Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(=O)CC.CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:9]([NH:11][CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])=[O:10])[NH2:8])=[CH:12][CH:13]=1
Reactant: O=S1(=O)CCCO1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The solid (1.96 g, 5.8 mmol) was dissolved in a minimum amount of water. To the solution was added aqueous NH4OH (28-30%, 15 mL). The reaction mixture was stirred at room temperature over weekend. The solvent was removed under reduced pressure and EtOAc (15 mL) was added. The mixture was heated under reflux. The hot solution was filtered. The filtrate was cooled to room temperature and was stored in the fridge. The solid was collected by filtration, washed with EtOAc, to give 4-iodophenylalanine amide. The amide (1.3 g, 4.4 mmol) was dissolved in 15 mL of 2-butanone with a few drops of DMF before 1,3-propane sultone (560 mg, 4.9 mmol) was added. The reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. The solid was suspended in MeOH (25 mL) and a small amount of water (1 mL). The suspension was stirred at reflux. The solid material was collected by filtration while the mixture was still hot. The solid was washed with hot MeOH (2×10 mL). Compound CO was obtained as a white solid (320 mg).
Reaction SMILES: [CH:1]1[C:6]2[CH:7]=[C:8]3[C:22](=[O:23])[O:21][CH2:20][C:9]3=[C:10]([C:11]3[CH:12]=[CH:13][C:14]4[O:19][CH2:18][O:17][C:15]=4[CH:16]=3)[C:5]=2[C:4]2[O:24][CH2:25][O:26][C:3]=2[CH:2]=1.[CH3:27][NH2:28]>C1C=CC=CC=1>[CH3:27][NH:28][C:22]([C:8]1[CH:7]=[C:6]2[C:5](=[C:10]([C:11]3[CH:12]=[CH:13][C:14]4[O:19][CH2:18][O:17][C:15]=4[CH:16]=3)[C:9]=1[CH2:20][OH:21])[C:4]1[O:24][CH2:25][O:26][C:3]=1[CH:2]=[CH:1]2)=[O:23]
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: CN
Solvent: c1ccccc1
Product: CNC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Temperature: 120 °C
Reaction time: 96 h

Procedure:
Helioxanthin (1.0 g) was suspended in benzene (10 ml), followed by addition of methylamine (40% methanol solution: 2 ml). The mixture was heated at 120° C. under stirring for 4 days. The reaction mixture was concentrated under reduced pressure. The resulting residue was recrystalized from DMF to yield the title compound (144 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH2:52])[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.CCOC(C)=O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)N)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC[C@@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3 N (200 μl, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (R)-3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid. 1H-NMR (CDCl3) δ 1.23–1.28 (m, 3 H), 1.38–1.41 (t, 3 H, J=7.3 Hz), 2.32 (s, 3 H), 3.50–4.13 (m, total 11 H), 4.36 (q, 2 H, J=7.3 Hz), 6.65–8.13 (series of m, total 12 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH:14]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:14]=[C:15]1[C:16]2[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: COc1cc(F)cc(B(O)O)c1
Product: COc1cc(F)cc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 52 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-fluoro-5-methoxyphenylboronic acid (300 mg, 1.76 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (450 mg, 1.6 mmol)provides 275 mg of title compound in 52% yield as a pale yellow oil. HPLC shows 97% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[CH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[NH:1]([C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[CH:6]2)[C:15]([CH3:16])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnn2cnc3ccccc3c12
Product: CC(=O)Nc1cnn2cnc3ccccc3c12
Yield: 90 %

