Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O
Temperature: 120 °C
Yield: 55 %

Procedure:
7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (250 mg, 0.8443 mmol) was dissolved in dry DMF and 4 Å molecular sieves were added to maintain dryness. 4-fluorophenyl-tri-n-butylstannane (392 mg, 1.013 mmol) and bis(triphenylphosphine)palladium(II) dichloride (71 mg, 0.1013 mmol) were added sequentially and the reaction heated to 120° C. in an oil bath. Upon completion, the reaction was cooled and diluted with ethyl acetate. The solution was washed with water then brine and the organic phase dried over sodium sulfate. The crude material was purified by medium pressure liquid chromatography (15 to 45% ethyl acetate in hexanes) to give the desired material in 55% yield as a thick yellow oil. 1H NMR (200 MHz, CDCl3): δ ppm=11.88 (s, 1H), 8.83 (s, 1H), 8.41 (d, 1H), 8.05 (s, 1H), 7.93 (d, 1H), 7.66 (m, 2H), 7.18 (t, 2H), 4.57 (q, 2H), 1.52 (t, 3H.)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>CO.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([NH2:30])[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(NC(=O)OC(C)(C)C)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.8 %

Procedure:
The compound obtained in Example 193 (4.08 g, 7.34 mmol) was dissolved in methanol (20 mL). To the solution was added a solution of 4N-hydrogen chloride in ethyl acetate (40 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added diethyl ether. The resulting precipitates were collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the titled compound (4.07 g) as white amorphous substance.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:36][O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47]Br)=[CH:41][CH:40]=1.CCOC(C)=O>C(Cl)Cl.CO>[CH3:36][O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(F)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 72.9 %

Procedure:
Analogous to the procedure described in Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (254.7 mg, 0.697 mmol) was alkylated with NaHMDS (1M in THF, 0.84 mL, 0.84 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (200 mg, 0.778 mmol). Purificaton by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (275.3 mg). 1H NMR (CDCl3) (selected peaks) δ7.94 (d, 2H), 7.23 (m, 3H), 6.87 (m, 3H), 3.88 (s, 3H), 3.86 (m, 1H), 3.63 (m, 1H), 3.50 (m, 1H), 2.94 (m, 1H), 0.84 (s, 9H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1[CH:11]=[C:12]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:18](=[O:40])[N:19]([C@H:30]2[CH2:33][C@H:32]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[CH2:31]2)[C:20]2[N:21]([N:26]=[C:27]([CH3:29])[N:28]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]>CS(C)=O.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:18](=[O:40])[N:19]([C@H:30]2[CH2:33][C@H:32]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[CH2:31]2)[C:20]2[N:21]([N:26]=[C:27]([CH3:29])[N:28]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2nc(C)nn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (834 mg), sodium hydrogen carbonate (1.34 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C. for 30 min, a solution of 3′-fluoro-4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (437 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (156 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (146 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (328 mg, 68%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][CH:40]=[C:16]2[N:15]1[C@H:41]1[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][CH:49]([OH:54])[C:50]([F:53])([F:52])[F:51])[CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([C@H:41]4[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][CH:49]([OH:54])[C:50]([F:53])([F:52])[F:51])[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][CH:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=2)[NH:34]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)(F)F)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)(F)F)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate (1.46 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). N,N′-Carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.53 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=1.[ClH:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[ClH:39]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Agent: Cl
Product: O=C(O)c1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 1E (200.0 mg, 0.556 mmol), tert-butyl 4-aminobenzoate (129 mg, 0.667 mmol), and concentrated HCl (0.08 mL, 2.63 mmol) was heated at 160° C. for 30 minutes in a Biotage microwave reactor. The solvent was decanted. The remaining residue was treated with water, sonicated, filtered, washed with water, and oven-dried to provide the title compound as an HCl salt.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[NH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][NH:16][C:4](=[O:6])[C:3]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[N:12][C:2]=1[CH3:1]
Reactant: NCCO
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Solvent: CCO
Product: Cc1ncc([N+](=O)[O-])cc1C(=O)NCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-methyl-5-nitronicotinate (1 g.) and 2-aminoethanol (4 ml.) in ethanol (5ml.) was stirred at room temperature for 16 hours. The solvent was distilled off, the residue was purified by silica gel chromatography and recrystallized from ethyl acetate n-hexane to give the desired yellow crystals. mp 144° - 145° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH2:34])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:39].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][CH3:39])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(N)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(NC)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Reaction time: 48 h

