Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([Si:14]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:15][C@@H:16]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C@@H:19]([OH:27])[CH2:18][CH2:17]1)([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.O>[CH:31]([Si:14]([CH:11]([CH3:13])[CH3:12])([CH:28]([CH3:30])[CH3:29])[O:15][C@@H:16]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19](=[O:27])[CH2:18][CH2:17]1)([CH3:33])[CH3:32]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](O)Cc2cccnc21)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]1CCC(=O)Cc2cccnc21)(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
In an oven-dried 250 mL round-bottom flask was dissolved oxalyl chloride (9.54 mL, 19.08 mmol) in methylene chloride (40 mL) to give a colorless solution at −55° C. under nitrogen. DMSO (2.71 mL, 38.2 mmol) was added dropwise slowly over 2 min. After the solution was stirred for an additional 30 min, (6S,9S)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol (2.91 g, 8.67 mmol) (crude, azeotroped with dry benzene) dissolved in 8 mL methylene chloride (plus 8 mL rinse) was added via cannula over 5 min. The reaction mixture was stirred at −50 to −55° C. for an additional 40 min. Triethylamine (6.04 mL, 43.4 mmol) was added via syringe at −50° C. and the reaction mixture was gradually warmed up to −20° C. for 30 min. TLC showed complete conversion. Water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 50% ethyl acetate/hexane afforded the desired product as a light yellow oil (2.08 g, 72%). MS(ESI)[M+H+]=334.35; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=5.04 Hz, 1H) 7.49 (d, J=7.55 Hz, 1H) 7.19 (dd, J=7.55, 4.78 Hz, 1H) 5.26 (dd, J=4.78, 2.27 Hz, 1H) 4.69 (d, J=14.35 Hz, 1H) 3.29 (d, J=14.35 Hz, 1H) 3.02 (ddd, J=12.15, 9.00, 6.04 Hz, 1H) 2.45-2.59 (m, 1H) 2.31-2.45 (m, 1H) 2.06-2.25 (m, J=8.53, 8.53, 5.98, 2.39 Hz, 1H) 1.06-1.19 (m, 3H) 1.01 (d, J=7.30 Hz, 9H) 0.89-0.97 (m, 9H).
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:20].[Na+]>CC(C)=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][I:20])[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: O=C1N(CCCCCl)CCN1N=Cc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Reaction time: 1 h
Yield: 65 %

Procedure:
A stirred mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone (36.4 g, 0.1301 mole), acetone (700 ml) and sodium iodide (42.9 g, 0.2862 mole) is heated to reflux which is maintained for 24 hours. The mixture is filtered hot, removing the solid. After cooling, the filtrate is poured into H2O (2000 ml) and stirred 1 hour. The solid is collected, washed with H2O, and air-dried to give 31.4 g, (0.0845 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1.CC([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CNc1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A mixture of 1.65 g (6.76 mmol) of 2,4-dichloro-6-nitro-quinazoline, 1.02 g (7.44 mmol) of (4-methoxy-phenyl)-methyl-amine, 0.6 g (7.43 mmol) of NaOAc in 6 mL of THF and 6 mL of water was stirred at ambient temperature for 18 hours. The reaction mixture extracted with EtOAc (2×15 mL) and organics were washed with NaHCO3, dried and concentrated. Isolation done by MPLC (0-30% EtOAc/hexanes as eluent) to give 1.86 g of the title compound. 1H NMR (DMSO-d6) δ 8.38-7.13 (7H), 3.84 (s, 3H), 3.59 (s, 3H); LC-MS (ESI+; 345 ([M+H]+)).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:20]=[N+:21]=[N-:22])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
41.2 g (0.02 mol) of p-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 29 ml (0.4 mol) of thionyl chloride are added. The reaction mixture is heated to the boil under a reflux condenser for half an hour and thereafter the solvent and excess thionyl chloride are removed by distillation in vacuo. The crude p-acetoxy-cinnamic acid chloride which remains is dissolved in 200 ml of absolute dimethoxyethane, 39 g (0.6 mol) of sodium azide are added and thereafter the mixture is stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated in vacuo at 30°C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. p-Acetoxy-cinnamic acid azide of melting point 114°C (decomposition) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Reaction time: 24 h
Yield: 77.5 %

