Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=S)[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH:31][NH2:32])(=O)[CH3:29]>C(#N)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:28]([CH3:29])=[N:31][N:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)NN
Reactant: CC(=O)O[C@@H]1C[C@H](C(=S)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@H](c2nnc(C)n2Cc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (2R,4R)-tert-butyl-2-((4-chlorobenzyl)carbamothioyl)-4-acetoxypyrrolidine-1-carboxylate from Step C (1.6 g, 3.88 mmol) and acetic hydrazide (575 mg, 7.76 mmol) in acetonitrile (18 ml) was added mercury (II) acetate (1.85 g, 5.82 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was filtered through a plug of celite and washed with acetonitrile. The combined filtrates were concentrated, the resulting residue taken up in EtOAc (200 ml), then washed with H2O (75 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc) provided the desired product.
Reaction SMILES: Cl[Sn]Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:8][CH2:7]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[CH2:10][CH2:11]1
Reactant: CN1CCN(Cc2cc([N+](=O)[O-])ccc2N2CCN(C)CC2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc(N)ccc2N2CCN(C)CC2)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of SnCl2 (0.398 g, 2.1 mmol), 1.6 mL of HCl 1M and 5 mL of THF was added to a solution of 1-methyl-4-{2-[(4-methylpiperazin-1-yl)methyl]-4-nitrophenyl}piperazine (0.175 g, 2.5 eq) in 15 mL of THF. The reaction mixture was refluxed for 3 h and allowed to cool to room temperature. A saturated aqueous solution of Na2CO3 was added. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (DCM/MeOH/NH4OH//8/2/0.1) to yield expected compound as a brown oil (100 mg, 63% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.CS([O-])=O.[Na+].[H-].[Na+].[OH:25][C@@H:26]([CH2:37][CH2:38][O:39][CH3:40])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=1)=[O:28]>C1COCC1.CCOC(C)=O>[Cl:17][C:16]1[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([O:25][C@@H:26]([CH2:37][CH2:38][O:39][CH3:40])[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=4)=[O:28])=[C:3]3[CH:10]=[N:9]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COCC[C@H](O)C(=O)Nc1ccc(C)cn1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: CS(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
4-Chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (219 mg, 0.82 mmol) was added to sodium methanesulfinate (75 mg, 0.73 mmol) and sodium hydride (38.0 mg, 0.95 mmol) in THF (5 mL) at 23° C. under nitrogen. The resulting suspension was stirred at ambient temperature for 5 minutes. (S)-2-Hydroxy-4-methoxy-N-(5-methylpyridin-2-yl)butanamide (Intermediate F1) (142 mg, 0.63 mmol) was added dropwise and the suspension was stirred at ambient temperature for a further 30 minutes. The mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 40 to 100% EtOAc in isohexane to afford (2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-4-methoxy-N-(5-methylpyridin-2-yl)butanamide (250 mg, 87%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:11]1[CH:13]2[CH2:14][C:15]3[C:20]([CH:12]12)=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C(OCC)C.O>[C:21]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:15]=2[CH2:14][CH:13]([OH:11])[CH2:12]3)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2cccc3c2CC2OC32)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
Under a dry argon atmosphere, a stirred solution of 9 g (0.067 mole) of aluminum chloride in 225 ml of anhydrous diethyl ether was cooled to 0° C. To this was added portionwise 9.4 g (0.245 mole) of lithium aluminum hydride. The cooling bath was removed, and the mixture stirred for 15 minutes. With the temperature being maintained at 25° C., a solution of 47.7 g (0.229 mole) of 1,2-epoxy-4-phenylindane in 175 ml of anhydrous diethyl ether was added dropwise. After complete addition, the mixture was heated at reflux for 18 hours, then cooled to 0° C. Water and an aqueous solution of sodium hydroxide were added to decompose the excess lithium aluminum hydride, and the mixture was filtered. The filter cake was washed with diethyl ether, and the filtrate and washes were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure to give an oil. The oil was subjected to column chromatography on silica gel, eluting with 98:2 toluene/ethyl acetate followed by 90:10 toluene/ethyl acetate to give 31.5 g of 4-phenyl-2-indanol, mp 72°-76° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([OH:21])[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([O:21][C:22](=[O:24])[CH3:23])[CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CC2(CCN(Cc3ccccc3)C2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)OC1CC2(CCN(Cc3ccccc3)C2)c2ccccc21

