Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O-])(O)=[O:10].[Na+].C=O.Cl>O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: O=C([O-])O
Reactant: Oc1cccnc1Cl
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: OCc1ccc(O)c(Cl)n1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO3 (19.5 g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask. The flask is placed in an oil bath at 90° C., and after 5 min, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3×8 mL, then 2.2 mL all at 90-min intervals and then the final 2.3 mL after the reaction stirs for 15 h at 90° C. The reaction is stirred at 90° C. for another 4 h and then cooled by placing the flask in an ice bath. The pH of the reaction is then adjusted to 1 using 6N HCl. The reaction is stirred for 1.5 h in an ice bath allowing an undesired solid to form. The undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc. The combined organic extracts are concentrated in vacuo, toluene is added to the flask and removed in vacuo to azeotrope water, and then CH2Cl2 is added and removed in vacuo to obtain 2-chloro-6-(hydroxymethyl)-3-pyridinol (C1) as a pale yellow solid (81% yield) sufficiently pure for subsequent reaction. MS (EI) for C6H6ClNO2, m/z: 159 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.OC1C=C2C(CCC(NCC(C3C=CC=C(Cl)C=3)O)C2)=CC=1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[C:46]([CH2:45][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1)([O:48][CH2:49][CH3:50])=[O:47]
Reactant: Oc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Reactant: CCOC(=O)CBr
Agent: Oc1ccc2c(c1)CC(NCC(O)c1cccc(Cl)c1)CC2
Product: CCOC(=O)COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2

Procedure:
Among the methods for the preparation of the products of formula (A) above, there is described an O-alkylation that, starting from 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol or from 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol, by reaction with ethyl bromoacetate gives the 2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-phenylethanol, hereinafter designated COMPOUND 1, or the 2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-(3-chlorophenyl)ethanol, hereinafter designated COMPOUND 2. This reaction does not actually give good results because of the very low yield in final product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([Pb+3])[CH:44]=2)=[CH:39][CH:38]=1>ClCCl.Cl>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([CH:6]3[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]3=[O:9])[CH:44]=2)=[CH:41][CH:42]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (described in U.S. Pat. No. 5,089,046A) (0.296 g, 1.74 mmol) and N,N-dimethylaminopyridine (1.06 g, 8.70 mmol) is added anhydrous chloroform (20 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (5 ml), followed by 4′-chloro-4-methylbiphenyl-3-yllead triacetate (1.12 g, 1.91 mmol) in one portion and the reaction mixture heated at 80° C. for 1-2 hours. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (150 ml) and dilute aqueous hydrochloric acid (30 ml), followed by stirring for 5 minutes and filtration through diatomaceous earth to remove inorganic residues (additional washing with solvents). All organic fractions are combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (100% hexane to hexane/ethyl acetate 5:1 ratio) then triturated with hexanes to afford 4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.318 g) as a cream powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10](OCC)=[O:11].CC(C)([O-])C.[K+]>>[OH:11]/[CH:10]=[C:4]1/[C:5](=[O:8])[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]/1
Reactant: CCOC=O
Reactant: CC1(C)CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC1(C)CCC(=O)/C(=C/O)C1

Procedure:
reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tert-butoxide to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:65][C@H:66]([C:71](O)=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:65][C@@H:66]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:71]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:72]
Reactant: CCCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To a solution of propyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (12, 190 mg, 0.44 mmol), DCC (111 mg, 0.54 mmol) and DMAP (6 mg, 0.045 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (158 mg, 0.45 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (6 mL) and cooled to 0° C. Dimethylamine (6 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 122 mg (51%) of the title compound as a colorless semi solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (30 mg, 0.1 mmol) in DMF (1 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (34 mg, 0.1 mmol), N,N-diisopropyl ethyl amine (83 μL, 0.48 mmol) and 4-aminotetrahydropyran (11 mg, 0.1 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and purification by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) afforded the title compound (29 mg, 76%) as a white solid. MS: m/e=395.2 [M+H]+.
