Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:14][CH2:15][C:16](N)([CH3:18])[CH3:17]>C(=S)=S>[CH3:17][C:16]1([CH3:18])[CH2:15][NH:14][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1
Reactant: CCCCCCCCCCCC#N
Reactant: CC(C)(N)CN
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NC(C)(C)CN1
Yield: 77.9 %

Procedure:
18.31 g (100 mmoles) of undecyl cyanide, 11 g (125 mmoles) of 1,2-diamino-2-methylpropane and 0.5 ml of carbon disulfide were heated at 125° C. for 24 hrs. and then worked up as under Example 23. Distillation at reduced pressure gave 19.66 g (78%) of the product.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[S:14])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.Br[CH2:21][C:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:22]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])/[C:13](=[N:12]/[C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:11])/[S:14][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COCCNC(=S)NC(=O)C12CC3CC(CC1C3)C2
Product: COCCn1c(C(C)(C)C)cs/c1=N\C(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of Example 14B (57 mg, 0.20 mmol) and 1-bromo-3,3-dimethyl-butan-2-one (36 mg, 0.027 mL, 0.20 mmol, Aldrich) was processed according to the method described in Example 14C. Purification by column chromatography (SiO2, 30-45% ethyl acetate/hexanes gradient) afforded title compound. 1H NMR (dimethylsulfoxide-d6 300 MHz) δ 1.37 (s, 9 H), 1.56-1.63 (m, 4 H), 1.69-1.79 (m, 4 H), 2.07-2.18 (m, 2 H), 2.24-2.30 (m, 2 H), 2.53-2.60 (m, 1 H), 3.26 (s, 3 H), 3.75 (t, J=6.78 Hz, 2 H), 4.40 (t, J=6.95 Hz, 2 H), 6.57 (s, 1 H); MS (DCI/NH3) m/z 363 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH:19]=O.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH2:19][NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: O=Cc1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(CNC2CC2)c1)C1CC1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Cyclopropylamine (1.39 mL, 19.8 mmol) was added to a sol. of cyclopropanecarboxylic acid 4-chloro-3-formyl-benzylamide (3.13 g, 13.2 mmol) in MeOH (28 mL). The mixture was stirred overnight, and NaBH4 (996 mg, 26.0 mmol) was added in portions. The mixture was stirred for 3 h, and aq. 1M NaOH (70 mL) was added. The solvents were partially removed under reduced pressure, and the aq. residue was extracted with EtOAc (2×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2→MeOH/CH2Cl2 1:9) yielded the title compound (3.37 g, 92%). LC-MS: tR=0.62 min; ES+: 279.35.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([CH2:32][C:29]5([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)cc1

