Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>CN(C)C(=O)C>[CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][N:6]([S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1C(=O)N(S(=O)(=O)C(C)C)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (40 mg) in N,N-dimethylacetamide (1 mL) under argon at 0° C. was added sodium hydride dispersion (55% in mineral oil, 6 mg). The mixture was stirred at 0° C. for 1.5 h. Isopropylsulfonylchloride (19 mg) was added. The mixture was stirred for 30 min at 0° C. and overnight at room temperature. Ice cold water was added and the mixture was extracted with ethyl acetate. The org. phase was washed with water and concentrated. The product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>0:1) to give 3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-1-(propane-2-sulfonyl)-imidazolidin-2-one (28 mg) as a colorless foam. MS: 465.3 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([OH:35])=[O:34])[CH:28]=[CH:29][C:30]=1[OH:31]>>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([OH:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCOC1CCCCO1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Product: COc1cc2c(Oc3ccc(CC(=O)O)cc3F)ncnc2cc1OCCOC1CCCCO1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] below Example 8 that is concerned with the preparation of starting materials, 4-chloro-6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy) quinazoline was reacted with 2-(3-fluoro-4-hydroxyphenyl) acetic acid to give 2-{3-fluoro-4-[6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy) quinazolin-4-yloxy]phenyl}acetic acid in 52% yield; Mass Spectrum: M+H+ 473.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17]C(=O)C(F)(F)F)[N:16]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[NH2:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:13][N:12]2[CH:14]=1
Reactant: O=C(Nc1cn2cc(Sc3ccccc3)ccc2n1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Nc1cn2cc(Sc3ccccc3)ccc2n1

Procedure:
A suspension of 0.200 g. of 6-(phenylthio) 2-(trifluoroacetamido) imidazo [1,2-a] pyridine in 1 ml. of 2.5 N aqueous sodium hydroxide is stirred for 90 minutes at room temperature. The reaction mixture is extracted with methylene chloride and the extracts are washed with water and dried over magnesium sulfate. Evaporation of the solvent yields 2-amino 6-(phenylthio) imidazo [1,2-a] pyridine, m.p. 110°-112° C.
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[N:19]=[N:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[C:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:21]=3)=[N:16]2)=[CH:10][CH:9]=1)(=[O:6])[O:4]C.C[Si](I)(C)C>C(Cl)Cl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:27]#[C:26][C:22]2[CH:21]=[C:20]([C:17]3[N:18]=[N:19][N:15]([CH2:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][P:3](=[O:2])([OH:6])[OH:4])=[CH:13][CH:12]=4)[N:16]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:30][CH:31]=1
Reactant: COP(=O)(Cc1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1)OC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=P(O)(O)Cc1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)benzyl] phosphonic acid dimethyl ester (0.25 g, 0.53 mmol) in methylene chloride (15 mL) was cooled to 0° C., then treated with trimethylsilyliodide (0.23 mL, 1.33 mmol). The reaction mixture was removed from the cooling bath and stirred at room temperature for 1 hour. The reaction mixture was concentrated on the rotary evaporator without heat and the residue was treated with chloroform. The resulting solid was collected by filtration, washed with chloroform, triturated with hot ether, collected by filtration and dried. High performance liquid chromatography (“HPLC”) indicates that this solid is 65% pure.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]([CH3:15])[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:9]#[N:10]>CO>[CH3:4][N:5]([CH3:15])[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:9]([NH:2][OH:3])=[NH:10]
Reactant: Cc1cc(C#N)cc(N(C)C)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(N(C)C)n1
Temperature: 0 °C
Yield: 33.7 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (1.71 g, 15.2 mmol) in methanol (50 mL), hydroxylamine hydrochloride (905 mg, 13.02 mmol) is added. The suspension is stirred for 30 min before 2-dimethylamino-6-methyl-isonicotinonitrile (699 mg, 4.34 mmol) is added. The mixture is refluxed for 2 h before it is evaporated. The residue is dissolved in a small amount of water and separated by MPLC on RP-C18-silica gel to give 2-dimethylamino-N-hydroxy-6-methyl-isonicotinamidine (284 mg) as a brownish resin; LC-MS: tR=0.60 min, [M+1]+=195.42.
