Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]2.[CH3:24][O:25][C:26](=[O:43])[CH:27](OS(C(F)(F)F)(=O)=O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([O:25][CH3:24])=[O:43])[CH:17]=[CH:16]2
Reactant: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(O)ccc2c1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3C)ccc2c1
Reaction time: 4 h
Yield: 94.7 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 1.00 mmol), prepared in step 2 of Example 5, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.469 g, 1.50 mmol) and cesium carbonate (0.653 g, 2.00 mmol) with the exception that this reaction was complete after 4 hours at ambient temperature. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 25% to 55% methylene chloride in hexane as the eluent gave methyl 2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.437 g, 94%), mp 117–118° C. Elemental Analysis for C31H27NO3 Calc'd: C, 80.67; H, 5.90; N, 3.03. Found: C, 80.35; H, 6.16; N, 2.91.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[C:39]([C:42]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:43])=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1>O1CCCC1>[CH2:1]([O:8][C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[C:39]([C:42]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:43])=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(Cl)nc1)C2
Reactant: OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(OCc3ccccc3)nc1)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.3 %

Procedure:
To a solution of benzylalcohol (0.025 mL, 0.241 mmol) in dry tetrahydrofuran (5 mL) at 0° C. under nitrogen was added a 1.0 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.26 mL, 0.26 mmol) and the reaction mixture stirred at 0° C. for 20 minutes. A solution of 10-[(6-chloropyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 117 (0.100 g, 0.219 mmol) in dry tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at room temperature for 72 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL) and then diluted with ethyl acetate (10 mL). The organic phase was separated, washed with water (10 mL) and brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam that was triturated with diethyl ether to afford the title compound (0.034 g, 30%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:12][N:11]=1)=[O:9])C.FC(F)(F)C1C=CC(C2N=CC(NC(C3C=CC(C(NCCC(O)=O)=O)=CC=3)CCC)=CN=2)=CC=1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH:16][C:13]1[CH:12]=[N:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])=[N:15][CH:14]=1)[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(Nc1cnc(C(=O)NCCC(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester Peak 1 (286.4 mg, 0.542 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M NaOH (2 mL, 2 mmol) was added. This was stirred at room temperature for 10 min. The reaction brought to pH 3 with 1 N HCl. This was extracted twice with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give an oil. The material was triturated with four portions of diethylether to give one enantiomer of 3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid (266 mg, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ): 12.21 (br. s., 1H) 8.39 (t, J=6.0 Hz, 1H) 8.16 (s, 2H) 7.83-7.91 (m, 2H) 7.75-7.81 (m, 2H) 7.70 (d, J=8.2 Hz, 2H) 7.54 (d, J=8.2 Hz, 2H) 7.27 (d, J=7.6 Hz, 1H) 4.60-4.72 (m, 1H) 3.36-3.46 (m, 2H) 2.44 (t, J=6.9 Hz, 2H) 1.74-1.85 (m, 1H) 1.67 (m, 1H) 1.51-1.60 (m, 1H) 0.98 (d, J=6.4 Hz, 3H) 0.92 (d, J=6.4 Hz, 3H); MS (M+1): 501.6.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].Br[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: BrCC1CCCCC1
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(CCC(OCC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-(cyclohexylmethoxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 8 equivalents of sodium hydride and 2.5 equivalents of bromomethylcyclohexane according to general procedure H.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1F.[H-].[Na+].[Cl-].[NH4+]>CN1CCCC1=O>[F:31][C:32]1[CH:33]=[C:34]([S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: CN(C)S(=O)(=O)c1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (65.0 mg, 0.151 mmol) synthesized in Example (38d) and 3,4-difluoro-N,N-dimethylbenzenesulfonamide (40.1 mg, 0.181 mmol) synthesized in Example (57a) were dissolved in N-methylpyrrolidone (5.0 mL), and sodium hydride (55%, 20 mg, 0.45 mmol) was added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-35%) to afford the desired compound (31.0 mg, yield 39%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.[I-].[K+].