Procedure:
56.0 g of 1'-benzyl-3-hydroxyspiro[indan-1,3'-pyrrolidine] are stirred at room temperature with 120 cc of pyridine and 120 cc of acetic anhydride for 20 hours. The mixture is then poured on ice, is made alkaline with 2 N caustic soda solution and is extracted thrice with 250 cc amounts of ether. The ether phase is washed with water, dried over sodium sulphate and concentrated by evaporation. 1'-Benzyl-3-acetoxyspiro[indan-1,3'-pyrrolidine] is obtained as light yellow oil, which is used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Br)cncc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cncc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 40.1 %

Procedure:
A sealed tube was charged with 101f (200 mg, 0.53 mmol), 101l (250 mg, 0.53 mmol), PdCl2(dppf) (42 mg, 0.05 mmol), K3PO4 (210 mg, 1.0 mmol), and NaOAc (85 mg, 1.0 mmol) in acetonitrile/H2O (8 mL/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. in a sealed tube for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on reverse phase Combi-flash eluting with 20:1 DCM/MeOH to afford 101m (135 mg, 40%). LCMS: [M+H]+ 635.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Zn+2:10].C(=O)=O>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Zn+2:10].[NH2:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Zn+2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
The glycine is dissolved in water and the zinc carbonate is added. CO2 is liberated and the solution is evaporated to dryness to obtain white crystals of zinc glycinate which may be the monohydrate form of zinc glycinate. A 1% aqueous solution has a pH of 7.9. In lieu of evaporation, the solution may be spray dried to obtain the zinc glycinate crystals.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:25].O>O.[Cu]Br>[Br:25][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Reaction time: 0.17 h

Procedure:
(4R)-4-(3-Amino-4-chlorophenyl)pyrrolidin-2-one (12 g, 57.14 mmol) was added to a mixture of 75 mL of 48% HBr/water and 150 mL of water. The solution was cooled in ice. Sodium nitrite (4.33 g, 62.85 mmol) in 10 mL of water was added dropwise. The resulting mixture was stirred for 10 min. Copper(I) bromide (8.9 g, 62.85 mmol) was dissolved in a mixture of 75 mL of 48% HBr/water and 150 mL of water and added dropwise to the reaction mixture. The mixture was then stirred overnight at room temperature. Ethyl acetate (250 mL) was added to the reaction mixture and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with 200 mL of ethyl acetate. The combined ethyl acetate layers were washed with water (3 times), brine and then concentrated to give the desired product as a brownish yellow oil, which was purified by silica gel column chromatography eluting with methylene chloride/methanol to provide 7.2 g of the title compound (60% yield). 1H-NMR (400 MHz, CD3OD): δ 7.62-7.63 d, J=2.0 Hz, 1H), 7.45-7.47 (m, 1H), 7.26-7.30 (m, 1H), 3.69-3.79 (m, 2H), 3.33-3.37 (m, 1H) 2.67-2.74 (dd, J=16.4, 8.8 Hz, 1H), 2.40-2.47 (dd, J=16.4, 8.4 Hz, 1H); MS (ESI) m/z 275.89 (M+H)+.
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].[C:38](=[O:41])([O-:40])[O-:39].[K+].[K+].CN(C=O)C>O>[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:6][C:8]2[O:41][C:38](=[O:40])[O:39][C:27]=2[CH3:12])[CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]2[O:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:3])[CH3:4]
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(Cc4oc(=O)oc4C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.5 %

