Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23](S(C)(=O)=O)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23]([NH:7][CH2:6][C:5]3[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COc1cc(CN)cc(OC)c1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCc3cc(OC)cc(OC)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 3,5-dimethoxybenzylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (10 mg, 0.02 mmol). 10 mg of 2-(3,5-Dimethoxy-benzylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.27 (s, 1H), 8.47 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.26 (s, 2H), 5.99 (br, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.28 (d, J=6.2 Hz, 2H), 3.74 (s, 6H), 2.98 (m, 4H), 2.16 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[Cl:35][C:36]1[CH:41]=[C:40]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Yield: 95.4 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.0 mmol), 3-chloro-phenylboronic acid (2.35 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, 5% ethyl acetate/petroleum ether) afforded 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 95.4%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.51 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.8 Hz), 7.68 (dd, 2H, J1=8.7 Hz, J2=1.5 Hz), 7.44 (m, 1H), 7.28-7.06 (m, 5H), 6.53 (s, 1H), 6.13 (d, 1H, J=10.2 Hz), 2.65 (m, 1H), 1.15-1.08 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:15]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1.ClCCl.C(N(CC)C(C)C)(C)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55]>>[CH3:22][N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])=[C:3]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])[CH2:28][CH2:29]3)[CH:4]=2)[C:9]1=[O:12])[CH3:23]
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2ccco2)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 7-amino-2-(3-dimethylaminomethyl-benzyl)-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 11b (73.70 mg, 0.15 mmol) was taken up in clean, dry, reagent-grade dichloromethane (3.00 ml, 46.52 mmol) and the mixture was stirred at room temperature under nitrogen atmosphere until the solids were all in solution. To this stirred solution was then added the N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) followed by the furan-2-carbonyl chloride (0.02 ml, 0.20 mmol) and the reaction was allowed to stir overnight. The reaction was quenched with 3 ml of 2N HCl. The product solution was diluted with 10 ml of water and 10 ml of dichloromethane. The layers were separated and the product was extracted using dichloromethane (3×10 ml). The organic phases were combined and washed with brine (1×25 ml) and the product solution was then dried over MgSO4. The solution was then filtered under vacuum and the collected solution was concentrated under reduced pressure. The resultant yellow oil was then purified using silica gel column chromatography, eluting 100% dichloromethane to 7.5% MeOH in dichloromethane. The product needed further purification and was subjected to reverse-phase HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. Furan-2-carboxylic acid [2-(3-dimethylaminomethyl-benzyl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide 11c (11.30 mg, 0.02 mmol) was isolated as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:40]1([CH:50]=[CH:51][CH2:52][CH2:53][OH:54])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16]([O:54][CH2:53][CH2:52][CH:51]=[CH:50][C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][CH:41]=3)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCCC=Cc1cccc2ccccc12
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC=Cc2cccc3ccccc23)C1c1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
332 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 238 mg (1.2 mM) of 4-(1-naphthyl)-3-buten-1-ol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 507 mg of methyl 4-(1-naphthyl)-3-butenyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (yield 99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:6])=[CH:3][C:2]=1[O:1][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCBr
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(N)c(OCCCCC)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 142.3 %

Procedure:
3-Hydroxy-4-nitrobenzoic acid (5 g, 27.4 mmol), DMF (40 ml), potassium carbonate (13.8 g, 100 mmol) and pentyl bromide (8.7 ml, 70 mmol) were mixed, and this solution was stirred at 100° C. for 1.5 hours. The reaction mixture was filtered to remove the inorganic salt, and DMF was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the obtained residue, and the mixture was washed 3 times with saturated brine (30 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (150 ml) and 10% palladium carbon catalyst (0.5 g) were added to the obtained residue, and the mixture was stirred at room temperature for 5.5 hours in a stream of hydrogen. The palladium-carbon catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=5/1) to give pentyl 4-amino-3-pentyloxybenzoate (5.72 g, 70% in 2 steps) as a pale-yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:15]=[CH2:14]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCn1c2ccccc2c2ccccc21