[CH3:30][NH2:31].O1CCCC1>C(OCC)(=O)C>[CH3:30][NH:31][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (0.30 g, 0.76 mmol), potassium iodide (0.13 g, 0.76 mmol) and 2M methylamine-tetrahydrofuran solution (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=7/3) and recrystallized from hexane/diisopropyl ether to give the title compound (0.20 g, yield 67%) as colorless crystals.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:48])[CH2:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]3[CH:29]=[N:30][C:31]([O:37]CC4C=CC(OC)=CC=4)=[C:32]([O:34][CH2:35][CH3:36])[CH:33]=3)=[CH:23][C:22]=2[F:47])=[CH:14][C:13]=1[C:49]([F:52])([F:51])[F:50])C1C=CC=CC=1>CO.[Pd]>[CH2:35]([O:34][C:32]1[C:31](=[O:37])[NH:30][CH:29]=[C:28]([C:24]2[CH:25]=[C:26]([F:27])[C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([C:49]([F:50])([F:52])[F:51])[CH:14]=3)=[O:48])=[C:22]([F:47])[CH:23]=2)[CH:33]=1)[CH3:36]
Reactant: CCOc1cc(-c2cc(F)c(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2cc(F)c(CC(=O)Nc3ccc(OCCO)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Yield: 14.4 %

Procedure:
A solution of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide (70 mg, 0.097 mmol) and Pd/C (10.31 mg, 0.097 mmol) in MeOH (10 mL) was stirred under a H2 atmosphere for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by preparative HPLC to yield a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,6-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide (7 mg, 0.014 mmol, 14.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.4 Hz, 1H), 7.71 (d, J=6.8 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.24 (dd, J=3.0, 5.4 Hz, 3H), 7.16 (d, J=9.0 Hz, 1H), 4.07-4.20 (m, 4H), 3.87 (t, J=5.0 Hz, 2H), 3.81 (s, 2H), 1.46 (t, J=7.06 Hz, 3H); ES-LCMS m/z 513.1 (M+H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH2:51][CH2:52][CH3:53])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH2:51][CH2:52][CH3:53])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CCC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (1.580 mL, 9.07 mmol) was added to a stirred suspension of 4-chlorobenzoic acid (0.473 g, 3.02 mmol) and TBTU (0.971 g, 3.02 mmol) in DCM (10 mL) at rt. The suspension was stirred for about 5 min before a solution of (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.62 g, 3.02 mmol) in DCM (3 mL) was added. The reaction was stirred at rt overnight. The reaction mixture was washed with an 8% aq. sol. of NaHCO3 (20 mL). The organic layer was dried through a phase separator and concentrated on the rotary evaporator. The residue was purified by preparative HPLC affording the title compound (0.760 g, 81%) as an oil. Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.80-0.88, 0.94-1.01, 1.09-1.65, 2.39-2.53, 2.62-2.99, 3.28-3.62, 3.65-3.76, 4.22-4.39, 4.64-4.76, 7.39-7.52. HRMS (M+H)+: calculated 311.1526. found 311.1539.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]2[CH2:11][CH2:10]2)[C@H:3]1[C:12]([OH:14])=[O:13].[C:16]([CH:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:15])[C@H:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]2[CH2:10][CH2:11]2)[C@H:3]1[C:12]([O:14][CH:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: N#CC(Br)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C=NOCC2CC2)[C@H]1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)[C@H](C=NOCC2CC2)[C@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of 1.8 g of (1R,trans)-2,2-dimethyl-3-((cyclopropylmethoxyimino)methyl)cyclopropanecarboxylic acid, 2.30 g of α-cyano-3-phenoxybenzyl bromide, 0.05 g of tetrabutylammonium hydrogen sulfate, 0.05 g of benzyltriethylammonium chloride, 0.58 g of potassium carbonate, 10 ml of toluene and 6 ml of water was heated at 60°-70° for 4 hours, let stand overnight at room temperature and reheated at 60°-70° for an additional eight hours. The resulting reaction mixture separated into layers. The toluene layer was separated, washed with water, then with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and stripped to give an oil. This oil was chromatographed on silica gel with a mixture of ether-pentane (1:4 ratio) as the eluant to give 2.7 g of desired product as a yellow oil, [α]D25 -16.2, (CHCl3 ; c=0.02 g/cc).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCCC1
Product: N#Cc1c(OC2CCCC2)cccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and cyclopentanol in 78% yield as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 1.64 (m, 2H), 1.77 (m, 4H), 1.97 (m, 2H), 5.14 (m, 1H), 7.73 (m, 1H), 7.88 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([O-:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1
Reactant: O=C([O-])C1=Cc2cc(OCc3c(F)cccc3F)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3c(F)cccc3F)ccc2CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
