Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:22])[N:5]([CH3:21])[C:6]([OH:20])=[C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[C:8]=1[CH3:9])#[N:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CC(N(C)C)=O>[C:1]([C:3]1[C:4](=[O:22])[N:5]([CH3:21])[C:6]([OH:20])=[C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])=[CH:14][CH:13]=2)[C:8]=1[CH3:9])#[N:2]
Reactant: Cc1c(N=Nc2ccc(CO)cc2)c(O)n(C)c(=O)c1C#N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Cc1c(N=Nc2ccc(COS(=O)(=O)c3ccccc3)cc2)c(O)n(C)c(=O)c1C#N
Yield: 49.3 %

Procedure:
14.9 g of Compound [2-a] was benzenesulfonylated in the same manner as described in Step 1-h using 12 g of benzenesulfonyl chloride in 50 ml of pyridine and 20 ml of dimethylacetamide to obtain 10.8 g of Compound [2-b].
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1
Reactant: NCCSCc1nccs1
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Product: O=c1[nH]c(NCCSCc2nccs2)nnc1Cc1cccnc1

Procedure:
3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (3.28 g) and 2-(2-thiazolylmethylthio)ethylamine (2.7 g) were heated together on an oil bath (160°-170°) for 1 hour. The cooled mixture was triturated with isopropanol and the solid was twice recrystallised from ethanol to give the title compound as pale yellow plates (3.1 g) m.p. 158°-59°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1.Br[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([O:22][CH3:23])[CH:14]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:22][C:15]1[CH:14]=[C:13]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C)CC2)cc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
After a mixture of palladium acetate (188 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (781 mg), cesium carbonate (4.09 g) and THF (20 mL) was stirred for 30 minutes, a mixture of 1-bromo-3-methoxy-5-nitrobenzene (1.94 g), 1-methylpiperazine (2.76 mL) and THF (20 mL) was added and heated under reflux for 14 hours. After cooling, the reaction liquid was diluted with ethyl acetate, and insoluble materials were separated by filtration. After extraction with 2M hydrochloric acid from the filtrate, the resulting aqueous layer was basified with 50% aqueous potassium hydroxide and then extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 20:1) to give 1-(3-methoxy-5-nitrophenyl)-4-methylpiperazine (1.01 g) as an orange syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[N:44]=[C:15]2[N:16]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:17]([CH3:33])=[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:14]2[N:13]=1)=[O:10])[C:2]1C=CC=CC=1.[OH-].[Li+].Cl>C1COCC1.O.C(O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:19]2[N:14]3[N:13]=[C:12]([NH:11][C:9]([O:8][CH2:1][CH3:2])=[O:10])[N:44]=[C:15]3[N:16]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[CH:35]=3)[C:17]([CH3:33])=[C:18]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:22]=1)#[N:27]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)OCc3ccccc3)nn2C1c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2n(n1)C(c1ccc(C#N)cc1)C(C(=O)OCC)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, ethyl 2-[(benzyloxy)carbonyl]amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (125 mg, 207 μmol) was dissolved in a mixture of THF (0.9 ml), water (0.6 ml) and ethanol (3.8 ml). After addition of solid lithium hydroxide (14.9 mg, 620 μmol, 3 eq.), the reaction mixture was heated at 55 C for 1.5 h. In an ice-bath, the mixture was acidified with 1 N hydrochloric acid (4.1 ml) and then purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (4.8 mg, 5% of theory).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (2.86 g, 74.4 mmol) in THF (300 ml) at 0°, is added methyl 4'-fluoro-4-biphenylyl-carboxylate (8.67 g. 37.7 mmol) as a solution in THF (100 ml). The resulting mixture is stirred for 1 hour and subsequently allowed to warm to room temperature. The reaction mixture is chilled to 0° and 2N HCl (100 ml) is slowly added. The resulting mixture then is extracted with Et2O (2×150 ml). The combined organic portions are washed with saturated NaHCO3 solution (400 ml), saturated NaCl solution (400 ml), dried over MgSO4 and concentrated in vacuo to yield 4'-fluoro-4-biphenylyl-methanol as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:23]([O:25][C:26]1[CH:37]=[CH:36][C:29]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][C:27]=1[O:38][CH3:39])[CH3:24].O>CN1C(=O)CCC1>[CH2:23]([O:25][C:26]1[CH:37]=[CH:36][C:29]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][NH:35][C:2]2[C:3]3[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[CH:28][C:27]=1[O:38][CH3:39])[CH3:24]
Reactant: CCOc1ccc(CCNCCN)cc1OC
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc(CCNCCNc2nc(C)nc3c2c(C)c(C)n3-c2c(C)cc(C)cc2C)cc1OC

