Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[N:3]1[CH:8]=C[CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].ClC1N=C(Cl)C(C)=C[N:14]=1.O>C1COCC1>[N:11]1[CH:10]=[CH:9][C:4]([CH2:5][C:6]#[N:14])=[N:3][CH:8]=1
Reactant: N#CCc1ccccn1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1ccncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of LiH (404 mg, 50.79 mmol) in anhydrous THF (10 mL), was added dropwise a solution of 2-pyridylacetonitrile (3 g, 25.39 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at zero degree for 1 hour. A solution of 2,4-dichloro-5-methyl-pyrimidine (4.55 g, 27.93 mmol), dissolved in anhydrous THF (5 ml), was added dropwise at zero degree. The reaction mixture was stirred and heated to reflux for 14 hours. The reaction mixture was allowed to warm to r.t. and water was added (20 mL). THF was evaporated under vacuum and a solution of 1N HCl (20 mL) was added. The precipitate was filtered and washed with water (10 mL) and cyclohexanes (10 mL) to give a yellow solid which was dried under vacuum at 40 degrees. The yellow crystalline product 4-pyrimidineacetonitrile, 2-chloro-5-methyl-alpha-2(1H)-pyridinylidene was isolated. (5.5 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[OH:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@:12]3([OH:27])[CH2:13][CH2:14][C@@H:15]2[CH:25]=O)[CH2:7]1.C([O-])(O)=O.[Na+]>O.O1CCOCC1>[CH3:1][N:2]([CH3:4])/[N:3]=[CH:25]/[C@H:15]1[CH2:14][CH2:13][C@:12]2([OH:27])[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:24])[C@@H:8]([CH2:7][C@@H:6]([OH:5])[CH2:23][CH2:22]1)[CH2:9][CH2:10]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: CN(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 0.80 g of NaH2PO4.H2O, 1.70 g of Na2HPO4.12H2O and 0.12 ml of N,N-dimethylhydrazine in 200 ml of water a solution of 0.64 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 20 ml of dioxane was added dropwise at room temperature. After 1.5 hrs the solution was alkalinized with an acqueous solution of NaHCO3 and extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash-chromatography (SiO2) using cyclohexane/chloroform/acetone 4/3/3 as eluant to give 0.37 g of the title compound (I-ai), as a white foam.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:18]2[O:17][C:16](=[O:19])[N:15]([CH2:20][C:21]([NH2:23])=[O:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1>S(=O)(=O)(O)O>[Cl:1][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:20][C:21]([NH2:23])=[O:22])[C:16](=[O:19])[O:17][C:18]=2[C:10]=1[F:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)Cn1c(=O)oc2c(F)cccc21
Agent: O=S(=O)(O)O
Product: NC(=O)Cn1c(=O)oc2c(F)c(Cl)ccc21
Reaction time: 120 h
Yield: 46.5 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, N-chlorosuccinimide (0.635 g, 4.75 mmol) is added to a suspension of 2-(7-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide 12 (1 g, 4.75 mmol) and sulfuric acid (90% w/w; 20 ml) at 0° C. The reaction is stirred 5 days then poured carefully into ice. The precipitate is collected by filtration and washed with water. The residue is recrystallized in EtOH/water (20/80 (v/v)) to afford 0.54 g of 2-(6-chloro-7-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide 19.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCCCO)cc1
Yield: 96.2 %

Procedure:
A Parr flask was charged with 3.25 g (15.98 mmol) of methyl 4-(4-hydroxy-1-butynyl)benzoate (Taylor et al. J. Org. Chem., 1990, 55, 3222-3227) and 0.26 g (8% wt equivalent) of 10% palladium-on-carbon catalyst in 40 mL of ethanol. Hydrogenation was carried out at 50 psi of hydrogen for 18 hours. The mixture was filtered through a silica gel pad that was subsequently washed with ethanol. The combined filtrates were concentrated under reduced pressure to give 3.20 g (97%) of methyl 4-(4-hydroxybutyl)benzoate as a light yellow oil. 1H NMR (CDCl3) δ 1.51 (1H, s), 1.57-1.82 (4H, m), 2.74 (2H, t, J=7.3 Hz), 3.71 (2H, t, J=6.0 Hz), 3.94 (3H, s), 7.27 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz).
Reaction SMILES: C([O:3][C:4]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH:5]=1)C>C(O)(=O)C.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][CH2:5][C:4](=[O:3])[C:13]=3[N:12]=2)=[CH:15][CH:16]=1
Reactant: CCOC1=CCCc2cnc(-c3ccc(OC)cc3)nc21
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2ncc3c(n2)C(=O)CCC3)cc1