Procedure:
19.8 g (0.1 mole) of 1-aminopyrazolo[1,5-c]quinazoline are boiled with 100 ml of acetic anhydride for 1 hour. On cooling the product separates. After filtration, washing and drying, 22.0 g (90%) of 1-acetaminopyrazolo[1,5-c]quinazoline are obtained. M.p.: 256°-258° C.
Reaction SMILES: Cl.[CH:2]1([CH:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([N:16]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[N:17]3)=[C:11]([CH3:25])[CH:10]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=1>CN(C)C=O.O>[CH:2]1([CH:7]([NH:8][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=2)[C:9]2[CH:10]=[C:11]([CH3:25])[C:12]([N:16]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[N:17]3)=[C:13]([CH3:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(C(N)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a mixture of (+/−)-cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine hydrochloride (1.002 g, 2.680 mmol) and potassium carbonate (1.51 g, 10.7 mmol) in N,N-dimethylformamide (5.36 mL) was added methyl 6-fluoronicotinate (472 mg, 2.95 mmol). The reaction was heated to 85° C. After 15 h, the reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organics were dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) gave methyl (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 8.67 (d, J=1.6 Hz, 1H), 7.99 (dd, J=9.0, 2.0 Hz, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 7.12 (s, 2H), 6.28 (d, J=9.0 Hz, 1H), 4.43-4.33 (m, 1H), 3.87 (s, 3H), 2.36-2.23 (m, 1H), 2.04-1.97 (m, 7H), 1.77-1.41 (m, 6H), 1.37-1.28 (m, 1H). MS (M+1): 473.2.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([O:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Oc1ccccc1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Temperature: 150 °C

Procedure:
A mixture of 3-chloro-6-(3-fluoro-4-methoxy-phenyl)-pyridazine (1.0 g, 4019 mmol), phenol (0.26 g, 5.03 mmol) and Cs2CO3 (1.64 g, 5.03 mmol) in 15 mL of DMF (in microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 150° C. for 15 min. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The solid was washed with 50% EtOAc/hexanes to provide the title compound as an off-white solid. MS (ESI pos. ion) m/z: 297.3 (M+H). Calc'd Exact Mass for C17H13FN2O2: 296.30.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([OH:33])[C:25]([C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([O:33][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:25]([C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A solution of 2-[N-(t-butoxycarbonyl)amino]ethyl bromide (0.032 g) in DMF (0.5 ml) was added to a stirred cooled solution of ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 36, 0.05 g) and cesium carbonate (0.065 g) in DMF (0.5 ml) at 0° C. The resultant mixture was allowed to warm to room temperature, stirred for 3 hours then partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 20-25% to give ethyl 6-(benzenesulphonylmethyl)-2-[2-(t-butoxycarbonyl)amino-ethoxy]-3-(furan-3-yl)-benzoate (0.031 g) as a colourless gum.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].Cl[CH2:16][CH:17]1[O:19][CH2:18]1.[OH-].[Na+]>>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH2:16][CH:17]1[O:19][CH2:18]1)([O-:3])=[O:2]
Reactant: ClCC1CO1
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1[N+](=O)[O-]
Yield: 78 %

Procedure:
2,3-Dinitro-4-methylphenol (see H. E. Dadswell and J. Kenner, J. Chem. Soc., 1927, 583) is reacted with 3-chloro-1,2-epoxypropane and 25% aqueous sodium hydroxide solution to give, in a yield of 78% of theory, 2,3-dinitro-1-(2,3-epoxypropoxy)-4-methylbenzene (m.p. 121°-123° C.). This compound is reacted in boiling ethanol with tert.-butylamine to give 2,3-dinitro-1-(2-hydroxy-3-tert.-butylaminopropoxy, 4-methylbenzene (m.p. 104°-106° C.), catalytic hydrogenation of which, in the presence of platinum dioxide, gives amorphous 2,3-diamino-1-(2-hydroxy-3-tert.-butylaminopropoxy)-4-methylbenzene trihydrochloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].C(N(CC)CC)C.[Cl-].[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>C(OCC)C>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[C:28](=[O:29])[CH2:27][C:26]([O:25][CH3:24])=[O:31]
Reactant: COC(=O)CC(=O)O
Reactant: COC(CNc1c(C)cccc1C)OC
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)N(CC(OC)OC)c1c(C)cccc1C
Yield: 33.9 %