Procedure:
Heat a solution of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (340 mg, 1.1 mmol) and N-(4-ethoxy-3-methoxy-phenethyl)-ethylenediamine in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Br[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1>>[CH3:31][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:30]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Cc1ccnc(Br)c1
Agent: Cl
Product: Cc1ccnc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1

Procedure:
The title compound was prepared according to Example 549 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Bromo-4-methyl-pyridine:
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>CO>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:22]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1
Reactant: Oc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Methyl α-bromo-α-[p-(phenoxy)phenyl]acetate (6.42 g) is reacted with 3.21 g of 4-chlorophenol in methanol as in Example 16 to afford a white solid, which is recrystallized from hexane to yield the product, mp 99°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]([O:16]C)=O)[O:11][N:10]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14](=[O:16])[NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:11][N:10]=1
Reactant: COC(=O)c1nc(-c2c(Cl)cccc2Cl)no1
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1nc(-c2c(Cl)cccc2Cl)no1

Procedure:
To a solution of 1 g of 3-(2,6-dichlorophenyl)-5-methoxycarbonyl-1,2,4-oxadiazole in 5 ml of toluene, was added 0.4 g of cyclohexylamine at room temperature.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[BH4-].[Na+]>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(Cc4cccc(F)c4)C3)cc2)nc1
Yield: 41.4 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.98 mL of 0.12 M stock solution in methanol, 0.0343 g, 0.115 mmol), 3-fluoro-benzaldehyde (0.0180 mL, 0.170 mmol), and sodium borohydride (0.0102 g, 0.270 mmol) provide 0.0193 g (41%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C24H25FN3O2 406.1931, found 406.1917; 1H NMR (CDCl3): 8.56 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4, 8.8 Hz), 7.28-7.21 (m, 3H), 7.09-7.02 (m, 4H), 6.95-6.88 (m, 2H), 5.74 (s br, 2H), 3.52 (d, 1H, J=13.7 Hz), 3.50 (d, 1H, J=13.7 Hz), 3.00-2.93 (m, 1H), 2.93-2.80 (m, 2H), 2.06-1.90 (m, 3H), 1.80-1.64 (m, 2H), 1.44 (dq, 1H, J=4.4, 12.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[BH4-].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH3:14])=[O:4]
Reactant: COC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2ccccc2N1C
Reaction time: 8 h

Procedure:
A solution of methyl-1-methylindole-carboxylate* (6.0 g) in trifluoroacetic acid (50 ml) is cooled in an ice bath as sodium borohydride pellets (6.0 g) are added slowly, keeping the temperature below 10° C. The slurry is allowed to rise to room temperature and then stirred overnight. The unreacted sodium borohydride is decomposed with 50% sodium hydroxide and the mixture is extracted several times with ether. The extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to dryness to obtain an orange oil. This is distilled in a kuegelrohr (b.p.=128-150/0.2 mm) to yield colorless liquid, methyl-2,3-dihydro-1-methylindole-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:11][CH:10]=1.C(O)C.[C:22]1([C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH:14]([NH:15][CH2:30][CH:29]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:16])=[CH:11][CH:10]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CC(N)Cc1ccc(OCc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(OCc2ccccn2)cc1)NCC=C(c1ccccc1)c1ccccc1