Procedure:
8-Ethoxy-2-(4-methoxy-phenyl)-5,6-dihydro-quinazoline (860 mg; 3.05 mmol) is dissolved in acetic acid/water (16 ml/1.6 ml) and refluxed for 15 minutes. Evaporation to dryness delivers the title compound as yellow crystals. 1H-NMR (400 MHz; DMSO-d6): 9.04 (s, 1H); 8.34 (d, 2H); 7.10 (d, 2H); 3.86 (s, 3H); 2.99 (t, 2H); 2.79 (t, 2H); 2.15 (m, 2H). MS (m/z) ES+: 255 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[H-].[Na+].CN(C)C=O.[CH2:16](I)[CH2:17][CH3:18]>C(OCC)(=O)C>[CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:16][CH2:17][CH3:18])=[O:7])[CH2:3]1
Reactant: C=C1CC(C(=O)O)C1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C1CC(C(=O)OCCC)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A mixture of 3-methylidenecyclobutanecarboxylic acid (18 g), sodium hydride (6.9 g) and N,N-dimethylformamide (300 mL) was stirred at room temperature for 10 min, propyl iodide (17 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by distillation (45-50° C., 2 mmHg) to give the title compound as a colorless oil (16 g, 66%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14].O>ClCCl>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[S:2]([Cl:1])(=[O:5])=[O:3])([O-:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(S(=O)(=O)Cl)c2c1
Yield: 51 %

Procedure:
A solution of chlorosulfonic acid (3 mL, 45 mmol) and Na2SO4 (700 mg, 4.9 mmol) in dichloromethane (30 mL) was treated dropwise with a solution of 5-nitroindole (800 mg, 4.9 mmol) in dichloromethane (20 mL) over 1 hour, stirred for another 30 minures, and decanted to provide a thick brown oil. The oil was slowly treated with water (20 mL), stirred for 10 minutes, filtered, and dried in a vacuum oven to provide 651 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Reactant: Nc1cccc(B(O)O)c1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)c1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a solution of (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (1.6 g, 5.0 mmol) in DMF (10 mL) was added 3-amino-phenyl boronic acid (0.75 g, 5.5 mmol), Pd(PPh3)4 (45 mg, 0.15 mmol), potassium carbonate (0.75 g, 5.5 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (25 mL×3). The combined organics were concentrated under reduced pressure to give the crude product, which was washed with EtOAc to give pure (R)-(1-(3′-aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol (C-2) (810 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.23-7.28 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.74 (dd, J=7.8, 1.2 Hz, 1H), 3.66-3.77 (m, 3H), 3.45-3.53 (m, 1H), 3.26-3.34 (m, 1H), 1.68-1.88 (m, 3H), 1.45-1.55 (m, 1H). MS (ESI) m/e (M+H+) 333.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([Cl:23])=[CH:17][N:16]=1>>[Cl:23][C:18]1[C:19]([NH:21][CH3:22])=[N:20][C:15]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])=[N:16][CH:17]=1
Reactant: CNc1nc(Cl)ncc1Cl
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Product: CNC(=O)c1ccc(Nc2ncc(Cl)c(NC)n2)c(OC)c1

Procedure:
4-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide was prepared by the procedure described in Example 7 using 4-amino-3-methoxy-N-methylbenzamide and 2,5-dichloro-N-methylpyrimidin-4-amine. 1H NMR δ (ppm) (CDCl3): 8.58 (1H, d, J=8.4), 7.95-7.92 (1H, m), 7.70 (1H, s), 7.45 (1H, d, J=1.9), 6.09 (1H, s), 5.30 (1H, s), 4.03-3.95 (3H, m), 3.15-3.09 (3H, m), 3.02 (3H, t, J=4.8).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1

Procedure:
A solution of 21 g. of methyl 16-bromohexadecanoate and 20 g. of ethyl 4-aminobenzoate in 150 ml. of hexamethylphosphoramide is stirred at 120° C. for 20 horus, cooled, diluted with water and filtered. A methylene chloride solution of the solid is dried over anhydrous magnesium sulfate, clarified with activated charcoal, and filtered through silica gel. The filtrate is evaporated and the residue crystallized from acetonitrile to yield ethyl 4-(15-carbomethoxypentadecylamino)benzoate as a white crystalline solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3]1.[H-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](F)[CH:31]=1.O>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[O:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:3]1
Reactant: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)cc1C
Reactant: Fc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2Oc2cccc(Cl)c2)cc1C
Reaction time: 2 h