Procedure:
To N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)-ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (1.0 g) were added the compound of Reference Example 8 (344 mg), potassium carbonate (45 mg) and DMF (30 ml), and the mixture was stirred at room temperature overnight. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the title compound (300 mg) as white amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([CH2:12][CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[N:14]=2)[NH:19][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:26][CH:27]=1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)cc3n2)cc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(Br)c3n2)cc(OC)c1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 5, 120 mg, 0.262 mmol) in methylene chloride (2 mL), a solution of N-bromosuccinimide (46.7 mg, 0.262 mmol) in methylene chloride (1 mL) was added dropwise at 0° C. After 30 minutes, the reaction was quenched with saturated aqueous NaHCO3, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane (DCM)) to give the desired product (110 mg, 78%). LCMS calculated for C27H31BrN5O2 (M+H)+: m/z=536.2. Found: 536.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]2[C:21]([O:22][CH3:23])=[CH:20][NH:19][C:18](=[O:24])[CH:17]=2)[CH:9]=1.Br[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Cl-].[Li+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]2[C:21]([O:22][CH3:23])=[CH:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C:18](=[O:24])[CH:17]=2)[CH:9]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(CC(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
3.18 g (23.0 mmol) of potassium carbonate were added to a solution of 4.00 g (15.3 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 2.92 ml (18.4 mmol) of benzyl bromoacetate in 53.3 ml of dimethylformamide, and the mixture was then stirred at 100° C. for 45 min. The reaction mixture was cooled to RT and the reaction was ended by adding 530 ml of water and 10.0 g (236 mmol) of lithium chloride. The mixture was extracted three times with 200 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50 ml of dichloromethane, applied to diatomaceous earth and purified by flash chromatography (120 g cartridge, 80 ml/min, ethyl acetate/cyclohexane gradient). Yield: 3.90 g (61% of theory)
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:37]([OH:39])=O)=[O:33].[CH2:44]([C:46]1[CH:61]=[C:60]([C:62](=[NH:65])[NH:63]O)[CH:59]=[C:58]([CH3:66])[C:47]=1[O:48][CH2:49][C@@H:50]([OH:57])[CH2:51][NH:52][C:53](=[O:56])[CH2:54][OH:55])[CH3:45]>>[CH2:44]([C:46]1[CH:61]=[C:60]([C:62]2[N:65]=[C:37]([C:36]3[CH:40]=[CH:41][C:42]([CH3:43])=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:63]=2)[CH:59]=[C:58]([CH3:66])[C:47]=1[O:48][CH2:49][C@@H:50]([OH:57])[CH2:51][NH:52][C:53](=[O:56])[CH2:54][OH:55])[CH3:45]
Reactant: Cc1ccc(C(=O)O)cc1C=O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3ccc(C)c(C=O)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 43.4 %

Procedure:
The title compound (405 mg) is prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-4-methyl-benzoic acid (338 mg, 2.06 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (670 mg, 2.06 mmol). LC-MS**: tR=0.68 min; [M+1]+=454.17; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.70-2.78 (m, 5H), 3.21-3.29 (m, 1H), 3.39-3.48 (m, 1H), 3.71-3.80 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.93-4.01 (m, 1H), 5.32 (d, J=5.3 Hz, 1H), 5.56 (t, J=5.5 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.71 (t, J=5.5 Hz, 1H), 7.81 (s, 2H), 8.33 (dd, J=8.0, 1.8 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 10.37 (s, 1H).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:16]1[N:20]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[N:19]=[CH:18][C:17]=1[C:31](=[O:39])[NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[CH:33]1([NH:32][C:31]([C:17]2[CH:18]=[N:19][N:20]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[C:16]=2[S:4][CH2:1][CH2:2][CH3:3])=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCCS
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h

Procedure:
Propane thiol (88 mg, 1.16 mmol) was dissolved in DMF (5 mL) and treated at ambient temperature with a 1M solution of NaHMDS in THF (1.16 mL). After stirring for 15 min the clear solution was added to a suspension of methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate #15) (378 mg, 1.05 mmol) in DMF (10 mL). Stirring was continued at ambient temperature for 2 h and then the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (4×25 mL) and dried (MgSO4). Volatiles were removed by evaporation under reduced pressure to give a clear oil which was purified by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient (0-50%) to give the title compound as a white solid. (363 mg, 86%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccncc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1cnccc1-c1ccc(CBr)cc1