Procedure:
The title compound is prepared from 5-(4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[O:13])=[CH:7][CH:6]=1>C(O)C>[F:3][C:4]([F:14])([F:15])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][OH:13])=[CH:9][CH:10]=1
Reactant: O=CCc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
NaBH4 (2 g, 0.055 mol) was added at 0° C. to a solution of 4-trifluoromethyl-phenyl)-acetaldehyde (9.4 g, 0.05 mol, from step (ii) above) in 154 ml ethanol and stirred at RT overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between 50 ml 1 N HCl and 50 ml diethyl ether. Organic layer was washed with water, dried over sodium sulfate and the solvent evaporated under reduced pressure to give 10 g of the sub-title compound as a liquid. This was directly taken for next step without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[O:14][N:13]=1)=O)(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[O:14][N:13]=1
Reactant: COc1ccccc1-c1cc(OCCNC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(OCCN)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-methoxyphenyl)isoxazole (0.31 g) was dissolved in a solution of 4N hydrochloric acid/1,4-dioxane (2.3 ml), and the solution was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixture of ethanol and isopropanol to obtain the title compound (0.21 g, 84%) as colorless crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:24])[CH:17]=[C:16]([C@@H:25]([NH:27][C:28]2[N:36]=[CH:35][N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][NH:32]3)[CH3:26])[N:15]=1.O>C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([O:10][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[N:15][C:16]([C@@H:25]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]3[C:29]=1[N:30]=[CH:31][NH:32]3)[CH3:26])=[CH:17]2
Reactant: CC(C)N1CCC(O)CC1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2nc([C@H](C)Nc3ncnc4[nH]cnc34)cc3cccc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 1-isopropylpiperidin-4-ol (120 mg, 0.83 mmol, 1.2 eq) in THF (10 mL) at 0° C., NaH (60% in mineral oil, 33.2 mg, 0.83 mmol, 1.2 eq) was added and the resulting mixture was stirred for 10 min. To this mixture, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine 38 (250 mg, 0.70 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux overnight, cooled to RT and then poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (5% MeOH-DCM) to afford the product, (S)—N-(1-(8-chloro-1-(1-isopropylpiperidin-4-yloxy)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 47. ESI-MS m/z: 466.2 [M+H]+.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.[Cl:12][C:13]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:14]=1[CH2:15][O:16][C:17]1[CH:32]=[CH:31][C:20]2[C:21]([O:27][CH2:28][O:29][CH3:30])=[C:22]([C:24](O)=[O:25])[S:23][C:19]=2[CH:18]=1.CN(C=O)C>O>[Cl:12][C:13]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:14]=1[CH2:15][O:16][C:17]1[CH:32]=[CH:31][C:20]2[C:21]([O:27][CH2:28][O:29][CH3:30])=[C:22]([C:24]([NH2:3])=[O:25])[S:23][C:19]=2[CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCOc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C(N)=O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
A mixture of HOBt ammonia complex (387 mg), EDCI (487 mg), 6-((2,4-dichlorobenzyl)oxy)-3-(methoxymethoxy)-1-benzothiophene-2-carboxylic acid (700 mg) and DMF (5 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the mixture was extracted with THF-AcOEt. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was washed with IPE and hexane to give the title compound (510 mg).
Reaction SMILES: O[N:2]=[C:3]([C:15](=[O:17])[CH3:16])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].O.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C.[Zn]>[C:19]([NH:2][CH:3]([C:15](=[O:17])[CH3:16])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5])(=[O:21])[CH3:20]
Reactant: COc1ccc(NC(=O)C(=NO)C(C)=O)cc1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(NC(=O)C(NC(C)=O)C(C)=O)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 11.8 g of 2-(hydroxyimino)-N-(4-methoxyphenyl)-3-oxobutanamide in 30 ml of acetic acid and 10 ml of acetic anhydride at 20°-30° C. is added 10 g of zinc dust and the mixture is stirred for 1 hour. Water (150 ml) is added, the mixture is stirred for 2 hours, and the zinc is removed by filtration. The solvent is evaporated from the filtrate under reduced pressure and the resulting residue is recrystallized from methanol to give 2-acetylamino-N-(4-methoxyphenyl)-3-oxobutanamide.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]CC)=O)[CH:3]=1.[NH3:13]>>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:13])=[O:10])[CH:3]=1
Reactant: CCOC(=O)c1cc(O)ncn1
Reactant: N
Product: NC(=O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
Ethyl 6-hydroxy-4-pyrimidinecarboxylate (Intermediate 6, 0.995 g, 5.92 mmol) was treated with 0.88 ammonia solution (9.95 mL, 460 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The resulting solid was collected by filtration, taken up in toluene and the solvent removed under reduced pressure to give the title compound as a yellow solid (563 mg);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:13])(=[NH:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:13])(=[N:12][C:18](=[O:19])[NH:17][CH:14]([CH3:16])[CH3:15])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)N=C=O
Reactant: CS(=N)(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 104 °C
Reaction time: 60 h
Yield: 78.3 %

Procedure:
8.24 g (41.2 mmol) (RS)—S-(3-nitrophenyl)-S-methylsulfoximide in 370 ml toluene were treated with 13.6 ml (138.3 mmol) isopropyl isocyanate. The mixture was stirred under argon at 104° C. for 5 hours and at room temperature for 60 hours. 4.5 ml (46 mmol) isopropyl isocyanate were added and the mixture was stirred under argon at 104° C. for 6 hours and at room temperature for 16 hours. 4.5 ml (46 mmol) isopropyl isocyanate were added and the mixture was stirred under argon at 104° C. for 7 hours and at room temperature for 17 hours. The mixture was cooled with ice for 40 minutes. The suspension was filtrated to give 9.2 g (78% yield) of the product.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22]>>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([NH:22][C:18]2[S:17][CH:21]=[CH:20][N:19]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1cccnc1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccnc1