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-2,6-dimethyl aniline (4.45 g, 0.02 mol), triethylamine (2.76 ml, 0.02 mol) in ethyl-ether (25 ml.), malonic acid methyl ester monochloride (2.1 ml, 0.02 mol) was added dropwise in 15' at 0°-5° C. under stirring. The reaction mixture was then stirred 1 hour at 0° C. and 10 minutes at room temperature, then it was filtered, washed twice with 10 ml of a hydrogen chloride solution (5%), then with water till a neutral pH (3×10 ml). The organic phase was anhydrified on anhydrous Na2SO4 and the solvent was evaporated. The residue (yellow oil) was purified by chromatography on a silica gel column using hexane-ethyl acetate (7:3) as eluent. Thereby 2.1 g of the desired product (oil) were obtained.
Reaction SMILES: [CH:1]1[C:6](C=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[K+]>C(Cl)Cl.CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([OH:17])=[CH:5][C:4]=2[O:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
commercial piperonal (Aldrich) (60 g) was dissolved in CH2Cl2 (500 ml), m--chloroperoxybenzoic acid (MCPBA) (90 g) added in portions and left to stir at room temperature (18 hrs.). The precipitate was filtered off and washed with CH2Cl2. The combined filtrate was then washed with cold saturated Na2CO3 solution, followed by H2O, dried over anhy. MgSO4 and evaporated to dryness. The resulting formate ester, δ (CDCl3, 300 Hz): 5.99 (2H, s, OCH2O), 6.56 (1H, d, J=8 Hz, H-6), 6.65 (1H, d, J=2 Hz, H-2), 6.70 (1H, d, J=8 Hz, H-5), 8.25 (1H, s, formate), was dissolved in MeOH (250 ml) and mixed with a solution of 30 g KOH in 200 ml MeOH. The reaction mixture was left at room temp for 15 hrs., evaporated to dryness, the residue dissolved in water (300 ml), acidified to neutral by dilute HCl (6N) and extracted with ethyl acetate. The organic layer was washed with NaHCO3 followed by water, dried over anhy. MgSO4 and evaporated to dryness. The crude product (57 g) was recrystallized from hexane (48 g), to yield colourless crystals, mp. 54°-55° C.; IR νmaxKBr cm-1 : 3580, 1625; UV νmaxMeOH nm (ε): 300.1 (2436), 234.2 (2269), 215.3 (2697), with KOH in methanol 314.2 (2477), 242.6 (2781), 225.6 (2746); 1H-NMR δ (CDCl3): 5.90 2H, s, OCH2O), 6.15 (1H, dd, J=2.4, 8.0 Hz, H-6), 6.24 (1H, d, J=2.4 Hz, H-2), 6.34 (1H, d, J=8.0, Hz, H-5), 4.68 (1H, bs, exchanged with D2O, phenolic); HRMS m/z: 138.0316 (M+, 100, C7H6O3), 137.0238 (M+ -H, 88.42, C7H5O3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1ccco1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2ccco2)cc1
Yield: 60.7 %

Procedure:
To a stirred suspension of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.41 g, 1 mmol), 2-furanboronic acid (0.14 g, 1.26 mmol), NaHCO3 (0.19 g, 2.3 mmol) in DME-water (6 mL-2 mL) was added dichlorobis(triphenylphosphine)palladium (80 mg, 0.115 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 6 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to give the title compound (0.24 g, 61% yield).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([C:13]23[CH2:20][CH:19]4[CH2:21][CH:15]([CH2:16][CH:17]2[CH2:18]4)[CH2:14]3)=[O:12])=[C:7]([C:22]([OH:24])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N.Cl.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[N:27]1([C:22]([C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[S:9][C:8]=2[NH:10][C:11]([C:13]23[CH2:20][CH:19]4[CH2:21][CH:15]([CH2:16][CH:17]2[CH2:18]4)[CH2:14]3)=[O:12])=[O:24])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)c1cc(C(=O)O)c(NC(=O)C23CC4CC(CC2C4)C3)s1
Reactant: C1CNC1
Agent: Cl
Agent: N
Product: CC(C)(C)c1cc(C(=O)N2CCC2)c(NC(=O)C23CC4CC(CC2C4)C3)s1

