Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC([CH:18]([NH2:21])[CH2:19][OH:20])=CC=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CC#N>[C:1]1([C@H:7]2[NH:21][CH2:18][C:19](=[O:20])[O:10][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(CO)c1ccccc1
Reactant: O=C([O-])C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CN[C@H](c2ccccc2)CO1
Reaction time: 0.25 h

Procedure:
To a solution of phenylbromoacetate (18.58 g, 86 mmol) in CH3CN under nitrogen was added a solution of (R)-phenylglycinol (10.17 g, 74 mmol) and di-isopropylethylamine (34 mL, 195 mmol) in CH3CN. The volatiles were removed under reduced pressure keeping the bath temperature below 25° C. to obtain an oil that was treated with EtOAc (120 mL) and stirred for 15 min. The resulting white precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the desired product was isolated using column chromatography (SiO2) with a step gradient of 10% to 50% [v/v] EtOAc in cyclohexane to give after evaporation (R)-5-phenylmorpholin-2-one EBE 06134 (3.17 g, 24% yield) as a white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[CH3:18][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:3][CH2:2][CH2:1][OH:4])=[CH:14][CH:13]=1)([CH3:16])[CH3:17]
Reactant: OCCO
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COCCO)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL). 1-(Bromomethyl)-4-(1,1-dimethylethyl)benzene (0.28 mL, 1.5 mmol) was added to the reaction, and the residual 1-(bromomethyl)-4-(1,1-dimethylethyl)benzene was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30% EtOAc/hexanes (fractions 3,4), and 50% EtOAc/hexanes (fractions 5,6) to give the title compound (312 mg, 51%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:35]1[CH2:34][CH2:33][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)=[O:5]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(C)c1
Yield: 83 %