Procedure:
Into a 500-mL, three-necked, round-bottomed flask, equipped with a magnetic stirrer, a thermometer, and a condenser connected to a nitrogen bubbler, were placed carbazole (8.4 g, 50 mmole), allyl bromide (10 mL, 115 mmole), powdered anhydrous potassium carbonate (41 g, 300 mmole), and anhydrous acetonitrile (300 mL). The resultant mixture was stirred and heated under reflux with a heating mantle for 18 hours. Dichloromethane (300 mL) was then added, and the mixture was filtered through a pad of Celite. The clear filtrate was evaporated, and the residue was recrystallized from methanol to yield the desired product as amber-colored crystals. The product had melting point 56°-57° C., and sublimation (100° C./0.1 mm Hg) yielded white crystals (8.65 g, 83%), melting point 57°-58° C. The proton NMR spectrum in carbon tetrachloride was
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:29]C(=O)OC(C)(C)C)[N:16]=[N:17][C:18]=3[C:19](=[O:21])[NH2:20])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH2:29])[N:16]=[N:17][C:18]=3[C:19]([NH2:20])=[O:21])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3cccn3)n2)c(C(N)=O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2cccn2)n1
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(5-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (70 mg, 142 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.01 g, 1.35 mL, 17.6 mmol) and the mixture stirred at 25° for 2 h. The mixture was concentrated in vacuo and then diluted with dichloromethane and then washed successively with 1N NaOH (3×5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and then dried in vacuo to give 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-((1R,2S)-2-aminocyclohexylamino)pyridazine-3-carboxamide (14.2 mg, 36.1 μmol, 25%) as a white solid. 1H NMR (DMSO-d6) δ: 11.93 (s, 1H), 8.63-8.71 (m, 1H), 8.45 (br. s., 1H), 7.78-7.94 (m, 3H), 7.71 (br. s., 1H), 7.51 (d, J=7.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.63 (dd, J=2.5, 1.8 Hz, 1H), 4.02 (br. s., 1H), 3.18 (br. s., 1H), 1.46-1.79 (m, 7H), 1.20-1.41 (m, 3H); MS (EI/CI) m/z: 394.3 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35])=[O:29])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:34]([C:33]3[CH:32]=[C:31]([NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])[CH:39]=[CH:38][CH:37]=3)=[O:35])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of Intermediate 7 (250 mg, 0,83 mmol) and 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)benzoic acid (196 mg, 0.83 mmol, e.g. available from Fluka) in N,N-dimethylformamide (4 ml) was treated with N,N-diisopropylethylamine (0.569 ml, 3.3 mmol) and (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (472 mg, 0.91 mmol) and allowed to stir at room temperature for 4 hours. An additional portion of (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (0.5 equivalents, 0.41 mmol) was added and the mixture stirred for an additional hour. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and aqueous sodium bicarbonate solution (50 ml); saturated sodium chloride solution was added and the layers allowed to separate overnight. The aqueous layer was further extracted with ethyl acetate (50 ml), and the organic fractions collected, dried (Na2SO4) and evaporated; however the residue contained very little product. A white solid was filtered off from the aqueous layer and dried to give the title compound (193 mg). LCMS showed MH+=523; TRET=2.99 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:24]=[C:16]2[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20](Cl)[N:15]2[N:14]=1)(=[O:12])=[O:11].C[O-].[Na+].CS(C)=O.[C:32](O)(=[O:34])C>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:24]=[C:16]2[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([O:34][CH3:32])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)O
Reactant: COc1ccc(Cl)n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(OC)n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc12
Temperature: 70 °C

Procedure:
N-(2,6-Difluorophenyl)-5-chloro-8-methoxy[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (1.0 g, 2.7 mmol), sodium methoxide (25 percent in methanol, 2.5 mL, 0.58 g, 11 mmol) and dimethyl sulfoxide (20 mL) were mixed with stirring and slowly heated to 70° C. over a 40-min period. After a short reaction period, the reaction mixture was acidified with acetic acid and diluted with dichloromethane and water. The solid that separated was recovered by filtration. The organic layer was separated, was washed several times with water, and was concentrated by evaporation under reduced pressure. The residue obtained was washed with water and combined with the previously obtained solid. The combined solids were washed with ether and hexane and dried to obtain 0.7 g of the title compound as an off-white powder melting at 319°-320° C. (d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 605 %