Procedure:
A solution of 5-hydroxyindan-1-one (1.00 q, 6.17 mmol), benzyl alcohol (800 mg, 7.40 mmol) and tributylphosphine (1.70 g, 8.40 mmol) in tetrahydrofuran (80 mL) was stirred at room temperature, 1,1′-(azodicarbonyl)dipiperidine (2.12 g, 8.40 mmol) was added, and the mixture was stirred for 24 hr. Hexane was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (1.14 g, yield 78%) as pale-yellow crystals.
Reaction SMILES: [N:1](OCCC(C)C)=O.[NH2:9][C:10]1[C:11]([NH:21][C@@H:22]2[CH2:26][C@H:25]([OH:27])[CH:24]=[CH:23]2)=[N:12][C:13]([S:17][CH2:18][CH2:19][CH3:20])=[N:14][C:15]=1[Cl:16]>C(#N)C>[Cl:16][C:15]1[C:10]2[N:9]=[N:1][N:21]([C@@H:22]3[CH2:26][C@H:25]([OH:27])[CH:24]=[CH:23]3)[C:11]=2[N:12]=[C:13]([S:17][CH2:18][CH2:19][CH3:20])[N:14]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@H]2C=C[C@@H](O)C2)n1
Reactant: CC(C)CCON=O
Solvent: CC#N
Product: CCCSc1nc(Cl)c2nnn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 70 °C

Procedure:
Isoamyl nitrite (1.08 ml) was added to a solution of the product of step b) (2.20 g) in acetonitrile (100 ml) and the solution heated at 70° C. for 1 hour. The cooled reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate:isohexane 1:2 as eluant) to afford the subtitle compound (1.79 g).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([CH:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])=[O:21])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: O=C1CC(=O)NC(=O)N1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCC(=O)C2C(=O)NC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a suspension of barbituric acid (6.4 g) in 48 ml of pyridine are added dropwise 11 g of 3-(4-methoxyphenyl)propionyl chloride and the mixture is stirred at room temperature for 18 hours. The reaction mixture is then poured into ice and acidified to pH=1 by adding 6 N hydrochloric acid. A solid precipitates, which is filtered and resuspended in methanol. The suspension is kept under stirring for 15 minutes, then the solid is recovered by filtration to give 12.2 g of the product, m.p. 248-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:17][CH3:18])=[CH:7][CH:6]=2.[C:19](=O)([O-])[O-].[K+].[K+].C=O.C(OCC)(=O)C>C1CCCCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12](=[CH2:19])[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:17][CH3:18])=[CH:7][CH:6]=2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1c(Cl)cnc2ccc(OC)nc12
Agent: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C(=O)OC)c1c(Cl)cnc2ccc(OC)nc12
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a solution of methyl [3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]acetate (43 g, 162 mmol) in cyclohexane (1060 ml) was added benzyltriethylammonium chloride (71.2 g, 313 mmol), potassium carbonate (42 g, 304 mmol) and paraformaldehyde (42 g). The reaction mixture was then heated at 80° C. for 24 hours, cooled and treated with ethyl acetate and water. The aqueous was extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a hexane and ethyl acetate gradient to provide the desired compound (40 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:7])[CH3:2].[H-].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[NH:8][C:9]2[C:10]([C:16]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:25])([F:26])[F:27])=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:28])[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Cc2ccccc2C(F)(F)F)c2cc(Cl)ccc2[nH]c1=O

Procedure:
The title compound was prepared in analogy to example 29 step B from N-[4-chloro-2-(2-trifluoromethyl-phenylethynyl)-phenyl]-malonamic acid ethyl ester (213 mg, 0.52 mmol) and NaH (31.2 mg, 0.78 mmol) in DMSO. Off white solid (95 mg, 45%). MS (ESI): 410 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)C.[CH2:5]([N:12]1[C@H:16]([C:17]([O:19][C:20](C)(C)C)=[O:18])[CH2:15][CH2:14][C@@H:13]1[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([N:12]1[C@@H:13]([CH2:24][CH2:25][C:26]([O:28][CH3:1])=[O:27])[CH2:14][CH2:15][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](CCC(=O)O)N1Cc1ccccc1
Solvent: CO
Product: COC(=O)CC[C@H]1CC[C@@H](C(=O)OC)N1Cc1ccccc1
Yield: 68.8 %