Procedure:
0.45 g (0.003 mol) of 2,4-dimethylbenzoic acid were boiled under reflux in 5.2 ml (0.06 mol) of oxalyl chloride for 3 hrs. After removal of the excess oxalyl chloride the mixture was concentrated twice with 5 ml of toluene each time. The residue was dissolved in 20 ml of toluene, treated with 0.74 ml (0.0053 mol) of triethylamine and 0.574 g (0.003 mol) of 1-benzyl-4-hydroxypiperidine and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 0.805 g (83%) of 1-benzyl-piperidin-4-yi 2,4-dimethyl-benzoate was obtained as a yellow oil. MS: me/e=324 (C21H26NO2 +).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]1[C:31]#[N:32].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[O:1]=[CH:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:12])([F:13])[F:11])[CH:6]=[C:5]1[C:31]#[N:32]
Reactant: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC=O
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 242 mg (0.51 mmol) of 1-(2,3-dihydroxypropyl)-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carbonitrile in 6 mL of acetone and 3 mL of water was added 114 mg (0.53 mmol) of sodium periodate. After stirring overnight, the solids were filtered and rinsed with acetone. The acetone was then concentrated in vacuo and the residue was diluted with brine and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to afford 208 mg of 1-(2-oxoethyl)-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carbonitrile which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:10]2([CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: CC1(O)CCCCC1
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(c2cc(F)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2C1-2(250 mL×3). The organic layer was washed with saturated a.q NaHCO3., dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil—47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (m, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][CH2:23][CH2:24][N:25]([CH3:43])[C:26](=O)[CH2:27][C:28]1([OH:41])[CH2:33][CH:32]2[CH2:34][CH2:35][CH:29]1[CH:30]=[C:31]2[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][CH2:23][CH2:24][N:25]([CH3:43])[CH2:26][CH2:27][C:28]1([OH:41])[CH2:33][CH:32]2[CH2:34][CH2:35][CH:29]1[CH:30]=[C:31]2[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(CCCc1nc2ccccc2[nH]1)C(=O)CC1(O)CC2CCC1C=C2c1cccs1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1C=C2c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
0.196 mL of a Red-Al solution (65% in toluene) was added dropwise at 0° C. to a solution of 70 mg of rac-(1R*,2R*,4R*)-N-[3-(1H-benzoimidazol-2-yl)-propyl]-2-(2-hydroxy-5-thiophen-2-yl-bicyclo[2.2.2]oct-5-en-2-yl)-N-methyl-acetamide in toluene (0.8 mL). The reaction mixture was stirred for 30 min at 0° C. then the temperature was allowed to increase to rt for 3.5 h. The mixture was carefully poured onto a mixture of 1M-NaOH (6.1 mL) and ice. The mixture was stirred for 5 min until rt and extracted with toluene. The aq. phase was extracted with toluene. The combined toluene phase was washed with 1M-NaOH and brine, dried over anh. Na2SO4 and concentrated in vacuo to yield 54 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-thiophen-2-yl-bicyclo[2.2.2]oct-5-en-2-ol as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.S(=O)(=O)([OH:31])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]([OH:31])=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(Oc3ccc(C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a round-bottomed flask containing 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (0.157 g, 0.426 mmol) was added 6 mL of an acetone:water (2:1) solution. The slightly turbid solution was cooled in an ice-water bath and sulfamic acid (0.097 g, 0.999 mmol, 2.3 eq) was added portionwise over five minutes. The reaction mixture was stirred for 5 min and sodium chlorite (80% tech. Grade) (0.059 g, 0.52 mmol, 1.23 eq) was added portionwise. The reaction mixture was stirred for 40 min. The acetone was removed in vacuo and the crude product was partitioned between water and CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 0.155 g of crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid as an amorphous solid. Flash chromatography over SiO2 with CH2Cl2:MeOH (96:4) gave the impure 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid. Attempted precipitation of the impurity from a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid in MeOH had failed to purify the compound. Therefore, the impure 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (0.105 g) was dissolved in CH2Cl2 (6 mL) and the stirred solution was cooled in an ice-water bath. To the cold solution was slowly added BBr3 (1 M in CH2Cl2) (0.82 mL, 0.82 mmol) and the reaction mixture was stirred under N2 with cooling for 3 h. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give 0.115 g of the crude title compound. The crude title compound was purified by reverse phase preparative HPLC using an CH3CN:H2O gradient (25:75 to 100:0) with 0.05% TFA as a modifier to give 0.013 g (8% from FN1, Step 5) of the title compound (19) as an off-white solid. 1H NMR (400 MHz; DMSO-d6): δ 2.14 (s, 3H), 6.64 (d, J=8.8 Hz, 2H), 6.98 (dd, J=2.2 Hz, 8.9 Hz, 1H), 7.15 (m, 3H), 7.21 (m, 1H), 7.27 (m, 2H), 7.48 (d, J=9.1 Hz, 1H), 7.58 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 9.86 (s, 1H), 12.58 (br s, 1H). HRMS (ESI) Calcd for C24H17O4: 369.1127 (M−H)−. Found: 369.1148.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:36][NH:37][CH3:38]>C1COCC1.O>[CH3:36][N:37]([CH2:30][C:26]1[CH:25]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[CH2:7]3)[CH:29]=[N:28][CH:27]=1)[CH3:38]
Reactant: Cc1cc(-c2cncc(COS(C)(=O)=O)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cncc(CN(C)C)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
Methanesulfonic acid 5-[7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-yl]-pyridin-3-ylmethyl ester (70 mg, 0.138 mmol) was dissolved in 2M dimethylamine in THF (5 mL) and stirred at 50° C. for 18 hrs. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (5% 2M N13 in MeOH/CH2Cl2) provided the title compound (37 mg, 59%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 8.75 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.44 (d, 2H), 7.37 (d, 2H), 7.20 (d, 2H), 4.81 (s, 2H), 4.31 (s, 2H), 3.52 (s, 2H), 2.84 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:19]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:20]([C:29](O)=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:29](=[O:30])[CH:20]([NH:19][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:21][C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cc1)C(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To an ice-cooled and stirred solution of 2-amino-3-benzoyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.775 mmol) in dry DMF (11 mL), was added BOC-Tyr-OH (0.08 mmol) and EDCl (0.08, 0.445 g) under an argon atmosphere. After stirring overnight, the mixture was evaporated under vacuum to give a solid residue, which was dissolved in a saturated sodium bicarbonate solution and is extracted with ethyl acetate (3×20 mL), then dried on magnesium sulfate. The organic layers were evaporated under vacuum to give a solid which is chromatographed on silica gel column eluting with ethyl acetate and petroleum ether to afford 2-amino-3-benzoyl-6-[2-t-butoxycarbonylamino-3-(4-hydroxyphenyl)-propion-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine a yellow solid.
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.B(Br)(Br)Br.CO>ClCCCl.ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:21]=3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine (0.9923 g, 2.377 mmol) in 1,2-dichloroethane (55 mL) was cooled to about 0° C., and boron tribromide (5.9 mL of a 1 M solution in dichloromethane) was added dropwise. After the reaction was stirred cold for 30 minutes, it was heated at 50° C. for six hours. An analysis by HPLC indicated the reaction was incomplete, and the reaction was again cooled to about 0° C., and additional boron tribromide (1.5 mL) was added dropwise. After the reaction was stirred cold for ten minutes, it was heated at 50° C. for 16 hours. Methanol (30 mL) was added, and the reaction mixture was allowed to cool to room temperature. After 16 hours, the precipitate from the reaction was isolated by filtration and washed sequentially with aqueous potassium hydroxide (30 mL of 1 N), methanol (15 mL), and diethyl ether (15 mL). The solid was then triturated with boiling acetonitrile and isolated by hot filtration to provide 0.161 g of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol as a white powder, mp 262.0-263.0° C.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:63][C@H:64]([C:69](O)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:63][C@@H:64]([CH2:65][CH:66]([CH3:68])[CH3:67])[C:69]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:70]
Reactant: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
To a solution of methyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (10, 180 mg, 0.45 mmol), DCC (112 mg, 0.54 mmol) and DMAP (6 mg, 0.045 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (158 mg, 0.45 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 150 mg (66%) of the title compound as a colorless semi solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl>[C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][C:11]=2[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1-c1ccccc1
Reaction time: 1.5 h