Reaction SMILES: [C:1]1([N:11]2[C:15](=[S:16])[N:14]=[N:13][NH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH:25]1[O:27][CH2:26]1.CCN(CC)CC>CO>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH:25]([OH:27])[CH2:26][S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[N:13][N:14]=1
Reactant: Clc1ccccc1CC1CO1
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(CSc1nnnn1-c1cccc2ccccc12)Cc1ccccc1Cl
Yield: 13.7 %

Procedure:
A solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (50.0 mg, 0.22 mmol), 2-chloro-1-(2,3-epoxypropyl)benzene (36.9 mg, 0.22 mmol) and Et3N (0.15 mL, 1.10 mmol) in MeOH (5 mL) was heated at reflux for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by HPLC using a gradient of MeCN/H2O containing TFA (0.1%) (CombiPrep ODS-AQ 50×20 mm, 5μ, 120 Å). The pure fractions were concentrated to give the title compound (12 mg, 14% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].CI.[CH2:27]1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[C:5]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 gm, 3 mmol) (example 9), methyl iodide (1 ml, excess) and 18-Crown-6 (500 mg) in acetone (250 ml), K2CO3 (10 gm, excess) was added and the reaction mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexanes to afford 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield 1.0 g, 98%; MS: 349 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
In 33 ml of tetrahydrofuran is dissolved 3.3 g of benzyl (2S,4R)-2-{[methoxy(methyl)amino]carbonyl}-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidine-carboxylate. After adding 0.64 g of lithium aluminum hydride at −70° C., the mixture thus obtained is stirred at −70° C. for one hour. After dropwise adding 33 ml of ethyl acetate to the reaction mixture over a period of 30 minutes and then 66 ml of tetrahydrofuran containing 20% of water over a period of 30 minutes, the mixture thus obtained is stirred at ambient temperature for 30 minutes. The mixture is filtered with Celite, and the organic layer is separated from the filtrate. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to obtain 1.25 g of benzyl (2S,4R)-2-formyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidinecarboxylate as a light yellow oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:23]1([C:27]([C:29]2[CH:30]=[C:31]([Cl:36])[C:32](Cl)=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:23]1([C:27]([C:29]2[CH:30]=[C:31]([Cl:36])[C:32]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (80 mg, 0.26 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (61 mg, 0.26 mmol) and caesium carbonate (172 mg, 0.53 mmol) in acetonitrile (3 mL) was stirred in a Smith Creator microwave at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue. The organic phase was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the title compound as a yellow foam (52 mg).
Reaction SMILES: Cl[C:2]1C=C(N2CCN(C)CC2)C=C[C:3]=1N.[Cl:16][C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[NH:30][C:31]1[N:32]=[CH:33][C:34]2[CH:40]=[CH:39][C:38](=[O:41])[N:37]([C:42]3[CH:43]=[C:44]([NH:48][C:49](=O)[O:50]C(C)(C)C)[CH:45]=[CH:46][CH:47]=3)[C:35]=2[N:36]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[NH:30][C:31]1[N:32]=[CH:33][C:34]2[CH:40]=[CH:39][C:38](=[O:41])[N:37]([C:42]3[CH:43]=[C:44]([NH:48][C:49](=[O:50])[CH:2]=[CH2:3])[CH:45]=[CH:46][CH:47]=3)[C:35]=2[N:36]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(-c5cccc(NC(=O)OC(C)(C)C)c5)c4n3)c(Cl)c2)CC1
Reactant: CN1CCN(c2ccc(N)c(Cl)c2)CC1
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4Cl)nc32)c1

Procedure:
The title compound was prepared according to the procedures described for Example 1, starting from 2-chloro-4-(4-methylpiperazin-1-yl)aniline (Aurum Pharmatech LLC, Wowell, N.J.). tert-Butyl (3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (15a): m/z (ESI, +ve ion) 562.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:23]=[C:22]([NH:24][C:25](=[O:39])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[Cl:38])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]1.Cl>CCO>[Cl:3][C:4]1[CH:23]=[C:22]([NH:24][C:25](=[O:39])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][C:29]=2[Cl:38])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCN(CCOc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCN2CCC(C(=O)O)CC2)c(Cl)c1