Procedure:
Employing the protocol described in EXAMPLE 1, 3-cyclopentyl-2-pyridin-3-ylpropionic acid (Preparation 2, 0.96 g, 4.4 mmol) was condensed with thiazol-2-ylamine (0.88 g, 8.8 mmol) to give the title compound: RTA=3.05 min; m/z (ES+)=302.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][C:11]([Cl:15])=[C:10]([N:16]2[CH2:20][C@@H:19]([O:21][CH3:22])[C@H:18]([OH:23])[CH2:17]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.CO>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.C(OCC)(=O)C.O>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][C:11]([Cl:15])=[C:10]([N:16]2[CH2:20][C@@H:19]([O:21][CH3:22])[C@H:18]([OH:23])[CH2:17]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2nc(Cc3ccccc3)c(I)cc2Cl)C[C@H]1O
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(c2nc(Cc3ccccc3)c(C#C[C@@]3(O)CN4CCC3CC4)cc2Cl)C[C@H]1O
Yield: 90 %

Procedure:
A mixture of 132 mg of 2-benzyl-5-chloro-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine, 49.4 mg of (3R)-3-ethynyl-3-quinuclidinol, 17.2 mg of tetrakis(triphenylphosphine)palladium(0), 11.3 mg of cuprous iodide, 124 μl of triethylamine and 1.5 ml of methanol was heated under reflux for one hour in a nitrogen atmosphere. After cooling as it was, water and ethyl acetate were added to the reaction mixture. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 125 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40]([C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]5[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]5)(=[O:10])=[O:9])=[CH:4][CH:3]=4)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1
Reactant: CN1CCCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCCN(C)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 55.6 %

Procedure:
A mixture of 0.5 g of 1-(4-bromo-benzene-sulfonyl)-4-methyl-[1,4]diazepane, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1″-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 027 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 22-15:1+1% NH4OH). Concentration of the chromatographically pure fractions, crystallization of the residue from ethyl acetate and recrystallization from ethylacetate/acetonitril (4:1) gives 0.275 g of the title compound as a solid of m.p. 160-162° C. The mass spectrum shows the molecular peak MH+ at 507.3 Da.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:17]=2)[C:12](F)=[N:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:17]=2)[C:12]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:13][CH:14]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3NC3CCOCC3)n2)cc1
Temperature: 120 °C
Yield: 74.4 %

Procedure:
A mixture of tetrahydro-2H-pyran-4-amine (130 mg, 1.285 mmol), 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (345 mg, 0.719 mmol), and cesium carbonate (165 mg, 0.506 mmol) in THF (2.5 mL) was heated under microwave irradiation (100° C., 15 min; 120° C., 2×15 min). The mixture was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with water, saturated NH4Cl, dried over Na2SO4 and concentrated. The resulting solid was triturated with hot MeOH (10 mL) to give a yellow solid (300 mg). LCMS (ES, pos.): calcd for C30H33ClN6O3: 560.2; found: 561.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.48 (d, J=7.24 Hz, 1H); 8.67 (d, J=2.54 Hz, 1H); 8.13 (d, J=2.54 Hz, 1H); 7.18 (t, J=9.10 Hz, 4H); 6.87 (d, J=8.61 Hz, 4H); 4.82 (s, 2H); 4.77 (s, 2H); 4.17-4.29 (m, 1H); 3.91 (dt, J=11.74, 3.62 Hz, 2H); 3.81 (s, 3H); 3.80 (s, 3H); 3.55 (td, J=11.25, 1.96 Hz, 2H); 2.52 (s, 3H); 1.96 (br. s., 2H); 1.33-1.48 (m, 2H).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[CH3:14][NH:15][CH3:16].[OH-].[Na+]>>[CH2:1]([N:15]([CH3:16])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CCCCCCCCCCl
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCCCCCCCCN(C)C
Yield: 98.1 %