Procedure:
A solution of 15.0 g (0.04 mol) of the trans-3-hydroxy-4-(3,4-dimethyl-phenoxy)-1-carbobenzyloxy-piperidine described in Example 19 in 100 ml of dimethylformamide is introduced in the course of 30 minutes, at 30°-35°, into a suspension of 2.8 g (0.062 mol) of a 55% strength oily dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture is then warmed to 50° and treated dropwise with 7.16 g (0.055 mol) of 1-chloro-3-fluorobenzene. The reaction mixture is subsequently stirred for 41/2 hours at 60°-70° and then for 15 hours at room temperature, cooled in an ice-water bath and treated with 250 ml of water. The mixture is extracted by shaking with 3 times 250 ml of ethyl acetate and the combined organic phases are washed twice with water, dried over magnesium sulphate and evaporated to dryness, first under a water pump vacuum and then under a high vacuum. The oil which remains behind is dissolved in 100 ml of toluene and the solution is filtered through a layer of silica gel. Elution with a toluene/ethyl acetate mixture (4:1) gives trans-3-(3-chlorophenoxy)-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine in the form of a pale yellow oil.
Reaction SMILES: CC1C=CC(S(O/[N:12]=[C:13]2\[CH2:14][CH2:15][CH2:16][C:17]3[O:21][CH:20]=[C:19]([C:22]([OH:24])=[O:23])[C:18]\2=3)(=O)=O)=CC=1.C([O-])(=[O:27])C.[K+].C(O)C>O>[O:27]=[C:13]1[NH:12][C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][O:21][C:17]=2[CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O/N=C2\CCCc3occ(C(=O)O)c32)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2occ(C(=O)O)c2N1
Yield: 35.8 %

Procedure:
A mixture of 1.0 g of (E)-4,5,6,7-tetrahydro-4-[[[(4-methylphenyl)sulfonyl]oxy]imino]-3-benzofurancarboxylic acid, 5.9 g of potassium acetate, 23 ml of ethanol and 39 ml of water is heated at reflux for 48 hours. The reaction mixture is concentrated in vacuo, 80 ml of methylene chloride added and the separated organic layer washed with water, brine and dried with Na2SO4. The organic layer is concen-trated in vacuo to a solid which is purified by chroma-tography on a preparative silica gel plate by elution with 0.5% acetic acid in ethyl acetate. The eluted band is washed with 1% acetic acid in ethyl acetate. The organic layer is dried with Na2SO4 and concentrated in vacuo to give 200 mg of off-white solid which is crystallized from ethyl acetate-hexane to give 165 mg of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[CH:9])=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)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>[NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[C:9][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#Cc1ccc(N)c(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(C#Cc2ccc(Cl)cc2)ccc1N

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 9, using 3.1 grams (0.022 mole) of 3-amino-2-cyano-6-ethynylpyridine, 7.4 grams (0.031 mole) of 4-chlorophenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile, yielding 3-amino-2-cyano-6-[(4-chlorophenyl)ethynyl]pyridine.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>O1CCOCC1>[CH3:25][N:23]([CH3:24])[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:41]2[CH2:42][CH:43]=[C:38]([C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][CH3:27])[CH:30]=4)[NH:34][CH:33]=3)[CH2:39][CH2:40]2)=[O:26])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3=CCN(C(=O)NCC4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Reaction time: 20 h
Yield: 32.1 %

