Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]=1[N:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc2C1
Reactant: C1CNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C1=C(N2CCC2)CCc2ccccc21
Temperature: 25 °C

Procedure:
A solution of azetidine (6.8 g, 0.12 mol), 3,4-dihydro-2(1 H)-naphthalenone (14.6 g, 0.10 mol), and p-toluenesulphonic acid (1.5 g) in dichloromethane (200 ml) was heated under reflux for 3 h in an apparatus fitted for the continuous removal of water, cooled to room temperature, washed with dilute aqueous sodium carbonate, dried (MgSO4), and evaporated in vacuo to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH2:23][CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:25]1[CH2:28][C:27](=O)[CH2:26]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:27]4[CH2:28][O:25][CH2:26]4)[CH2:19][C@@H:18]3[CH2:23][CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: O=C1COC1
Reactant: CC[C@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 67.6 %

Procedure:
A mixture of 161d (263 mg, 0.67 mmol), oxetan-3-one (96 mg, 1.34 mmol), NaBH3CN 104 mg, 1.68 mmol), and zinc chloride (227 mg, 1.68 mmol) in methanol (10 mL) was stirred at 50° C. for 5 hours. Water (10 mL) was then added to the reaction. The resulting mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane three times. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 161e (203 mg, 68%). MS: [M+H]+ 448.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:19][CH:18]([N:2]1[N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=[N:1]1)[CH3:20]
Reactant: CCOC(=O)c1cn[nH]n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(C(C)C)n1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2H-1,2,3-triazole-4-carboxylate (1 g), potassium carbonate (1.76 g) and 2-iodopropane (1.27 ml) in dry acetonitrile (20 ml) was stirred at 50-60° C. under nitrogen for 2 h. Further 2-iodopropane (0.70 ml) was added and the mixture stirred at 50-60° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was filtered through a 2 g SPE-Silica column with ethyl acetate and the filtrate concentrated in vacuo, Purification of the residue by chromatography on silica gel (70 g silica cartridge), eluting with a gradient of 0-25% ethyl acetate in cyclohexane over 40 min gave the title compound (670 mg) as a colourless oil.
Reaction SMILES: C([NH:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[N:9]=[C:8]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21]([F:25])[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([O:30]CC)=[O:29])=[CH:15]2)[C:7]=1[F:33])(C)(C)C.Cl>C(O)(=O)C>[NH2:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[N:9]=[C:8]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21]([F:25])[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[C:7]=1[F:33]
Reactant: CCOC(=O)c1cn(-c2nc(F)c(F)c(NC(C)(C)C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Yield: 67.6 %

Procedure:
To 300 mg of ethyl 1-(4-t-butylamino-3,5,6-trifluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate were added 3 ml of 12N hydrochloric acid and 0.5 ml of acetic acid, and the mixture was heated under reflux for 1.5 hour. The reaction solution was allowed to cool, and the solid precipitated was collected by filtration and washed with ethanol and diethylether successively to obtain 168 mg of the title compound as a colorless powder.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:12][N:11]([C:9](=[O:10])[C@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][O:6][Si:26]([CH3:28])([CH3:27])[C:29]([CH3:32])([CH3:31])[CH3:30])[O:13][CH3:14]
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl (tert-butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chloride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers were washed with brine and concentrated. The crude product was purified by column chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ═O (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer and nitrogen inlet, was placed 411 g of the previously prepared methyl 3-bromomethyl-4-nitrobenzoate, 441 g of anhydrous potassium acetate and 2 l of glacial acetic acid. The resulting mixture was refluxed for 4 hours, cooled to room temperature and stirred overnight. The solvent was removed in a rotary evaporator and the resulting light yellow solid treated with a mixture of 2 l of ethyl acetate and 1 l of water. The organic phase was separated, washed with water (3×400 mL), brine (1×400 mL) dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator. The crude reaction mixture was triturated with hexane and filtered yielding 318 g of the expected methyl 3-acetoxymethyl-4-nitrobenzoate. This compound was used as such in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:31][CH:32](OC)OC)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:29][N:28]([CH3:30])[CH2:27][CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]2[CH:32]=[CH:31][N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:16]2=[O:17])=[CH:24][CH:23]=1
Reactant: COC(CN(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCc2ccccc2)cc1)OC
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCOc1ccc(-n2ccn(-c3ccc(O)cc3)c2=O)cc1
Reaction time: 5 h

