Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33]O)[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:35])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:43])CC)C.O>ClCCl>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33][F:43])[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:35])[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(-c4ccccc4CO)nn23)ccc1C(=O)NC1CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(-c4ccccc4CF)nn23)ccc1C(=O)NC1CC1
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of 329 mg (677 μmol) N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 220 in 13 mL dichloromethane at 3° C. were added 98 μL N-ethyl-N-(trifluoro-lambda4-sulfanyl)ethanamine. After stirring for 10 minutes, the solution was poured into water and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 28.6 mg (8%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O:11][CH3:12])=[O:10]>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=Nc2ccc(C)cc2)cc1

Procedure:
p-toluidine (0.20 moles), p-carbomethoxybenzaldehyde (0.20 moles), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) were azeotropically refluxed in toluene (150 cc.). The required amount of water had been removed after 3 hours. The solvent was removed on the rotary evaporator and the residue was recrystallized with 95% ethanol to yield N-(p-carbomethoxybenzylidene)-p-methylaniline.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N>ClCCl.CO>[C:18]1([C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:25][CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of ethyl 4-piperazin-1-ylbenzoate (1.36 g) and 3,3-diphenylacrylaldehyde (1.56 g) in dichloromethane (10 mL) and methanol (10 mL) was treated with polymer-supported cyanoborohydride (2.47 mmol/g, 6 g), shaken at room temperature for 24 hours, and filtered. The resin was washed with 1:1 dichloromethane/methanol (10 mL×3) and the combined filtrates were concentrated. The concentrate was purified by silica gel chromatography eluting with a gradient from 10%-50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].CC(O)=O.O>C1COCC1>[OH:2][CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(C)(C)CCC(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CO)CCC(=O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g, 12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0 mmol). The mixture is stirred at room temperature for 16 hours and refluxed for 2 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 1M aqueous HCl (14 ml) is added and the solution is extracted with ether. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.97 g, 88%); 1H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H), 1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H). To a suspension of 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.00 g, 5.75 mmol) in THF (3 mL), 1M LiBHEt3 in THF (38.0 ml, 38.0 mmol) is added dropwise maintaining the temperature below 10° C. under nitrogen. The mixture is stirred at 10° C. for 1 hour. To the mixture, 50% AcOH (4.6 mL) and H2O are added. The solution is extracted with AcOEt, and the organic layer is washed with H2O, dried over MgSO4, and concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid (850 mg, quant.); 1H NMR (400 MHz, chloroform-d) ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.98 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 10 mmol morpholine in DMF at room temperature for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 50% ethyl acetate and 50% hexane to obtain 1-(2,4-dichlorophenyl)-2-morpholin-4-ylethan-1-one.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][S:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:25])[F:26])[CH:16]=2)(=[O:23])=[O:22])=[N:9][C:10]=1[CH3:11])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOCc1ccc(N)nc1C
Product: CCOCc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-Ethoxymethyl-6-methyl-pyridin-2-ylamine (0.066 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.108 g) as a light yellow solid (0.115 g). MS (ESI−): 373.1 ([M−H]−)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[C:18](=O)([O-])[O-:19].[K+].[K+]>CN(C)C=O>[CH:18]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc2ccccn2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nn2ccccc2c1C=O
Temperature: 0 °C
Yield: 67 %

Procedure:
One gram of 2-isopropylpyrazolo[1,5-a]pyridine was dissolved in 0.6 ml of dimethylformamide, and 5 ml of phosphorus oxychloride was added to the resulting solution. The reaction mixture was refluxed for 20 min., poured into ice-water, and neutralized with potassium carbonate. The precipitate was collected by filtration and washed with water. Recrystallization from n-hexane gave 800 mg of colorless needles, mp 81.0°-81.5°. Yield 67%.
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=[O:9])[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].Cl.[CH3:15][NH2:16]>CN(C1C=CN=CC=1)C>[CH3:3][C@@:2]1([C:1]([OH:10])=[O:13])[CH2:12][CH2:11][C@H:7]([C:8](=[O:9])[NH:16][CH3:15])[C:4]1([CH3:6])[CH3:5]
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Reactant: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CNC(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 40% aqueous methylamine (70 mL) and camphoric anhydride (5 g) was stirred at room temperature for 30 minutes. To this N,N-dimethyl-4-aminopyridine (DMAP) (0.67 g, 5.4 mmol) was added and stirred further for 24 hours. The reaction mixture was allowed to cool to room temperature and acidified with con. HCl at 0-5° C. White precipitate formed was filtered and dried (5.2 g). m/z (M+H): 214.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:35](CC)[CH2:36]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10](=[O:11])[N:35]([CH3:36])[CH3:33])=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Temperature: 25 °C