Procedure:
In a 1-gallon stainless steel autoclave was charged 4.5 moles of isododecyl chloride, 13.5 moles of dimethylamine (as 40% aqueous solution), and 4.5 moles of sodium hydroxide (as 50% aqueous solution). The mixture was heated at 175°-190° C. for 6 hours. The mixture was cooled. The top organic layer was collected and the residual dimethylamine evaporated. The isododecyldimethylamine was obtained in 98.1% yield.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[C:10](Cl)=[O:11]>C(#N)C>[CH3:19][O:18][C:14]1[CH:13]=[C:9]([CH:8]=[C:7]([O:6][CH3:5])[C:15]=1[O:16][CH3:17])[C:10]([N:3]=[C:2]=[S:1])=[O:11]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)N=C=S)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
Potassium thiocyanate is added to a solution of 3,4,5-trimethoxybenzoylchloride (2.3 g) in acetonitrile (40 ml). After stirring for 15 minutes at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure in order to produce the expected compound in the form of a beige powder (2.4 g, 96% yield). Melting point=101° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9]
Reactant: O=Cc1cnccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1cnccc1Br

Procedure:
4-Bromo-pyridine-3-carbaldehyde (240 mg) in ethanol (10 mL) at 0° C. was treated with sodium borohydride (139 mg) for 30 min. The reaction mixture was then diluted with ethyl acetate and washed with aqueous ammonium chloride and brine to yield (4-bromo-pyridin-3-yl)-methanol as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]2[C:19](=[O:42])[CH2:20][NH:21][C:22](=[O:41])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])=[CH:26][CH:25]=2)[CH:5]=[CH:6][CH:7]=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]2[C:19](=[O:42])[CH2:20][NH:21][C:22](=[O:41])[NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC(=O)N1C(c2ccccc2)CCC1c1cccc(O)c1)Nc1ccc(CC(=O)OCc2ccccc2)cc1
Solvent: CO
Product: O=C(O)Cc1ccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2cccc(O)c2)cc1
Yield: 33.1 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 1.8 g of benzyl (2RS,5SR)-4-{3-{2-[2-(3-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate in solution in 30 cm3 of methanol and 0.27 g of potassium hydroxide in solution in 6 cm3 of water, and after treatment and crystallization in diethyl ether, 0.5 g of (2RS,5SR)-4-{3-{2-[2(3-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetic acid, melting at 260° C., is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:37]=[CH:36][CH:35]=[CH:34][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:21][C@@H:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:29]C)=[O:28])[CH3:23])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:37]=[CH:36][CH:35]=[CH:34][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:21][C@@H:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([OH:29])=[O:28])[CH3:23])=[O:20])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)N[C@H](C)c3cccc(C(=O)OC)c3)cn2)C1
Agent: [Li+]
Agent: [OH-]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)N[C@H](C)c3cccc(C(=O)O)c3)cn2)C1

Procedure:
3-((R)-1-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoic acid was prepared from methyl 3-((R)-1-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoate using Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 12.9 (br s, 1H), 8.76 (s, 2H), 8.70 (d, 1H), 7.96 (s, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 7.45 (dd, 1H), 7.03 (d, 1H), 6.89 (m, 3H), 5.18 (m, 1H), 4.30 (m, 1H), 4.19 (dd, 1H), 3.89 (m, 4H), 3.77 (m, 1H), 2.01 (m, 1H), 1.83 (m, 2H), 1.51 (m, 1H), 1.46 (d, 3H), 1.21 (t, 3H). MS (ES+) 491 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].CCN(CC)CC.CN(C1C=CC=CN=1)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(Cl)Cl>[C:32]([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1=CCCC(C)(C)C1C(=O)CC(C)O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 77.2 %

Procedure:
To a solution of 3-hydroxy-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-butanone (4.00 g, 92% pure, 17.5 mmol), NEt3 (3.2 ml, 22.85 mmol) and dimethylamino pyridine (DMAP) (400 mg) in CH2Cl2 (100 ml) was added benzoylchloride (2.43 ml, 20.94 mmol). The reaction medium was stirred for 65 h at room temperature. Then, the mixture was acidified with 5% aqueous HCl and extracted twice with ether and washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl. Finally, the organic phases were dried over Na2SO4, concentrated at 50-60°/0.03 mbar) and purified by flash-chromatography over SiO2 (cyclohexane/AcOEt=97:3). 4.25 g of product were thus obtained (yield: 73%).