous NaOH (15% w/v; 0.06 mL) then water (0.18 mL) and magnesium sulfate (2 g) were added. The mixture was filtered and the filter-cake washed with ethyl acetate. The filtrate was concentrated in vacuo and purification by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide (9:1:0)→(90:8:2)] gave a colourless oil which crystallised on standing (53 mg, 74%). The oil was dissolved in acetone (0.5 mid) and treated with ethereal HCl (1M; 0.71 mL, 0.71 mmol) followed by ether (5 mL). The resultant precipitate was filtered, washed with ether and dried to afford the title compound (51 mg, 83%) as a white solid: mp 260° C. (dec); Found C, 55.63; H, 6.28; N, 10.61%. C12H16Cl2N2 requires: C, 55.61; H, 6.22; N, 10.80%.