Procedure:
The starting material is prepared as follows: The mixture of 12.1 g of dl-4-(2-pyridylmethoxy)-amphetamine, 400 ml of absolute ethanol and 10.4 g of β-phenylcinnamaldehyde is treated dropwise under stirring with the solution of 3.5 g of sodium borohydride in 10 ml of water. The whole is then stirred and refluxed overnight, concentrated and the concentrate diluted with water. It is extracted with ethyl acetate, the organic layer washed with saturated aqueous sodium chloride, dried and evaporated to yield the dl-1-[4-(2-pyridylmethoxy)-phenyl]-2-(3,3-diphenylallylamino)-propane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([O:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)=[CH:12][CH:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O.[Pd]>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[N:10][C:11]([O:14][CH:15]2[CH2:20][C:19]([CH3:21])([CH3:22])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cc(Cl)ccc1-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2cn[nH]c2)ccc1-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 160 °C
Yield: 0 %

Procedure:
SiliaCat® DPP-Pd (0.37 g, 0.10 mmol) was added to a microwave vial containing a mixture of 3-(4-chloro-2-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (0.36 g, 0.96 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.47 g, 2.4 mmol), and K2CO3 (0.53 g, 3.8 mmol) in ethanol/water (10:1, 6.6 mL). The reaction mixture was sealed, then heated in a microwave reactor at 160° C. for 1 h. After cooling, the reaction was purified by solid phase extraction (5 g SiliaBond Carbonate®, MeOH as eluent). The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel saturated with Et3N, 2 to 25% MeOH in DCM) to give the desired product (0.08 mg, 21%). [M+H]: 408.4; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.33 (bs, 1H), 8.05 (bs, 1H), 7.94 (d, J=9.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 7.34 (dd, J=8.0, 1.5 Hz, 1H), 7.14 (d, J=9.5 Hz, 1H), 5.57-5.74 (m, 1H), 3.90 (s, 3H), 2.00-2.14 (m, 2H), 1.17-1.31 (m, 8H), 1.11 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:6]=[CH:5][N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:7]2[C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:4][CH:5]=[N:6]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CN)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CNC(=N)N)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution 2-(((Z)-(2-(((2R,3S)-2-((5-(aminomethyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (25 mg, 0.047 mmol) and pyrazole-1-carboxamidine hydrochloride (10.9 mg, 0.099 mmol) in DMF (470 μL) was added DIPEA (33 μL, 0.188 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (13 mg, 42%) as a white powder. LCMS: Rt=0.29 min, m/z=574.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 7.96-7.78 (m, 1H), 7.41-6.96 (m, 5H), 6.80-6.71 (m, 1H), 6.55 (s, 1H), 5.42-5.32 (m, 1H), 4.75-4.63 (m, 1H), 4.62-4.42 (m, 1H), 4.39-4.28 (m, 1H), 1.38 (s, 3H) 1.34 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:34]([CH3:35])[C:14]3=[N:15][CH:16]=[C:17]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH:22]4[C:30]([O:32][CH3:33])=[O:31])=[O:20])[CH:18]=[C:13]3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>CO>[ClH:36].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:34]([CH3:35])[C:14]3=[N:15][CH:16]=[C:17]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH:22]4[C:30]([O:32][CH3:33])=[O:31])=[O:20])[CH:18]=[C:13]3[N:12]=2)=[CH:5][CH:4]=1)(=[NH:41])[NH2:2]
Reactant: [NH4+]
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccccc2N1C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C
Yield: 20 %

Procedure:
Prepared analogously to Example 1 from 2-[2-(4-cyanophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 20% of theory, C27H26N6O3 (482.54) Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) EKA mass spectrum: (M+H)+ =483
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[S:26].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[O:19])[CH:2]([NH:1][C:25](=[S:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=3)[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: OC(=S)c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1NC(=S)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (80.0 mg, 0.318 mmole), 3-trifluoromethylthiobenzoic acid (70.7 mg, 0.318 mmole), HBT (43.0 mg, 0.318 mmole) and EDC(61.0 mg, 0.318 mmole) were combined in dry DMF (2 ml) and stirred at room temperature. The pH of the mixture was adjusted to 9.0-9.5 with triethylamine (64.4 mg, 0.636 mmole) and the mixture stirred for 10 minutes. The DMF was removed in vacuo, and the residue was treated with 10% citric acid and extracted with EtOAc. The combined organic fractions were washed with sodium carbonate solution, dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue was crystallized from EtOAc to give the title compound which was dried in vacuo at 100° C.: (m.p. 230°-232° C.).
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[F:14][C:15]([C:17]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:19]#[CH:20])=[CH2:16].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:14][C:15]([C:17]([O:25][Si:26]([CH3:29])([CH3:27])[CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18]/[CH:19]=[CH:20]/[Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH2:16]
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(=C)F
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=C(F)C(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)O[Si](C)(C)C
Temperature: 140 °C