Procedure:
Acetyl chloride (1.50 ml, 21.10 mmol) was added dropwise to MeOH (7.5 mL) at 0° C. After 15 min of stirring a solution of 3-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (200 mg, 0.600 mmol) in MeOH (7.5 mL) was slowly added to the reaction. The reaction mixture was then heated at reflux overnight. The reaction was concentrated. The residue was partitioned between EtOAc and 10% Na2CO3. The organic phase was separated, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) to give the product (2S,5R)-methyl 1-benzyl-5-(3-methoxy-3-oxopropyl)pyrrolidine-2-carboxylate (126 mg, 0.413 mmol, 68.8% yield) as colorless syrup. 1HNMR (400 MHz, CDCl3) δ ppm 7.35-7.17 (5 H, m), 3.95 (1 H, d, J=13.7 Hz), 3.71-3.61 (4 H, m), 3.47 (3 H, s), 3.37-3.26 (1 H, m), 2.86-2.73 (1 H, m), 2.53-2.41 (1 H, m), 2.38-2.25 (1 H, m), 2.08-1.79 (4 H, m), 1.79-1.66 (1 H, m), 1.66-1.53 (1 H, m).
Reaction SMILES: [Cl:1][C:2]([O-:4])=[O:3].[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([O:3][C:2]([Cl:1])=[O:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])Cl
Reactant: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)Oc1ccccc1

Procedure:
Alternatively, a compound of formula II can be treated with a chloroformate, e.g., an alkylchloroformate or phenylchloroformate, at a temperature of 25°-125° C. in a solvent such as toluene or benzene to provide the corresponding N-alkoxycarbonyl or N-phenoxycarbonyl compound.
Reaction SMILES: [OH-].[Na+].CC(O)CC.[F:8][C:9]([F:46])([F:45])[C:10]1[CH:44]=[CH:43][C:13]2=[N+:14]([O-])[N:15]([C:17]3[CH:22]=[C:21]([C:23]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:31]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)([CH3:33])[CH3:32])[C:18]=3[OH:41])[N:16]=[C:12]2[CH:11]=1.ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2>C(C(C)=O)C>[F:46][C:9]([F:8])([F:45])[C:10]1[CH:44]=[CH:43][C:13]2=[N:14][N:15]([C:17]3[CH:22]=[C:21]([C:23]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[CH3:25])[CH:20]=[C:19]([C:31]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)([CH3:33])[CH3:32])[C:18]=3[OH:41])[N:16]=[C:12]2[CH:11]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3cc(C(F)(F)F)ccc3[n+]2[O-])c(O)c(C(C)(C)c2ccc(F)cc2)c1
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccc(F)cc2)c1
Temperature: 83 °C

Procedure:
To a 500 mL three-necked flask equipped with a mechanical stirrer, 3.7 g of sodium hydroxide pellets and 50 mL of 2-butanol are charged and heated to 83° C. To this solution is added over a 90-minute period a solution of 230 mL of methyl ethyl ketone, 20 g of the benzo-triazole-N-oxide prepared in Example 15 and 0.85 g of 2,3-dichloro-1,4-naphthoquinone. The mixture is refluxed at 88° C. for one hour while distilling off methyl ethyl ketone. After cooling down to ambient temperature, 25 g of water and 30 mL of ethyl acetate are added at which time the pH is reduced to 3 with 30% aqueous sulfuric acid. After splitting off the aqueous layer, the solvent is removed by distillation. The crude solid is purified by silica gel chromatography using heptane/ethyl acetate (49/1) as eluent. After collecting the desired fractions and crystallizing from methanol/toluene, the title compound is obtained in a yield of 14 g as a light yellow solid melting at 120-122° C. The structure is consistent with analyses by 1Hnmr, 19Fnmr and mass spectroscopy.
Reaction SMILES: C(O)(C)C.[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:10]=2[C:9]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:8][N:7]=1>[Pd].CO>[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:10]=2[C:9]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:8][N:7]=1
Reactant: CCCCC#Cc1cnc(N)c2nc(CCC)n(CCOCCNS(C)(=O)=O)c12
Agent: [Pd]
Solvent: CC(C)O
Solvent: CO
Product: CCCCCCc1cnc(N)c2nc(CCC)n(CCOCCNS(C)(=O)=O)c12