Procedure:
5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoic acid ethyl ester (210 mg, 0.43 mmol), sodium hydride (17 mg, 0.43 mmol), iodomethane (0.027 mL, 0.43 mmol), in 3 mL of DMF were stirred at room temperature for 24 hrs, then another 0.027 mL of iodomethane were added and the reaction mixture was stirred for another 48 hrs. The mixture was then poured into water and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), and concentrated. Purification was carried out on SPE using iso-hexane containing a gradient of ethylacetate (20–30%) to give the required product as a yellow oil. (85 mg, 39%).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O)[CH3:17].Cl>CN(C)C=O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:18]([CH2:16][CH3:17])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To a 40 ml. solution of NaOEt (1.0 g. Na--0.042 mole) was added 6.8 g. (0.042 mole) of diethyl malonate and this is stirred 10 minutes, then stripped to dryness. Dimethylformamide was added until a solution formed and to this was added 5.7 g. (0.021 mole) of 1-ethyl-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione and the mixture heated at reflux for 2 hours. The reaction was then cooled and poured into dilute HCl and the resulting precipitate filtered off and rinsed well with water. Recrystallization with hexane-ethyl acetate gave 5.1 g. of the title product--m.p. 177°-180° C.
Reaction SMILES: CN(C([O:8][N:9]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=O)[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1.C(N(CC)CC)C.NO.Cl>CS(C)=O>[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([NH:9][OH:8])=[O:53])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)NO
Reaction time: 0.08 h