Procedure:
The title compound was prepared as described in Example 166C from Example 269B and azetidine hydrochloride. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H), 1.66 (dd, J=10.9, 2.7 Hz, 4H), 1.84-1.98 (m, 4H), 2.30-2.45 (m, 4H), 2.77 (t, J=6.6 Hz, 1H), 4.36 (t, J=7.6 Hz, 4H), 6.65 (s, 1H), 12.31 (s, 1H); MS (DCI/NH3) m/z 387 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][Si](C(C)(C)C)(C)C)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Yield: 76.8 %

Procedure:
A solution of 13.4 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(tert-butyl-dimethylsilanyloxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester and 6.15 g of tetrabutylammonium fluoride in 140 ml of anhydrous tetrahydrofuran is stirred at ambient temperature for 30 minutes. The solvent is evaporated off under vacuum. The reaction crude is taken up with 50 ml of dichloromethane and the organic phase is washed with 2 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate. After filtration and concentration under vacuum, the reaction crude is purified by flash chromatography on 450 g of 40-63 μm silica. Elution is carried out with 100% dichloromethane and then a 98/2 then 95/5 dichloromethane/methanol mixture to Obtain 8.54 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:21](=[O:23])[CH3:22])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 6.8 g of ethyl[p-(p-aminophenoxy)phenyl]acetate, 7.5 ml of acetic acid, 5.4 ml of water and 8.75 g of crushed ice, maintained at 0°-5° C. is added 2.8 g of acetic anhydride. The temperature immediately rises to 15° C. The stirring is continued for two hours, and extracted with two 50 ml portions of ether. The combined extracts are washed with 50 ml of H2O, 50 ml of saturated NaHCO3, 50 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent affords the product as a tan solid, mp 95°-102° C. A portion is recrystallized from ethanol-hexane to give the product, mp 105°-107° C.
Reaction SMILES: [Na+].[OH:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([C:9]([O-:11])=[O:10])[CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+]>[OH:2][C@H:3]1[CH2:8][N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][C@@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1
Reactant: O=C([O-])[C@@H]1CNC[C@H](O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
To cis-(3RS,5RS)-5-hydroxy-3-piperidinecarboxylic acid sodium salt (5.2 g; 31.0 mmol) in 0.5 N NaOH (100 ml) was added benzyl chloroformate (7.0 ml; 50.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 14 hours. The reaction was extracted with diethyl ether (2×50 ml), acidified with 6N HCl (pH=2) and extracted with EtOAc (4×100 ml). The combined organic extracts were dried with Na2SO4, the solvents were removed to provide the desired compound (6.2 g; 72%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[OH-].[Na+].Cl>C(#N)C>[C:8]([C:6]1[CH:7]=[C:2]2[NH:1][C:18](=[O:19])[N:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]3)[C:3]2=[N:4][CH:5]=1)#[N:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1cnc2c(c1)[nH]c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-5-cyano-2-(trans-4-hydroxycyclohexylamino)pyridine (3.1 g) and 1,1′-carbonyldiimidazole (6.49 g) in acetonitrile (31 mL) was stirred at 50° C. under nitrogen atmosphere for 15 minutes. After adding 1N-NaOH(35 mL), the mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was neutralized with concentrated hydrochloric acid to yield a precipitate. The resulting precipitate was collected by filtration and washed successively with water and aqueous ethanol to give 6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (1.93 g) as a brown solid.