Procedure:
A suspension of 1-(4-benzyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]urea (4.9 g), palladium (10% on carbon, 1.0 g) and ethanol (40 mL) was stirred under hydrogen for 5 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was taken up in trifluoroacetic acid (20 mL) and the solution was stirred for 48 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated. The solid residue was stirred with acetonitrile, and the product was filtered off. The product with the molecular weight of 339.40 (C19H21N3O3); MS (ESI): 340 ([M+H]+), was obtained in this way.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:20][C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:41][CH2:42][CH2:43][CH2:44]O.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)(C)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:44][CH2:43][CH2:42][Br:41])[C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: OCCCBr
Reactant: Nc1ncnc2nc(Sc3cc4c(cc3Br)OCO4)[nH]c12
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCCBr
Yield: 21 %

Procedure:
A solution of 8-(6-Bromo-benzo[1,3]dioxol-5-ylsulfanyl)adenine (513 mg, 1.4 mmol), PPh3 (808 mg, 3.08 mmol), 3-bromo-1-propanol (253 mg, 165 L, 1.82 mmol), DBAD (1612 mg, 7 mmol) in toluene (43.8 mL) and CH2C12 (8.75, mL) was stirred at room temperature for 20 min. The reaction mixture was loaded to a silica gel column (CHC13 then CHC13:EtOAc:hexanes: i-Propanol at 4:4:2:1) to provide the 9N-alkylated compound, 8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-bromo-propyl)adenine) (142.6 mg, 21% yield). A solution of this product (142.6 mg, 0.29 mmol) in 1,4-dioxane (12 mL) and i-propylamine (3 mL) was stirred at 100° C. for 2.5 h. The solvent was removed under vacuum and the crude purified by preparatory thin layer chromatography on silica gel (CHC13:MeOH:NH4OH at 10:1:0.5 then EtOAc:CH2C12:MeOH at 2:2:1) to afford 12 (51 mg, 8% yield). 1H NMR (400 MHz, CDC13) 8.30 (s, 1H), 7.04 (s, 1H), 6.81 (s, 1H), 6.48 (bs, 2H), 5.94 (s, 2H), 4.29 (t, J=7.0 Hz, 2H,), 2.74-2.68 (m, 1H), 2.57 (t, J=6.8 Hz, 2H,), 2.02-1.95 (m, 2H), 1.02 (d, J=6.0 Hz, 6H). 13C NMR (100 MHz, CDC13) 154.8, 152.9, 151.5, 148.8, 148.0, 145.2, 123.8, 120.0, 116.7, 113.2, 112.2, 102.3, 48.6, 43.8, 41.7, 30.2, 22.8; MS m/z 465.0 (M+H)+. HPLC: (a) 99.1% (65% water-35% acetonitrile); (b) 98.0% (20% to 40% acetonitrile).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][C@@H:19]([OH:22])CO)[CH2:14]2)[N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:9])#[N:2].[Na]>CO.O.C(OCC)(=O)C>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][CH:19]=[O:22])[CH2:14]2)[N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OC[C@@H](O)CO)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-{[(2S)-2,3-dihydroxypropyl]oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 23–1 (250 mg) in methanol (5 mL) and water (5 mL), was added sodium periodinate (522 mg). The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo to give the target compound (238 mg). This compound was used immediately without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][CH:23]=[N:24][C:16]=3[CH3:15])[CH3:13])[CH2:11][O:10]1
Reactant: Cc1ncnc2nc[nH]c12
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: Cc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 46 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (587 mg) and 6-methylpurine (353 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methyl-9(9H)-purinyl]ethyl]oxirane (383 mg) was obtained as a white powder by the same way as in Reference Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]3[N:34]([CH2:38][CH3:39])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:38]([N:34]1[C:33]2[C:40]([CH3:42])=[CH:41][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:23]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37])[CH3:39]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)oc2cc(C(=O)c3cc(N4CCC(N5CCc6cc(OC)ccc6NC5=O)CC4)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 mg (0.20 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 50 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one and 56 μL (0.30 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3N3C=NN=C3CN=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[O:22]>C(O)=O>[C:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1)(=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NCc3nncn3-c3ccccc32)cc1
Reactant: C=O
Solvent: O=CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 1, 8-chloro-1-[[ (2-propynyl)amino]3-[-6-phenyl-4H-s-triazolo[4,3-a][1,4-]benzodiazepine is heated in formic acid with aqueous formaldehyde to give 5-chloro-2-[3[(2-propynyl)methylamino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:5]=[C:6]([CH3:10])[C:7]([OH:9])=[O:8].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: COc1ccc(C=C(C)C(=O)O)cc1F
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(CC(C)C(=O)O)cc1F