To 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (486 mg, 1.41 mmol) dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml) was added a 1N aqueous solution of sodium hydroxide (4.4 ml), and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.4 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (450 mg, 1.36 mmol, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1)#[N:28]>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:27]#[N:28])[CH:30]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and 3-cyanophenyl isocyanate (0.017 g, 0.12 mmol) was added. The solution was stirred at 50° C. for 24 h. 3-Cyanophenyl isocyanate (0.09 g, 0.06 mmol) was added. The solution was stirred at 50° C. for 24 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using MeOH/CH2Cl2 1:100 as the eluent. This afforded the title compound as yellow oil. 13C NMR (DMSO-d6) δ 195.1, 158.8 (dd), 155.8 (dd), 152.4, 149.2, 140.5, 139.3, 137.0, 133.5, 131.6, 130.2, 130.1, 126.9, 126.5 (dd), 125.4, 124.3 (dd), 123.0, 121.1, 120.8, 118.9, 118.8, 114.9, 112.0 (dd), 111.9, 111.6, 105.1 (dd), 19.1
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([S:21]([CH3:22])=[O:32])=[CH:19][CH:20]=4)[C:11]=3[CH:23]=2)=[N:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Solvent: ClCCl
Product: Cc1nnc(-c2ccc3occ(-c4ccc(S(C)=O)cc4)c3c2)o1
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
To a solution of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (322 mg, 1.00 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (70%, 259 mg, 1.05 mmol) at room temperature, and the resulting mixture was stirred for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from tetrahydrofuran to give the title compound (284 mg, yield 84%) as colorless crystals.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:21]1[C:29]([NH2:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][C:22]=1[NH2:31]>>[NH2:31][C:22]1[N:23]=[C:24]2[C:28]([N:27]=[CH:26][N:25]2[CH:2]([C:4]2[O:5][C:6](=[O:20])[C:7]3[C:12]([C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:3])=[C:29]([NH2:30])[N:21]=1
Reactant: Nc1nc(N)c2nc[nH]c2n1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1cnc2c(N)nc(N)nc21
Yield: 31.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1 from 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 50 mg, 0.15 mmol) and 9H-purine-2,6-diamine (34 mg, 0.23 mmol) to give the title compound (19 mg, 31%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30]>CN(C=O)C.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]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27]([C:36]4[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Temperature: 70 °C

Procedure:
3.89 ml of 2 M aqueous sodium carbonate solution and 105.9 mg (0.13 mmol) of PdCl2(dppf) are added to a mixture of 1000 mg (2.59 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (free base: Example 31A) and 430.2 mg (2.59 mmol) of 3-carboxyphenylboronic acid in 8 ml of DMF. The reaction mixture is heated at 70° C. for 18 h and then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of a 3:1 mixture of methanol and 1N hydrochloric acid, concentration and drying under high vacuum result in 142.5 mg (12% of theory) and a further 627.9 mg (of 80% purity) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[N+:17]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH2:17])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Product: CCOc1ccc(N)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (5-ethoxy-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A14) (8.65 g, 30.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a purple solid (6.45 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[CH:16]=3)=[CH:9][CH:8]=1)=[N+]=[N-].Cl>[Pd].CO>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[CH:16]=3)=[CH:9][CH:8]=1
Reactant: CCn1c(-c2ccc(OCCN=[N+]=[N-])cc2)c(C#N)c2ccc(OC)cc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Reaction time: 1 h
Yield: 77.9 %

Procedure:
2-[4-(2-Azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (410 mg, 1.14 mmol), prepared as in step A, above, is suspended in a solution of MeOH (20 mL) and concentrated HCl (500 μL). Pd/C (150 mg, 10%) is added, and this mixture is hydrogenated at 30 p.s.i. for 1 h. This is filtered and the filtrate is concentrated. The filtrate residue is partitioned between EtOAc and 0.5N NaOH. The organic layer is dried and concentrated. Purification by silica gel chromatography (10-30%, MeOH/CH2Cl2) yields 2-[4-(2-aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (298 mg, 78%), compound 267, as a white solid.