Procedure:
The hydrogenated compound 60 (2.2 g, 4.96 mmol) was dissolved in CH2Cl2 and stirred at room temperature under an atmosphere of argon. Triethylamine (0.829 mL, 5.95 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 2.413 g, 5.456 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 12.4 mL, 24.8 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×50.0 mL) and brine (1×50.0 mL). Drying and concentration of the organic layer gave the desired amide crude (1.2 g, ˜98%). Flash chromatography on silica gel (methanol-chloroform 1%-2%) yielded the desired amide 75(0.8 g 98%) 1H NMR (400 MHz, DMSO-d6): 7.32 (dd, J=7.6 and 2 HZ, 1H), 7.21 (m, 3H), 7.08 (dd, J=14 and 7.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.0 Hz, 1H), 4.53 (m, 1H) 3.55 (s, 3H), 2.89 (s, 3H), 2.85-2.58 (m, 7H), 2.59 (t, J=7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=O.[CH3:27][NH:28][CH3:29].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O.C(O)(=O)C>[CH3:27][N:28]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:29]
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C=O)cc3)cc2)C1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(CN(C)C)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.3 g of 4-formyl-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.81 mmol) were dissolved in 20 ml of dichloromethane, 0.6 ml of a 2 M solution of dimethylamine in tetrahydrofuran (1.21 mmol) added, followed by addition of 0.07 ml of acetic acid and 0.256 g sodium triacetoxyborohydride. The reaction mixture was stirred for 15 h at room temperature, water added, the pH adjusted to alkaline conditions with 1 N aqueous sodium hydroxide, and the aqueous layer extracted twice with diethylether. The combined ether extracts were dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product was purified via preparative HPLC on a 40 mm Deltapak column with methanol/water/0.1% acetic acid. Fractions containing the product were combined, the solvent evaporated and the product isolated after extraction of an alkaline aqueous layer. (0.051 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]([F:31])([F:32])[F:33])=[C:25]([CH:29]=1)[C:26](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:27]
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF at 0° C. was added Et3N (0.37 mL, 2.7 mmol) followed by 5-chloro-2-trifluoromethyl-benzoyl chloride (Matrix, 0.26 g, 1.3 mmol) in 5 mL THF dropwise via syringe. This mixture was stirred at ambient temperature for 1 hour then was warmed to reflux and allowed to stir for 8 hours. The mixture was then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash column chromatography (SiO2, 4:1 hexanes:EtOAc) to provide the title compound (0.23 g, 0.57 mmol, 53% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.71 (t, J=4.9 Hz, 2H), 4.36 (t, J=4.9 Hz, 2H), 7.45 (ddd, J=8.5, 2.0, 0.7 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 393 (M+H)+; Anal. calculated for C16H16ClF3N2O2S: C, 48.92; H, 4.11; N, 7.13. Found: C, 48.66; H, 3.81; N, 7.01.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:15])([CH3:14])[CH:12]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:10]/[C:11]([CH3:15])([CH3:14])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)/C=N/CC(=O)OC(C)(C)C
Yield: 100.4 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with trimethylacetaldehyde (Aldrich) (0.42 g, 5 mmol) in CH2Cl2 at room temperature for 20 h to give [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.0 g, 100%).
Reaction SMILES: C[N:2]1[CH:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:6]([N+:12]([O-])=O)=[CH:5][CH:4]=[C:3]1[C:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=1.[CH:21]([O-])=O.[NH4+]>[Pd].CO>[CH3:21][N:18]1[CH2:19][CH2:20][CH:15]([C:3]2[N:2]=[C:7]([O:8][CH:9]([CH3:10])[CH3:11])[C:6]([NH2:12])=[CH:5][CH:4]=2)[CH2:16][CH2:17]1
Reactant: CC(C)OC1C([N+](=O)[O-])=CC=C(C2=CCNCC2)N1C
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1nc(C2CCN(C)CC2)ccc1N
Temperature: 80 °C
Yield: 107.5 %

Procedure:
In a microwave tube, 300 mg of 1-methyl-5-nitro-6-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine are introduced into 22 ml of methanol. 410 mg of ammonium formate and 345 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 288 mg of 6-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)pyridin-3-amine in the form of a brown gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 100 %