Procedure:
A solution of 3-cyano-4-(4-tolyl)pyridine (485 mg, 2.66 mmol), N-bromosuccinimide (929 mg, 5.22 mmol), and dibenzoylperoxide (64 mg, 0.266 mmol) in CCl4 (15 mL) was heated to reflux for 6 h. The mixture was cooled and water (50 mL) and CH2Cl2 (30 mL) were added. The organic layer was dried (MgSO4) and purified by flash chromatography (10% EtOAc/hexanes). The product is not kept in concentrated form for more than 5 minutes and stored only in CH2Cl2 at 0° C. to minimize polymerization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH:38]1([CH2:41]Br)[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][O:22][CH2:21][C@@:19]23[CH2:18][N:17]([S:23]([C:26]4[CH:27]=[N:28][C:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:30][CH:31]=4)(=[O:24])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COCC2CC2)C1

Procedure:
The title compound was prepared by the method of Preparation 25b using [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol and cyclopropylmethyl bromide. 1H NMR (400 MHz, CHCl3-d): δ 8.54 (d, 1H), 7.80 (dd, 1H), 7.51-7.39 (m, 3H), 7.14 (t, 2H), 6.62 (d, 1H), 4.17 (dd, 1H), 3.80 (t, 4H), 3.65 (t, 4H), 3.45 (d, 1H), 3.30 (dd, 2H), 3.27-3.14 (m, 2H), 2.75-2.65 (m, 1H), 2.43-2.33 (m, 2H), 2.21-2.10 (m, 1H), 2.10 (d, 1H), 1.12-1.01 (m, 1H), 0.49 (dd, 2H), 0.26-0.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([CH3:23])[CH:18]=[CH:17][C:16]=1B(O)O.[F-].[Cs+]>C(COC)OC.O>[NH2:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([O:21][CH3:22])[C:15]=2[F:14])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COc1c(C)ccc(B(O)O)c1F
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C)c(OC)c2F)cc(N)c1Cl
Temperature: 85 °C
Yield: 18.2 %

Procedure:
A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid, methyl ester (0.24 g, 1.1 mmol), 2-fluoro-3-methoxy-4-methylphenyl boronic acid (0.30 g, 1.63 mmol) and cesium fluoride (3.0 g, 3.26 mmole) in dimethoxyethane (2 mL) and water (2 mL) was purged with a stream of nitrogen for 15 minutes before adding dichlorobis(triphenylphosphine) palladium (0.07 g, 0.1 mmol) and then heated to 85° C. for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (33% ethyl acetate in hexanes) to give 4-amino-3-chloro-6-(2-fluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylic acid, methyl ester (0.08 g, 0.2 mmol): mp 95-96° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:21])[CH2:12][O:13]C2C=CC(C)=CC=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CN(C)C1C=CC=CC=1.C(OC(C)C)(C)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:11]2[CH:21]=[C:4]([CH3:5])[CH:1]=[CH:2][C:12]=2[OH:13])[C:7]([CH3:8])=[CH2:6])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccc(C(C)C)cc1)COc1ccc(C)cc1
Solvent: CN(C)c1ccccc1
Solvent: CC(C)OC(C)C
Product: C=C(C)C(c1ccc(C(C)C)cc1)c1cc(C)ccc1O
Temperature: 215 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 1-isopropyl-4-(2-methyl-3-(4-methylphenoxy)propene-1-yl)benzene obtained in Reference Example 87 (8.2 g, 29.2 mmol) in N,N-dimethylaniline (50 mL) was stirred under argon atmosphere at 215° C. for 16 hours. After cooling, the reaction mixture was diluted with diisopropyl ether, washed with 5 N hydrochloric acid and water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 7.80 g (yield 95%) of the title compound. Oily matter.