Procedure:
Solid palladium on carbon (0.5 g of 10%) was added to a Parr vessel and then wetted with isopropanol (1 mL). N-{2-[2-(4-Amino-7-hex-1-ynyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}methanesulfonamide (˜0.5 g) was added to the vessel followed by the addition of methanol (˜10 mL). The vessel was placed on a shaker and placed under hydrogen pressure (50 psi, 3.4×105 Pa). After 20 hours the reaction mixture was filtered through a layer of CELITE filter agent to remove the catalyst and the filter cake was washed with methanol (˜100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel eluting with 95:5 dichloromethane:methanol) to provide N-{2-[2-(4-amino-7-hexyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}methanesulfonamide as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([CH3:13])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:12]
Reactant: Cc1cncc(B(O)O)c1
Reactant: CN1C(=O)Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cncc(-c2ccc3c(c2)CC(=O)N3C)c1
Temperature: 100 °C

Procedure:
To 5-bromo-1-methyl-1,3-dihydro-indol-2-one (CAS#20870-90-0, 80 mg, 0.35 mmol) was added 5-methyl-3-pyridinyl boronic acid (CAS#173999-18-3, 55 mg, 0.39 mmol), in 1,2-dimethoxyethane (2.7 mL) and 2 M aqueous sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (195 mg, 0.018 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-5-(5-methyl-pyridin-3-yl)-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 239.1181 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 2.42 (s, 3H), 3.27 (s, 3H), 3.61 (s, 2H), 6.93 (d, J=8.1 Hz, 1H), 7.45-7.58 (m, 2H), 7.67 (s, 1H), 8.42 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]([CH2:36][CH3:37])[C@@H:27]([C:29]1[N:33]=[C:32]([CH2:34][CH3:35])[O:31][N:30]=1)[OH:28]>>[CH2:34]([C:32]1[O:31][N:30]=[C:29]([C:27]([C@@H:26]([NH:25][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:24])[CH2:36][CH3:37])=[O:28])[N:33]=1)[CH3:35]
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Product: CCc1nc(C(=O)[C@H](CC)NC(=O)C(CC(=O)N2CCOCC2)CS(=O)(=O)Cc2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)c1
Reaction time: 5 h

Procedure:
A microwave vial was charged N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 650 mg, 2.02 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 403 mg, 2.22 mmol) and DIPEA (1058 μl, 6.06 mmol) in dry DMSO (6.7 ml). The reaction was subjected to microwave irradiation at 120° C. for 2 hours and then at 140° C. for 5 hours. Upon cooling the mixture was partitioned between ethyl acetate and water, washing with water and brine, dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by column chromatography (basic silica 0-100% DCM/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][NH2:2].CO.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:13][C:14]([F:55])([F:54])[C:15]1[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=1)[CH2:18][NH:19][C:20](=[O:50])[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]2[CH:32]=[C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:30]=[CH:29][C:28]=2[NH:39][C:40](=[O:49])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47]Br)[CH:42]=2)[CH:22]=1>CN(C)C=O.O>[F:13][C:14]([F:55])([F:54])[C:15]1[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=1)[CH2:18][NH:19][C:20](=[O:50])[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]2[CH:32]=[C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:30]=[CH:29][C:28]=2[NH:39][C:40](=[O:49])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH:2][CH3:1])[CH:42]=2)[CH:22]=1
Reactant: CN
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CNCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methylamine in methanol (126 mg, 1.22 mmol, 4.00 equiv, 30%), potassium carbonate (124 mg, 0.90 mmol, 3.00 equiv), potassium iodide (10 mg, 0.06 mmol, 0.20 equiv), and a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (200 mg, 0.31 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 250 mL of water. The resulting solution was extracted with 4×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 200 mg (crude) of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-((methylamino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][O:29][CH2:30][C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:31](=[O:32])[CH2:30][O:29][CH2:28][C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:26])[CH3:27])[N:17]=2)=[O:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](COCC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CNC
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](COCC(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from [((2S,4S)-1-(tert-Butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)methoxy]acetic acid (step 1 of Example 21) and dimethylamine.