Procedure:
(4-dimethylamino-4-phenylcyclohexyl-methyl)-carbamic acid phenyl ester (528.7 mg, 1.5 mmole) was added to a solution of 5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (317.9 mg, 1.5 mmole) in dioxane (10 ml). The reaction mixture was then boiled for 20 hours under reflux. The reaction mixture was a suspension at RT. The solid was filtered off, washed with cold dioxane (3×1 ml) and dried. The solid was part of the polar diastereomer of 4-(5-methoxy-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl-methyl)-amide (99 mg, m.p. 120°-125° C., 14%). The reaction solution (filtrate and wash phases) was concentrated by evaporation. The residue contained phenol as well as the non-polar product and the remainder of the polar product. The diastereoisomers were separated and purified by flash chromatography on silica gel (75 g). Methanol (900 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (234 mg, m.p. 98°-104° C., 32%) and a further part of the polar diastereoisomer (120 mg, m.p. 108°-111° C., 16%) were thereby obtained in pure form.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][NH2:21]>C1COCC1.CCN(C(C)C)C(C)C>[CH3:20][NH:21][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2N methylamine in THF and DIEA to give 2-methylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 270 (MH+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O1CCCC1.C([Li])CCC.O[CH:38]1[CH2:42][C:41]2[C:43]([Cl:48])=[C:44]([Cl:47])[CH:45]=[CH:46][C:40]=2[O:39]1>CCCCCC>[CH2:42]([C:41]1[C:43]([Cl:48])=[C:44]([Cl:47])[CH:45]=[CH:46][C:40]=1[OH:39])[CH:38]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OC1Cc2c(ccc(Cl)c2Cl)O1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC=CCc1c(O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Twenty-five grams of n-hexyltriphenylphosphonium bromide were dissolved in 350 ml. of dry tetrahydrofuran and cooled to -10° C. To the solution were added 37 ml. of a 1.6M solution of n-butyllithium in hexane. The solution was slowly warmed to room temperature and stirred for one hour. The solution was then cooled to 0° C. and a solution of 2.38 g. of 2,3- dihydro-2-hydroxy-4,5-dichlorobenzofuran in 20 ml. of tetrahydrofuran was added. The reaction was allowed to reflux for approximately 18 hours. The solution was then cooled and evaporated to dryness. Ethyl acetate and water were added and the pH was adjusted to 2.5. The layers were separated. The organic layer was washed with a saturated sodium chloride solution, filtered through sodium sulfate, and evaporated to dryness. The residue was purified by high pressure liquid chromatography giving 2.51 g. of the desired intermediate as a mixture of cis and trans isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C)[CH:12]=[O:13].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:12]=[O:13])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
N-Butyl lithium (50 mL, 2.5M in hexane) was added drop wise to a solution of 5-Bromo-2-methoxy-pyridine (22.4 g, 119.1 mMol) in dry tetrahydrofuran (240 mL) at −78 degrees. After complete addition the solution was stirred at −78 for an additional ninety minutes at which time dimethylformamide (18.5 mL, 238.3 mMol) was added drop wise and the solution stirred for ninety more minutes at −78 and then allowed to warm to room temperature. The mixture was then poured into saturated sodium bicarbonate solution (1000 mL) and extracted with diethyl ether (3×250mL). The combined organics were dried with magnesium sulfate, filtered, and concentrated to dryness to yield 15.4 g (94% yield) of 6-Methoxy-pyridine-3-carbaldehyde as a pale yellow solid. 1H NMR (DMSO-d6): δ=9.97 (s,1H), 8.77 (m, 1H), 8.12 (dd, 1H, J=8.6, 2.3 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.97 (s, 3H). LC/MS (Method A), rt=0.25 mins., purity=92.8%, calculated mass=137, [M+H]+=138. HPLC (Method C): rt=4.9 mins., purity=95.9% @ 210-370 nm and 98.7% @ 256 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:25])[N:13]([CH3:24])[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][CH:16]=1.Br.[OH-].[Na+]>CC(O)=O.O>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:25])[N:13]([CH3:24])[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][CH:16]=1
Reactant: COc1cc(F)c(-c2cnc(Nc3ccccc3)n(C)c2=O)cc1F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(O)cc2F)c1=O
Temperature: 125 °C
Reaction time: 72 h

Procedure:
5-(2,5-difluoro-4-methoxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.066 g, 0.192 mmol) was dissolved in AcOH (2 mL) and HBr (1.087 ml, 9.612 mmol; 48 wt % in H2O) was added. The mixture was stirred at 125° C. for 3 days. The reaction mixture was cooled to room temperature and then diluted with H2O. The pH of the reaction mixture was adjusted to a pH of about 5 with 6M aqueous NaOH, which resulted in the formation of an off-white precipitate that was filtered and washed with H2O. The solid was dried directly in the fritted funnel under vacuum overnight and then dissolved through with MeOH/THF and concentrated. The product was obtained (58 mg; 92%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (br s, 1H), 8.91 (br s, 1H), 7.70 (s, 1H), 7.55-7.48 (m, 2H), 7.36 (t, 2H), 7.23 (m, 1H), 7.14 (m, 1H), 6.77 (m, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 330 (M+1).