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (100 mg) in dry THF (10 ml) containing potassium carbonate (380 mg) was treated slowly with morpholine (0.32 ml, 317 mg). The resulting mixture was stirred at room temperature under nitrogen for 18 h, before filtering and concentrating in vacuo to give the title compound as a white solid (620 mg). m.p. 82°-83° C.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1.[CH3:12][Al](C)C.[NH4+].[Cl-].Cl>C(Cl)Cl.CCCCCCC>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]([OH:11])[CH3:12])[S:8][CH:9]=1
Reactant: C[Al](C)C
Reactant: O=Cc1nc(CCl)cs1
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(O)c1nc(CCl)cs1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-chloromethyl-thiazole-2-carbaldehyde (1.05 g, 6.49 mmol) in CH2Cl2 (65.0 mL) was treated at 0° C. with trimethylaluminum (32.45 mL of a 1M solution in heptane, 32.45 mmol). The reaction mixture was then stirred at 0° C. for 45 min. CH2Cl2 (100.0 mL) followed by sat. aq. NH4Cl (80 mL) was then added. The mixture was then treated with 1N HCl (100 mL) and the aq. layer was extracted with CH2Cl2 (100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.66 min, [M+H]+=178.50.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[CH:30][CH:29]=1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 6-methoxypyridin-3-ylcarbamate (0.244 g, 1.00 mmol, from Step 1) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and heated to 50° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (280 mg, 58%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 485.30; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 3.76 (s, 3H) 6.38 (s, 1H) 6.69 (d, J=8.77 Hz, 1H) 7.03 (m, 2H) 7.12 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.60 Hz, 1H) 7.4 (dd, J=8.5 Hz, 1 Hz, 1H) 7.73 (dd, J=8.9 Hz, 2.7 Hz, 1H) 8.14 (d, J=2.5 Hz, 1H) 8.20 (dd, J=8.77 Hz, 2.5 Hz, 1H) 8.49 (s, 1H) 8.55 (d, J=2.5 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH3:22])[CH:14]=2)=[N:10][CH:11]=1)=[O:4].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:23]([C@H:2]1[NH:1][C:26](=[O:28])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH3:22])[CH:14]=3)=[N:10][CH:11]=2)[C:3]1=[O:4])[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1cc(Oc2ncc(NC(=O)[C@H](N)CC)cn2)ccc1C
Solvent: ClCCl
Product: CCOc1cc(Oc2ncc(N3C(=O)N[C@H](CC)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 132 %

Procedure:
To a solution of ((2R)-2-amino-N-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)butanamide (Intermediate 94, 62 mg) in dry dichloromethane (4 mL), TEA (158 μl, 1.13 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (25.2 mg, 0.085 mmol) in dry dichloromethane (2 mL) was then added dropwise and the reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was evaporated under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, 12 g silica cartridge) with Cyclohexane/EtOAc as eluents from 100/0 to 50/50 in 20 minutes and then 50/50 during 15 minutes to afford the title compound as a white solid (40 mg).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[N+]([O-])=[O:13]>[N+]([O-])(O)=O>[OH:13][C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2
Reactant: O=[N+][O-]
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: O=[N+]([O-])O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Adamantanone (12 g, 80 mmol) was added under stirring to nitric acid (98%, 100 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 h and then heated to 60° C., for 2 h until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling (NO3 adduct of the hydroxyketone). Water (40 mL) and conc. H2SO4 (98%, 15 mL) were added. The resulting clear yellow solution was heated on the steam bath in a hood (nitrous fumes) for 1 h. The solution was then cooled and extracted with a 2:1 mixture of n-hexane and diethylether to remove unreacted adamantanone (1.0 g). The acid layer was neutralized with 30% aq. NaOH solution, and while warm, extracted with chloroform. The extracts were combined, washed with brine solution, and concentrated in vacuum. The crude product was dissolved in CH2Cl2 (15 mL) and hexane was added until no more precipitate was formed. The solid material was isolated by filtration and dried to get 5-hydroxy-adamantan-2-one. Yield: 9.0 g (70%). Solid; M.R: 278.8-300° C. (decomposes) m/z (M+1) 167; 1H NMR (CDCl3) 300 MHz δ 2.70-2.55 (m, 2H), 2.36-2.32 (m, 1H), 2.11-1.93 (m, 10H). 13C NMR (CDCl3) 75 MHz δ 217.0, 66.7, 46.7, 46.6, 44.7 (2C), 43.8, 37.9 (2C), 29.5.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:28]=1[CH:29]=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:29]/[C:28]1[C:27]([O:26][CH3:25])=[CH:34][CH:33]=[CH:32][C:31]=1[O:35][CH3:36]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(OC)c1C=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(OC)cccc1OC
Temperature: 0 °C
Yield: 93.5 %

Procedure:
35.6 g of (methoxycarbonylmethylene)-triphenylphosphorane is added to a solution of 8.48 g of 2,6-dimethoxybenzaldehyde in 450 ml of tetrahydrofuran under nitrogen and refluxed for 16 hours. It is poured on 200 ml of ice water, extracted three times with ethyl acetate, the combined organic phases are washed once with saturated sodium chloride solution, dried on sodium sulfate and after filtration, concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-40% ethyl acetate, a solid is obtained, which is recrystallized from hexane/toluene. 10.6 g of the title compound is obtained in this-way as crystalline substance (melting point: 76°-78° C).