Procedure:
A mixture of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (36.7 mmole) and platinum oxide (0.15 g) was hydrogenated in ethanol for 1.5 hr. The catalyst was removed by filtration and the ethanol removed in vacuo to give the product (100%, mp: 51-53° C.). Calc'd for C14H15FO2 : C, 71.17%; H, 7.26%. Found: C, 71.16%; H, 7.35%.
Reaction SMILES: N1[C:9]2C(=C[C:6]([N:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=5)[CH:17]=4)[NH:12][C:11]3=[O:31])=[CH:7][CH:8]=2)C=C1.BrCC1CC1.C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O.C(Cl)Cl.BrC1C=C2N(CC3CC3)C(=O)NC2=NC=1.COC1C=C(B(O)O)C=C(OC)C=1OC.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.CC#N.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>[CH:7]1([CH2:6][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[CH:17]=3)[NH:12][C:11]2=[O:31])[CH2:9][CH2:8]1
Reactant: COc1cc(-c2cnc3[nH]c(=O)n(-c4ccc5[nH]ccc5c4)c3c2)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: BrCC1CC1
Agent: COc1cc(B(O)O)cc(OC)c1OC
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]c(=O)n(CC4CC4)c3c2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
Intermediate 5 from Example 124 was alkylated with (bromomethyl)cyclopropane using K2CO3 in acetone, after which it was deprotected using TFA/CH2Cl2. To the resulting 6-bromo-1-(cyclopropylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 3.7 mg of the title compound. HPLC retention time: 1.90 minutes; MS ESI (m/z): 356.2 (M+1)+, calc. 355.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.C1(C2C=CC=CC=2)C=CC=CC=1.[C:29](=O)=[O:30].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])N>C(#N)C>[CH2:1]([N:9]=[C:29]=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=O
Reactant: CCCCCCCCN
Agent: NC(=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCCCCCCCN=C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A Fischer-Porter bottle was charged with 0.65 g (5 mmol) of octyl amine, 1.17 g of P1 -tBu (5 mmol), 1.02 g (10 mmol) of triethylamine, 25 mL of acetonitrile and 154 mg (1 mmol) of biphenyl as an internal standard. The bottle was pressurized to 80 psig with carbon dioxide and the solution was stirred for 30 min. at room temperature. A second Fischer-Porter bottle was charged with 14.1 g (50 mmol) of phosphorus pentoxide, and 25 mL of acetonitrile then pressurized to 80 psig with CO2. The carbamate solution was added rapidly to the P2O5 suspension at room temperature causing some of the P2O5 to dissolve. An aliquot taken after three minutes gave a 89% yield of octyl isocyanate by G.C. analysis. The reaction was monitored for a total of 18 hrs during which time the yield of octyl isocyanate increased to a maximum of 97% (2.5 hr).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:27])[N:4]2[C:8](=[C:9]([C:20]([NH:22][O:23][CH2:24][CH2:25][OH:26])=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.[Si]([C:32]#[CH:33])(C)(C)C.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO.[Cu](I)I.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.C1COCC1.CN(C=O)C>[C:32]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[C:9]([C:20]([NH:22][O:23][CH2:24][CH2:25][OH:26])=[O:21])=[C:8]3[N:4]([CH2:5][CH2:6][CH2:7]3)[C:3](=[O:27])[C:2]=2[F:1])=[C:13]([F:19])[CH:14]=1)#[CH:33]
Reactant: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)c3n(c(=O)c2F)CCC3)c(F)c1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Example 4 (25 mg, 0.051 mmol), TMS-acetylene (6 mg, 0.051 mmol), copper iodide (1 mg, 0.0005 mmol), triethylamine (1.0 mL, 0.014 mmol), and dichlorobis(triphenylphosphine)palladium(II) (1 mg, 0.0005 mmol) were stirred in 1:1 THF/DMF (2 mL) at room temperature for 3 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give a tan oil. The intermediate was dissolved in 1:1 THF/MeOH (2 mL) and solid potassium carbonate (14 mg, 0.10 mmol) was added and the mixture stirred for 1 hr. The potassium carbonate was filtered off and the solution was concentrated in vacuo and purified by prep HPLC (25/50, water/acetonitrile) to give 12 mg (60%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4): δ 7.15-7.27 (m, 2H), 7.00 (t, 1H, J=8.3 Hz), 4.16 (t, 1H, J=7.3 Hz), 3.83-3.84 (m, 2H), 3.68-3.69 (m, 2H), 3.51 (s, 1H), 3.27 (t, 2H, J=7.6 Hz), 2.28 (s, 1H), 2.24 (m, 2H). MS (ES) [m+H] calc'd for C19H17F2N3O4, 390. found 390.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[CH:23]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:24]1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:23]2[CH2:24][CH2:25]2)=[CH:36][CH:35]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([F:19])[F:20])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(difluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-(cyclopropylmethoxy)benzoic acid prepared in Example 18 (18a) to give the title compound.