Procedure:
3-fluoro-4-methoxy-α-methylcinnamic acid, 49.5 g (0.236 mol) in 800 ml methanol is hydrogenated at 43 lbs. pressure and room temperature until the theoretical uptake of hydrogen has occurred (24 min. at 20° C., using 1.5 g platinum oxide catalyst). The solution is filtered and is evaporated with warming to 60° to give 3-fluoro-4-methoxy-α-methyl dihydrocinnamic acid, Rf 0.5 on silica-gel G with methylene chloride-methanol (9: 1).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].[N:42]1([C:47](N)=[NH:48])C=CC=N1>CN(C=O)C>[ClH:41].[C:35]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:26]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH:15][C:47](=[NH:42])[NH2:48])=[O:9])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 73.4 %

Procedure:
Prepared according to the method described in Example 6(e) above from (R)-N2 -(diphenylacetyl)-(R)-N-[1-(4-benzyloxyphenyl)ethyl]ornithine amide (0.38 g; 0.71 mmol; from step (d) above), 1H-pyrazole-1-carboxamidine monohydrochloride (0.10 g; 0.71 mmol), TEA (0.14 g, 1.42 mmol) and DMF (5 mL), 18 hours reaction time. The resulting solution was concentrated and chromatographed on silica eluting with MeOH:CHCl3 :conc. NH4OH (3:6:1) and converted to the hydrochloride salt to afford the title compound as a white solid (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[C:71]2[CH2:70][CH2:69][NH:68][CH2:67][C:66]=2[N:65]=[CH:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][C:71]3[NH:63][CH:64]=[N:65][C:66]=3[CH2:67]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCc4[nH]cnc4C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine in DMSO at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)CCC>O1CCOCC1.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:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(C)N1CCC(C(=O)Nc2ccc(-c3ccncc3)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 8 h
Yield: 10 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.52 g, 0.98 mmol), dichlorobis(triphenylphosphine)palladium(II) (34 mg, 0.05. mmol), and lithium chloride (0.15 g, 3.56 mmol) in 1,4-dioxane (5 mL) was added 4-(tributylstannyl)pyridine (1.16 g, 3.14 mmol) and dioxane (5 mL). The reaction mixture was heated to reflux, stirred overnight, and then filtered through diatomaceous earth. The filtrate was partitioned between 3:1 chloroform:isopropanol and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 10-25% 2 M ammonia/methanol solution in dichloromethane. The chromatography product was recrystallized from methanol and ethyl acetate to give 47 mg (10%) of a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pt](=O)=O>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)CCc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
Ethyl 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]acrylate (5.45 g) was dissolved in 100 mL of ethanol, and 200 mg of platinum dioxide was added to the solution, and then the mixture was stirred under atmospheric hydrogen pressure at room temperature for 5 hours. After the purge with nitrogen, the catalyst was filtrated off, and the solvent was removed to provide 5.07 g of ethyl 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]propionate as a pale yellow oil.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C@H:7]1[N:14]([C:15]([C:17]2[N:18]=[C:19]([CH3:29])[S:20][C:21]=2[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][CH:10]([CH3:30])[CH2:11]2)=O.C([O-])([O-])=O.[K+].[K+].CCOCC>CO>[NH2:5][CH2:6][C@H:7]1[N:14]([C:15]([C:17]2[N:18]=[C:19]([CH3:29])[S:20][C:21]=2[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][CH:10]([CH3:30])[CH2:11]2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-trifluoro-N-[(1S,2S,5R)-3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-acetamide (1.96 g) was dissolved in MeOH (20 mL) and a sat. aq. K2CO3 solution was added (20 mL). The reaction mixture was stirred overnight at RT. Ether was added to the reaction mixture and the org. layer was extracted with aq. HCl (25%) and aq. HCl (1M). The org. phase was discarded and the aq. layers were basified with aq. 30% NaOH and then extracted with DCM. The combined org. extracts were washed with a sat. aq. NaHCO3 solution, dried over anh. MgSO4, filtered and concentrated to yield the title compound as a light orange oil which was used without further purification.