Procedure:
Methyl 4-phenylpyrrole-3-carboxylate (920 mg., 4.6 mmoles) and benzoyl chloride (0.53 ml., 4.6 mmoles) were combined in 50 ml. methylene chloride and stirred under nitrogen at room temperature. Stannic chloride (1.15 ml., 10 mmoles) was added. The resulting solution was stirred for 1.5 hours. Hydrochloric acid (1N, 25 ml.) was added slowly. The mixture was stirred for 10 minutes, the methylene chloride layer separated, back-washed with two 20 ml. portions of water, approximately 50 mg. of solids removed by filtration, and the filtrate evaporated to dryness. Recrystallization of the residue from acetone afforded purified methyl 4-phenyl-5-benzoylpyrrole-3-carboxylate (673 mg., m.p. 201°-203° C.).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[CH2:11][O:12][CH3:13].[Si:14]([O:21][CH2:22][CH:23]([OH:38])[CH2:24][N:25]1[C:30](=[O:31])[CH:29]=[N:28][C:27]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[N:35][C:26]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[Si:14]([O:21][CH2:22][CH:23]([O:38][CH2:11][O:12][CH3:13])[CH2:24][N:25]1[C:30](=[O:31])[CH:29]=[N:28][C:27]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[N:35][C:26]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)nc21
Reaction time: 24 h
Yield: 67.3 %

Procedure:
N,N-Diisopropylethylamine (1.93 ml, 11.10 mmol) and chloromethylmethyl ether (0.56 ml, 7.40 mmol) were added under cooling on ice to a solution of 4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.35 g, 3.70 mmol) in dichloromethane (20 ml) and the mixture was stirred for 24 hours. The reaction solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 1.02 g (67%) of the title compound in the form of a yellow oily product.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[N:1]1[N:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]3[C:22]=2[O:21][C:20](=[O:23])[CH:19]=[C:18]3[NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=2[Cl:32])[N:3]=[N:4][CH:5]=1
Reactant: c1nnn[nH]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCn1ncnn1

Procedure:
The title compound was prepared from tetrazole and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 98. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.94 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.19 (d, 1H), 4.72 (t, 2H), 4.63 (s, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 1.98 (m, 2H), 1.70 (m, 2H), 1.46 (m, 2H); MS (ESI): 490.9.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[NH2:11][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH2:13][OH:12])[CH:15]=[CH:16][CH:17]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1
Reactant: Nc1cc(Cl)n2nccc2n1
Reactant: OCc1cccc(B(O)O)c1
Product: Nc1cc(-c2cccc(CO)c2)n2nccc2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and 3-(hydroxymethyl)phenylboronic acid were used as starting materials. 1H NMR (400 MHz, MeOD) δ ppm 4.72 (s, 2H) 6.27-6.31 (m, 1H) 6.47 (s, 1H) 7.56 (t, J=7.58 Hz, 1H) 7.62 (d, J=7.58 Hz, 1H) 7.84 (d, J=7.33 Hz, 1H) 7.91-7.97 (m, 2H).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=4)=[S:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:69])([F:70])[F:68])[CH:62]=4)=[S:59])=[CH:55][CH:56]=3)=[CH:47][CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 67 %

Procedure:
The compound of example 76 was prepared analogous to compound of example 52 by hydrolysis of compound of example 75.