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])[CH3:6])(C)C.[CH2:10]([S:17][C:18]1[N:23]=[C:22]([NH2:24])C=C(Cl)[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:26]>CN1C(=O)CCC1>[NH2:24][C:22]1[N:23]=[C:18]([S:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:19]=[C:8]([NH:4][C@H:5]([CH3:6])[CH2:7][OH:26])[CH:9]=1
Reactant: Nc1cc(Cl)nc(SCc2ccccc2)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: O
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2)n1

Procedure:
N,N-Diisopropylethylamine (6.0 ml) was added to a solution of R-alaninol (12.0 ml) and 2-(benzylthio)-6-chloropyrimidin-4-amine (1.9 g) (Nugent, R. A., et al. PCT Int. Appl. 1996. 252 pp. WO9635678-A1) in NMP (6 ml) and stirred at 100° C. for three days before pouring into H2O (200 ml) and filtration of the precipitate. This solid was dried in vacuo to afford the subtitle compound as a pale sandy yellow solid. Yield: 4.1 g.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH:6]1([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>ClC(Cl)C>[CH3:5][O:4][N:3]([CH3:2])[C:12](=[O:13])[CH2:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNOC
Reactant: O=C(Cl)CC1CCCC1
Agent: Cl
Solvent: CC(Cl)Cl
Product: CON(C)C(=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (13 g, 0.12mole) was stirred in 250 mls of dichloroethane and cooled to 0° C. under argon. Triethylanime (25 g, 0.25mole) was added dropwise over 15 minutes and the mixture stirred cold for 30 minutes. The acid chloride of Example A (15 g,0.1mole) was dissolved in dichloroethane (50 mls) and added at 0° C. over 1/2 hour to the mixture. The mixture was then stirred for an additional hour at 0° C. The mixture was allowed to warm to room temperature over 2 hours and the solvent was removed in vacuo. The residue was treated with 100 mls of ethyl acetate/ether (25:75) and the triethylamine hydrochloride filtered. The filtrate was stripped of solvent and the residue distilled at 0.1 mm Hg, b.p.=62°-63° C. to give 12 g (70% yield) of the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:7]2[C:8](=[C:13]([CH3:22])[N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1>C1(C)C(C)=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[C:7]2[C:8](=[C:13]([CH3:22])[N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(Cl)c2nn(-c3ccccc3)c(C)c2n1
Reactant: NCCO
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2nn(-c3ccccc3)c(C)c2n1

Procedure:
A mixture of ethanolamine (1.0 ml) and 7-chloro-3,5-dimethyl-2-phenylpyrazolo[4,3-b]pyridine (0.080 g) in dry xylene (5 ml) was heated under reflux for 48 h. After cooling, the resulting brown oil solidified. The solvent was decanted off and the solid washed several times with xylene. The brown solid was dissolved in aqueous methanol and the pH adjusted to pH 8-9 with 10% sodium carbonate solution. The resulting solid was filtered off, dried and recrystallised from chloroform/pentane to give the title compound as a beige solid (0.029 g), m.p. 159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([C:30](=[O:32])[CH3:31])[CH:38]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Product: CC(=O)c1cccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 60.2 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 3-acetylphenyl-boronic acid (14.5 mg, 0.089 mmol) as described in Example 35 part c), affording 1-[2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-3-yl]ethanone (16.8 mg, 60%). δH (360 MHz, CDCl3) 2.66 (3H, s), 7.39-7.44 (1H, dd, J 9.8 and 8.4), 7.47-7.52 (1H, m), 7.58-7.62 (3H, m), 7.80-7.85 (2H, m), 8.01 (1H, dt, J 7.7, 1.2), 8.18 (1H, d, J 1.4), 8.55 (1H, d, J 8.8), 9.30 (1H, d, J 4.6). m/z (ES+) 411 [MH]+.