Reaction time: 16 h

Procedure:
2 mL aqueous NaOH (1 M) was added at RT to a solution of 150 mg (0.270 mmol) ethyl 1-(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-piperidine-4-carboxylate (Example 146) in 4 mL EtOH and the mixture was stirred for 16 h. The reaction mixture was neutralised with 2 mL aqueous HCl (1 M), evaporated down i. vac. and the crude product was purified by column chromatography (silica gel, dichloromethane/MeOH 4:1).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[Si]([C:35]#[N:36])(C)C.O>C(Cl)Cl.[Zn+2].[I-].[I-]>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]([OH:30])[C:35]#[N:36])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2ccc3cc(C(O)C#N)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a suspension of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthaldehyde (0.4 g, 1.01 mmol) and ZnI2 (0.07 mg, 0.02 mmol) in anhydrous CH2Cl2 (5 mL) stirring at 0–5° C. under an argon atmosphere was added trimethylsilylcyanide (0.16 mL, 1.18 mmol). The reaction mixture was stirred for 1.0 hour at 0–5° C. before it was allowed to warm to room temperature and stirred for 26 hours. It was poured into water, extracted with CH2Cl2. After removal of the solvent, the residue was dissolved in 1,3-dioxolane (10 mL) and 2N HCl added. After stirring at room temperature for 1.5 hours, it was poured into water, extracted with EtOAc, washed with water, brine and recrystallized from hexane/CH2Cl2 to afford 2-[6-(3-[1-adamantyl]-4-methoxyphenyl)-2-naphthyl]-2-hydroxy-acetonitrile as an orange powder 0.340 mg (80%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.18 (m, 9H), 2.86 (s, 1H), 3.90 (s, 3H), 5.71 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.51–7.61 (m, 3H), 7.78–7.82 (m, 1H), 7.90–8.02 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[CH:15]([S:17]([N:20]1[CH2:27][CH:26]2[CH:22]([CH2:23][NH:24][CH2:25]2)[CH2:21]1)(=[O:19])=[O:18])=[CH2:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:24]2[CH2:23][CH:22]3[CH:26]([CH2:27][N:20]([S:17]([CH:15]=[CH2:16])(=[O:18])=[O:19])[CH2:21]3)[CH2:25]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: C=CS(=O)(=O)N1CC2CNCC2C1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CS(=O)(=O)N1CC2CN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a stirred solution of 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetic acid (90 mg, 0.385 mmol) in DMF (15 mL) at room temperature, 2-(vinylsulfonyl)octahydropyrrolo[3,4-c]pyrrole (110 mg, 0.46 mmol) was added followed by HOBt (78.05 mg, 0.58 mmol), EDCI.HCl (110.7 mg, 0.46 mmol) and Et3N (116.7 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/dichloroethane) to afford the desired product (20 mg, 10% yield) as a solid. 1H NMR (400 MHz, DMSO-d6)δ: 10.17 (s, 1H), 6.91 (dd, J=10.0, 16.4 Hz, 1H), 6.79 (s, 1H), 6.62 (s, 1H), 6.17-6.10 (m, 2H), 5.25 (t, J=4.0 Hz, 1H), 3.85-3.82 (m, 2H), 3.71-3.66 (m, 1H), 3.61-3.56 (m, 1H), 3.45-3.39 (m, 3H), 3.29-3.25 (m, 1H), 3.09-3.00 (m, 3H), 2.92-2.89 (m, 1H). ESI-MS m/z: 420.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[I-:19].[Na+].I>CC(C)=O>[I:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: Ic1nnc(Cc2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Under exclusion of air, a suspension of 12.8 g (50 mMol) of 1-chloro-4-(4-pyridyl-methyl)-phthalazine (Example 67A.1 in WO 98/35958) and 25 g (166.8 mMol) of sodium-iodide in 0.3 l of acetone is mixed with 20 ml hydroiodic acid (55% HI in water; 144 mMol) and stirred in the dark during 6 days at RT. Filtration and washing with acetone follow. The remaining solid is suspended in 1 l of water, neutralized with 100 ml of an 1 M Na2CO3 solution, stirred during 10 min, filtered and washed with water, yielding the title compound: An. calc. (C14H10N3I·0.05 H2O) C, 48.31%; H, 2.92%; N, 12.07%; I, 36.46%; H2O, 0.26%; An. meas. C, 48.60%; H, 3.10%; N, 12.08%; I, 36.28%; H2O, 0.28%; FAB-MS (M+H)+=348.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([O:20]CC)=[O:19])=[C:13]([CH3:23])[N:12]=1.[OH-].[Na+].O>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([OH:20])=[O:19])=[C:13]([CH3:23])[N:12]=1