Procedure:
A mixture of 21.4 ml. of tributylstannane, 18.3 g. of 4-(1'-fluorovinyl)-4-trimethylsilyloxy-1-octyne and azobisisobutyronitrile is heated under an inert atmosphere on an oil bath. Upon reaching 85° C. a rapid exotherm occurs which is moderated to maintain 140° C. using a water bath. After the exotherm the mixture is heated at 135° C. for one hour, then cooled to room temperature. The resulting oil is distilled via a Kugelrohr to give the desired product as 33.68 g. of a light yellow liquid (air bath 160° C., 0.15 mm.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[F:47][C:48]1[CH:53]=[CH:52][C:51](I)=[CH:50][C:49]=1[F:55]>CS(C)=O.[I].[Cu]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:51]3[CH:52]=[CH:53][C:48]([F:47])=[C:49]([F:55])[CH:50]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: Fc1ccc(I)cc1F
Agent: [Cu]
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(c3ccc(F)c(F)c3)C2)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 36.7 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (110 mg, 0.25 mmol) in dimethylsulfoxide (0.2 ml) was added L-proline (4.4 mg, 0.04 mmol), potassium carbonate (52.5 mg, 0.38 mmol), and copper iodine (3.6 mg, 0.02 mmol). The reaction was degassed under nitrogen and 1,2-difluoro-4-iodobenzene (45.4 mg, 0.19 mmol), was added, the reaction was again degassed and then heated to 90° C. The reaction was stirred over 48 hours. The reaction was partitioned between EtOAc/H2O, washed with H2O (3×) and brine (1×). Purification by silica gel chromatography (Isco) gave the desired product, (39 mg, 37%). Calcd for C32H34F5NO2 (M+H) 559.60, Found 560.4.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18][C:12]=3[C:11]([CH3:21])([CH3:20])[O:10][C:9]=2[CH:8]=[C:7]([CH3:22])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(O)(=[O:29])C>>[C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][C:18](=[O:29])[C:12]=3[C:11]([CH3:21])([CH3:20])[O:10][C:9]=2[CH:8]=[C:7]([CH3:22])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)cc2c1C1=C(CCC(C)C1)C(C)(C)O2
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(C)cc2c1C1=C(C(=O)CC(C)C1)C(C)(C)O2
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a stirring mixture of 1-acetoxy-7,8,9,10-tetrahydro-3,6,6,9-tetramethyl-6H-dibenzo[ b,d]pyran (601 mg., 2 mmole) in 7 ml. of 50% acetic acid and 5 ml. of chloroform held under a nitrogen atmosphere, was added dropwise a solution of ceric ammonium nitrate (4.39 g., 8 mmole) in 12 ml. of 50% acetic acid. After the addition was completed, the reaction mixture was stirred over a steam bath. After 3 hours, the mixture was poured onto ice with stirring. The product was extracted into ether, washed to neutrality with 5% NaHCO3, washed with water, dried over Na2SO4 and concentrated under reduced pressure. Elution of the product from a mganesium silicate column with graded ether/petroleum ether gave 120 mg. (14.2%) of the desired product which showed a blue fluorescent spot on tlc at Rf 0.67 (silica gel, 40% EtOAc/hexane). Ir(neat) 1770(m), 1740(s), 1660(s), 1640(s), 1620(m) CM-1 ; nmr (CDCl3) δ 1.08(d,3H, J=4Hz), 1.38(S,3H), 1.7(S,3H), 2.3(S,6H), 1.0-3.0(broad m,5H), 6.5(S,1H), 6.62(S,1H).