Reaction SMILES: C(OC(=O)CN(C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CO)[N:10]=1)(C)(C)C.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:46]=[CH:45][C:33]([CH2:34][NH:35][S:36](C2C=CC=CN=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:31]=[CH:32][C:33]([CH2:34][NH:35][S:36]([C:12]2[CH:11]=[N:10][CH:9]=[CH:14][CH:13]=2)(=[O:38])=[O:37])=[CH:45][CH:46]=1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccccn1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (279 mg, 0.824 mmol) obtained in Reference Example 3-(b), and using N-[4-(thiazol-2-yl)benzyl]pyridin-2-ylsulfonamide (275 mg, 0.830 mmol) obtained in Reference Example 5 in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide to afford the title compound (496 mg) as a white foam. (Yield: 92%) Mass spectrum (FAB, m/z): 652 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B(O)O)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[C:34]1[CH:35]=[N:36][NH:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:32][C:21]1([CH3:31])[C:22]2=[N:23][CH:24]=[C:25]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:26]=[C:27]2[N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH2:20]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Reactant: Brc1cn[nH]c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3cn[nH]c3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (60 mg, 0.14 mmol), 4-bromopyrazole (21 mg, 0.14 mmol), PdCl2(PPh3)2 (9.8 mg, 0.014 mmol), sodium carbonate (29.7 mg, 0.28 mmol) and heating in the microwave for 1 h at 120° C. After purification 4-(3,3-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.71-8.79 (1H, m), 8.10-8.17 (1H, m), 7.78-7.97 (4H, m), 7.69-7.75 (2H, m), 7.38-7.45 (1H, m), 7.30-7.37 (1H, m), 6.34 (1H, quin, J=2.2 Hz), 3.83-3.93 (2H, m), 2.33-2.46 (3H, m), 1.63-1.70 (3H, m), 1.56-1.62 (3H, m). Mass Spectrum (ESI) m/e=451 (M+1).
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](O)=[O:22])=[CH:16][CH:15]=1>CO>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:22])[N:4]([CH2:3][CH:2]([F:12])[F:1])[C:5]3[C:6]([N:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:16][CH:15]=1
Reactant: Nc1ccccc1NCC(F)F
Reactant: O=C(O)C(=O)c1ccc(Cl)cc1
Solvent: CO
Product: O=c1c(-c2ccc(Cl)cc2)nc2ccccc2n1CC(F)F
Yield: 31.7 %

Procedure:
To a solution of 400 mg (2,32 mM) of N-(2,2-difluoroethyl)benzene-1,2-diamine in 7 ml of methanol were added 428 mg (2,32 mM) of 4-chloro-α-oxo-benzeneacetic acid. The mixture was refluxed for 3 h. A solid was filtered, washed and dried under vacuum to give 236 mg of 3-(4-chlorophenyl)-1-(2,2-difluoroethyl) quinoxalin-2(1H)-one Yield: 32%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1N
Yield: 98.7 %

Procedure:
[1-(3-Methyl-4-nitrophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (1.744 g), iron powder (1.52 g), ammonium chloride (1.45 g), ethanol (50 ml) and water (50 ml) were heated to reflux temperature under nitrogen for 2 hours. The mixture was cooled and the iron filtered off. Water (200 ml) was added to the residue and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4), and concentrated to give the sub-title compound (1.56 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:9]([O:4][CH2:3][CH:2]([NH2:1])[CH2:5][O:6][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NC(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(N)COCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-amino-1,3-propanediol in THF is added dropwise with vigorous stirring to a suspension of sodium hydride over a period of 45 minutes to 2 hrs. The reaction mixture is stirred at room temperature for an additional hr and sequentially treated with a solution of one equivalent each of octadecyl bromide and benzyl bromide, respectively. The reaction mixture is stirred at room temperature for 4-14 hrs. The reaction mixture is worked up by extraction with methylene chloride. The methylene chloride layer is washed with water (3×50 mL), saturated NaCl (1×50 mL) and dried (MgSO4). The dried organic layer is evaporated under vacuum to afford the product as a white solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][CH3:7])([CH3:4])[CH3:3].C([Li])CCC.