Reactant: CCOC(=O)c1c(C)nc(N2CCc3ccccc3C2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCc3ccccc3C2)nc(C)c1C(=O)O

Procedure:
A mixture of 6c (1.43 g, 4.5 mmol) and an aqueous solution of NaOH (10M, 20 ml) in ethanol (20 ml) was refluxed for 6 hours. To the mixture was added 100 ml of water and then the mixture was washed with dichloromethane (100 ml). The aqueous phase was neutralized with hydrochloric acid to pH=6. Product was precipitated at pH=6. After filtration, 6d was obtained as white powder (1.10 g, 3.88 mmol, 86%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:42]([O:49][C:50]1[C:55]([CH:56]=O)=[CH:54][CH:53]=[CH:52][N:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH2:42]([O:49][C:50]1[C:55]([CH:56]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)=[CH:54][CH:53]=[CH:52][N:51]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccnc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=Cc2cccnc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (16.6 g, 33.8 mmol) was suspended in THF (70 ml) under Argon. Lithium bis(trimethylsilyl)amide (1M in THF, 40.5 ml) was added. The reaction mixture was stirred for 1 hour at ambient temperature; the colour changed to orange. 2-Benzyloxy-3-pyridinecarbaldehyde (7.2 g, 33.8 mmol) was added as a solution in THF (50 ml) and the reaction mixture was stirred at amibent temperature overnight (shielded from light). The reaction mixture was partitioned between EtOAc/water, the organic phase was dried (MgSO4) and evaporated. Purification by chromatography (SiO2, eluting with CH2Cl2 /hexane) gave methyl 4-[2-(2-benzyloxy-3-pyridyl)ethenyl]benzoate (9.2 g, 79%).
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21].IC>O1CCCC1>[Cl:16][C:17]1[C:18]([CH3:2])=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(F)c1Cl
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
BuLi (68.8 mL, 110 mmol) was diluted with tetrahydrofuran (THF) (80 mL) and cooled to −20° C. 2,2,6,6-tetramethylpiperidine (18.56 mL, 110 mmol) was added dropwise and the mixture stirred at −20° C. for 15 minutes. The solution was cooled to −50° C. whereupon 3-chloro-4-fluorobenzoic acid (8.73 g, 50 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (20 mL) was added dropwise. The mixture was stirred at −50° C. for 4 hours before iodomethane (12.51 mL, 200 mmol) was added dropwise. The mixture was allowed to reach room temperature overnight and quenched with water (100 mL). The mixture was acidified with 5N HCl (200 mL) and extracted with tert-butyl methyl ether (3×300 mL). The combined extracts were washed with water (100 mL), brine (100 mL) dried over anhydrous magnesium sulfate and concentrated to a crude product. The solid was recrystalised from cyclohexane (note: some insolubles not satisfactorarily removed) to afford product in 5.73 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=3)[N:12]=2)=[C:4](F)[CH:3]=1.C1(=O)O[CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH:10]=[C:11]([C:13]4[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=4)[N:12]=3)[CH2:25][CH2:24][O:23][C:4]=2[CH:3]=1
Reactant: O=C1OCCO1
Reactant: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A solution of 5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole (10.0 g, 28.6 mmol) in DMF (100 mL) was treated with ethylene carbonate (5.3 g, 60.1 mmol) and cesium carbonate (13.9 g, 42.5 mmol) and then heated at 100° C. for 72 h. Further cesium carbonate (9.0 g, 27.5 mmol) and water (0.5 mL) were added and heating continued for 24 h before concentrating the reaction mixture in vacuo. The resultant residue was partitioned between DCM and water, the organic layer was isolated, washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 1% MeOH in DCM) to give 95 as an off-white solid (5.78 g, 58%). 1H NMR δ (ppm) (CDCl3): 8.04 (1H, s), 7.83 (1H, s), 7.50-7.38 (3H, m), 5.93-5.84 (1H, m), 4.07-4.02 (2H, m), 3.93-3.88 (2H, m), 1.53-1.46 (6H, m)