Procedure:
HATU (25 mg, 0.066 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (25 mg, 0.053 mmol, Example 44), triethylamine (0.05 mL, 0.36 mmol), and DMSO (0.5 mL). After 5 min, NH2OH•HCl (10 mg, 0.14 mmol) was added. After an additional 17 h, the mixture was diluted with DMSO (1 mL), filtered through cotton, and the filtrate purified by reverse-phase HPLC (1:9→3:2; acetonitrile:water) to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)-N-hydroxyhexanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.96 (t, 2H), 3.92 (s, 3H), 1.96 (t, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.43 (m, 2H); MS (ESI): 481.9.
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][CH:9]([N:13]3[CH2:17][C:16]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:15][C:14]3=[O:26])[C:10](O)=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:27]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[OH:49][C@@H:50]([CH2:80]O)[CH2:51][N:52]1[CH:56]=[CH:55][C:54]([NH:57]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:53]1>ClCCl>[CH:1]12[CH:7]([CH2:8][CH:9]([N:13]3[CH2:17][C:16]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:15][C:14]3=[O:26])[C:10]([NH:57][C:54]3[CH:55]=[CH:56][N:52]([CH2:51][C:50]([OH:49])([CH3:80])[CH3:27])[N:53]=3)=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: O=C(O)C(CC1C2CCC1CC2)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2C3CCC2CC3)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
In a round bottom flask under argon was placed 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (32 mg, 0.085 mmol) in dichloromethane (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 μL, 0.094 mmol) and 1-hydoxybenzotriazole (12 mg, 0.089 mmol) and stirred at 25° C. for 2 h. After this time, 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 16 mg, 0.102 mmol) was added and stirred for 16 h at 25° C. The reaction was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL), a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (27 mg, 61%) as yellow foam: HR-ES-MS m/z calculated for C27H33N4O4Cl [M+H]+ 513.2263, observed 513.2263; 1H NMR (300 MHz, CDCl3) δ ppm 1.15 (s, 6H), 1.15-1.31 (m, 4H), 1.43-1.59 (m, 3H), 1.65 (d, J=8.5 Hz, 2H), 1.70-1.87 (m, 1H), 1.90-2.09 (m, 3H), 2.80 (br. s., 1H), 3.93 (s, 2H), 4.16 (d, J=18.1 Hz, 1H), 4.32 (d, J=18.1 Hz, 1H), 4.76 (t, J=7.7 Hz, 1H), 4.89 (s, 1H), 6.70 (s, 1H), 7.17-7.25 (m, 1H), 7.27-7.37 (m, 3H), 7.48 (d, J=8.2 Hz, 1H), 8.74 (br. s., 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:2]1.B.[O:20]1CCCC1>>[N:13]1([CH2:12][CH2:11][CH2:10][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][CH:2]2[OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1CCOC1
Reactant: C1=C(CCCN2CCCCC2)c2ccccc2C1
Agent: B
Product: OC1Cc2ccccc2C1CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[3-(3-Indenyl)propyl]piperidine (48.2 g, 0.2 M) is dissolved in 400 ml tetrahydrofuran and stirred in a nitrogen atmosphere while 400 ml 1 M borane in tetrahydrofuran is added dropwise over a period of 1 hour. The mixture is left stirring overnight at room temperature. Most of the solvent is then removed in vacuo. The viscous residue is dissolved in 500 ml 95% ethanol, treated with 20 g NaOH and then 65 ml of 30% H2O2 is added dropwise over a period of 30 minutes. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 21/2 hours. The mixture is then taken to near dryness in vacuo. The residue is then extracted three times with benzene. The benzene extracts are dried, filtered and the solvent is removed in vacuo leaving 57 g of oil. The VPC of this material indicates ~97% of purity.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH2:18]([Mg]Br)[CH3:19]>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH2:18][CH3:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)CC)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 10 ml of dry tetrahydrofuran, cooled to 0° C., is added 1 63 ml of 2.0M ethyl magnesium bromide in tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 0° C. and quenched with 20 ml of saturated ammonium chloride solution and 20 ml of water. The reaction mixture is extracted with 9:1 chloroform-methanol, dried over magnesium sulfate, filtered and evaporated in vacuo to give 0.26 g of the desired product. CI MASS SPEC 261(MH+) .
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15].ClCCl.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(N(CC)CC)C>[CH3:19][S:20]([OH:22])(=[O:1])=[O:21].[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15]
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred solution of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine. Then there are added dropwise (slowly) 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 15 parts (58%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate; mp. 125° C.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(OC(C)(C)C)=O.N1C=CC=CC=1>C(OCC)(=O)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1.[C:21]([O:20][C:18]([O:17][C:10]1[CH:5]=[CH:4][C:3]([CH:8]=[CH2:7])=[CH:2][CH:1]=1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: C#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1

Procedure:
In 250 mL of ethyl acetate, 50.0 g of poly(p-hydroxystyrene) (from Nippon Soda Co., Ltd.; weight average molecular weight (Mw) is about 15,000 and distribution (Mw/Mn) thereof about 1.05) was dissolved, then14.8 g of di-tert-butyl dicarbonate and 11.0 g of pyridine were added and reacted at room temperature for 4 hours. Said reaction solution was then concentrated under reduced pressure, followed by dissolving in 250 mL of acetone, then poured into 3 L of water for precipitation. The thus deposited crystal was filtered off and dried under reduced pressure to obtain 50.8 g of poly(p-hydroxystyrene/p-tert-butoxycarbonyloxystyrene) as a white powder crystal. The thus obtained crystal was named polymer A2. A composition ratio of p-hydroxystyrene unit and p-tert-butoxycarbonyloxystyrene unit in polymer A2 was found to be about 85:15 from the measurement results by 13CNMR. Weight average molecular weight (Mw) of polymer A2 was about 16,500 and distribution (Mw/Mn) thereof was about 1.05 from the measurement results by gel permeation chromatography using polystyrene as a standard.