[Si:13]([O:20][CH:21]1[CH2:25][C:24](=[O:26])[CH:23]=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1.CCCCCC>[Si:13]([O:20][CH:21]1[CH2:25][C:24]([OH:26])([CH2:7][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:23]=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1C=CC(O)(CC#C[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution mixture of 6.5 g of trimethylsilyl-1-propyne and 50 ml of tetrahydrofuran was added under nitrogen stream and at -30° C. 17.4 ml of 1.56 M hexane solution of n-butyllithium and the resulting mixture was stirred at the same temperature for 1 hour. Then, a solution mixture of 10 g of (RS)-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 100 ml of tetrahydrofuran was added by drops to the reaction solution obtained above, and the resulting mixture was stirred for further one hour. The reaction liquid thus obtained was after-treated and purified in the same manner as in (2) of the intermediate preparation example 1 to obtain 8.9 g of (1RS,4RS)-4-hydroxy-4-(3-trimethylsilyl-2-propynyl)-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 59%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[N:12]=2)=[CH:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.[Cl-].[Na+].O>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:3][CH:4]=3)[NH:9][CH:10]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Clc1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)c[nH]2)cn1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 2-Chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine (72.8 g) and piperazine (61.8 g) in DMSO (478 mL) was heated to 105 degrees 16 hours. The reaction mixture was cooled to room temperature and diluted with 2500 mL half-saturated brine. The resultant precipitate was collected by filtration and triturated with 2000 mL hot methanol. The solids were collected by filtration, the mother liquor was concentrated to about 100 mL, and the additional precipitate was collected and combined with the original solids to provide 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (49 g). MS m/z 374 (M++1).
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.C([Cl:22])(=[O:21])CCCC.[C:23]1([CH3:29])C=C[CH:26]=[CH:25][CH:24]=1>>[ClH:22].[CH2:23]([C:29]1[NH:8][C:7](=[O:21])[C:2]2([CH2:6][CH2:5][CH2:4][CH2:3]2)[N:1]=1)[CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccccc1
Reactant: N#CC1(N)CCCC1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC1=NC2(CCCC2)C(=O)N1
Product: Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To the solution made of 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane and 12.2 g (0.12 mol) of triethylamine in 80 ml of toluene, 13.0 g (0.1 mol) of valeroyl chloride was added at 30° C. After the addition the mixture was stirred at 60° C. for 1 hour, then it was cooled and washed three times with water. The phases were separated and to the organic phase at first 25 g of 20 w/v % sodium hydroxide solution and 7 g of tetrabutyl ammonium hydrogen sulfate, then at 10-15° C. 40 g of 30-35 w/v % hydrogen peroxide solution were added. The reaction mixture was heated to 25-30° C. and was stirred at that temperature for 2 hours. The mixture was then heated to 60° C. and the phases were separated again. To the toluene phase the solution of 3 g of sodium in 30 ml methanol was added and the mixture was heated to reflux temperature to distille out the solvent and the volatile components. The concentration was continued until the mixture was stirrable. To the resulting product 100 ml of acetone was added, the mixture was filtered and the pH of the filtrate was adjusted to 1-2 with conc. hydrochloric acid. The precipitated product was filtered off and dried to obtain 14 g of the title compound, yield 60.8%.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([N:7]([CH3:20])[C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(-c2ccccc2)cc1)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(F)F)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
13.00 g (49.0 mmol) N-(Biphenyl-4-yl)-2,2,2-trifluoro-acetamide (II.1.a) is dissolved in 200 mL acetone and 13.5 g (98.0 mmol) potassium carbonate is added. 3.50 mL (55.7 mmol) methyl iodide is added and the mixture is stirred at RT over night. The solvent is evaporated. The residue is taken up in water and extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated.