Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:24][NH:25][CH3:26]>C(O)C.ClCCl>[CH3:24][N:25]([CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1)[CH3:26]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Br)c1cnoc1C1CC1
Reactant: CNC
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[bromo-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (1.2 g) and dimethylamine (2.0 g of a 33% solution in ethanol) in dichloromethane was stirred at 0° C. for 2 hours and then at room temperature for a further 16 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with petroleum ether and ethyl acetate to give 4-[N,N-dimethylamino-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 300, 0.27 g) as a yellow oil: NMR (CDCl3); 1.02(4H,m), 2.08(1H,m), 2.12(6H,s), 4.9(1H,s), 7.8(1H,m), 7.9(1H,m), 8.0(1H,s), 8.1(1H,m).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[CH:42]2[CH2:43][NH:44][CH2:45][CH2:46][N:41]2[CH2:40][CH2:39][S:38]1(=[O:48])=[O:47].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(OCC)(=O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[CH2:45][CH2:46][N:41]4[CH:42]([CH2:37][S:38](=[O:48])(=[O:47])[CH2:39][CH2:40]4)[CH2:43]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S1(=O)CCN2CCNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCS(=O)(=O)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A 8 ml sealed vial was charged with 180 mg (0.31 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577); 168 mg (0.62 mmol) of octahydropyrazino[2,1-c][1,4]thiazine 2,2-dioxide (D19), 128 mg (0.701 mmol) of potassium carbonate; the reagents were dissolved in 1 ml of DMSO and stirred at 150° C. for 18 h. The reaction mixture was diluted with water and ethyl acetate and the aqueous phase was extracted with ethyl acetate. The combined organic fractions were dried and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc 50/50 to EtOAc) affording the title compound as a white solid 105 mg.
Reaction SMILES: [N:1]1([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:17]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[C:39]3[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[N:1]1([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][C:30]2[CH:31]=[CH:32][C:33]3[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:27]([C:23]4[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=[CH:25][N:24]=4)[C:28]=3[CH:29]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Oc1cccc(-n2ncc3ccccc32)c1
Reactant: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(Br)cc32)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(Oc4cccc(-n5ncc6ccccc65)c4)cc32)c1
Temperature: 95 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
To a dry Shlenck tube equipped with a magnetic stir bar was added 3-(1H-indazol-1-yl)phenol 2 (630 mg, 3.0 mmol, 1.0 eq), 9-(4-tert-butylpyridin-2-yl)-2-bromo-9H-carbazole (1365 mg, 3.6 mmol, 1.2 eq), CuI (57 mg, 0.3 mmol, 0.1 eq), picolinic acid (74 mg, 0.6 mmol, 0.2 eq) and K3PO4 (1273 mg, 6.0 mmol, 2.0 eq). The tube was evacuated and backfilled with nitrogen. The evacuation and backfill procedure was repeated another two times. Then solvent DMSO (9 mL) was added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 90-100° C. for 3 days and then cooled down to ambient temperature. Water was added to dissolve the solid. The mixture was extracted with ethyl acetate three times. The combined organic layer was washed with water three time, dried over sodium sulfate, and then filtered. The solvent was removed under reduced pressure, and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1) as eluent to obtain the desired product Ligand ON12-tBu as a colorless solid 1378 mg in 90% yield. 1H NMR (DMSO-d6, 400 MHz): δ 1.17 (s, 9H), 7.05-7.08 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.34 (dd, J=5.6, 1.2 Hz, 1H), 7.37-7.42 (m, 4H), 7.53-7.54 (m, 2H), 7.57 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.50 (d, J=4.8 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): 529.93, 34.74, 101.50, 110.41, 111.15, 111.77, 113.13, 115.70, 116.34, 116.37, 119.21, 119.82, 120.12, 121.11, 121.53, 121.78, 121.84, 123.20, 125.19, 125.90, 127.58, 131.12, 136.01, 137.97, 139.42, 139.91, 141.08, 149.34, 150.61, 155.25, 158.09, 162.96.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([CH3:11])=[CH:10][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH:20]1([O:1][C:2]2[C:7]3[O:8][C:9]([CH3:11])=[CH:10][C:6]=3[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCCC1
Reactant: Cc1cc2c(C=O)ccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(C=O)ccc(OC3CCCC3)c2o1
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To a well stirred suspension of 7-Hydroxy-2-methylbenzo[b]furan-4-carbaldehyde (39.0 g, 0.221 moles) in DMF (200 mL) was added powdered potassium carbonate (76.0 g, 0.555 moles) and cyclopentyl bromide (43.0 g, 0.287 moles) and stirred at 70-75° C. for 4-5 hrs. The reaction mixture was then cooled to room temperature and water (1.5 L) was added to it. The organic material separated was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water ((2×500 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (55.0 g) as light brown viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][CH:20]=3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH:28]O>CO.C(OCC)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])(=[O:28])=[O:26])=[CH:21][CH:20]=3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)c1ccc(-c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)cc1
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)cc1
Temperature: 25 °C

Procedure:
0.5 g (1.4 mmol) of the product of Example 44 was dissolved in a mixture of 4 mL of methanol and 16 mL of ethyl acetate. The solution was treated 0.045 g sodium tungstate dihydrate and 0.63 mL (5.6 mmol) of 30% hydrogen peroxide solution while heating at reflux over a period of 4 hours. A further 0.3 mL (2.8 mmol) hydrogen peroxide was added. The mixture was refluxed overnight and then cooled to room temperature. A white solid was recovered by filtration and was washed with water to provide the desired product.
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[CH:14]C=CN=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C1([NH2:19])CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:14]1[C@@H:15]([NH2:19])[C@@H:10]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(CO)(c2ccccn2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyridin-2-yl)cyclohexanone (410 mg, 2.0 mmol, 1.0 equiv) in 1,2-dichloroethane (15 mL) was treated at 0° C. with cyclopropylamine (280 uL, 4.0 mmol, 2 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (848 mg, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed (brine), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 5% MeOH/CH2Cl2 containing 2.5% NH4OH) to provide the trans amine. Further elution afforded the cis amine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:44]1[CH2:50][CH2:49][CH2:48][C@@H:45]1[CH2:46][OH:47]>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31][N:44]4[CH2:50][CH2:49][CH2:48][C@@H:45]4[CH2:46][OH:47])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CCCN1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC[C@@H]2CO)C1

Procedure:
The title compound is prepared in analogy to Example 116 from cis-{3-[4-amino-5-(3-benzoyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol of Example 124, p-toluenesulfonyl chloride and D-prolinol (Fluka, Buchs, Switzerland). Analytical HPLC-MS: tR=1.48 min; ES-MS: m/eo=512.48.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:56]1[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][N:57]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[N+:62]([C:59]1[CH:60]=[CH:61][C:56]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[N:57][CH:58]=1)([O-:64])=[O:63]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCCN1c1ccc([N+](=O)[O-])cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
Pyrrolidin-2-one (129 mg), cesium carbonate (412 mg), Pd2(dba)3 (116 mg), and Xantphos (146 mg) were added to a 1,4-dioxane (10 ml) solution containing 2-chloro-5-nitropyridine (200 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 5 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a light red solid of 1-(5-nitropyridin-2-yl)pyrrolidin-2-one (261 mg) was thus obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([NH2:10])[CH3:9]>C(O)C>[CH2:8]([NH:10][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:9]
Reactant: C=CC(=O)OCC
Reactant: CCN
Solvent: CCO
Product: CCNCCC(=O)OCC
Reaction time: 3 h
Yield: 70 %

Procedure:
Dissolved in 500 ml of ethanol was 50 g (0.50 mol) of ethyl acrylate. While stirring the thus-prepared solution while ice cooling, a liquid mixture of 36 g (0.55 mol) of a 70% aqueous solution of ethylamine and 100 ml of ethanol was added dropwise over 3.5 hours. After allowing the reaction to proceed for further 3 hours, the solvents were distilled off. The residue was distilled under reduced pressure to obtain 50.5 g of the intended product as colorless liquid (yield: 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)[C:9]3[CH:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[CH:23]=[CH:24][C:8]=3[S:7][C:6]=2[CH:28]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:34](=[O:35])[C:33]4[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=4)[CH2:16][CH2:17]3)[C:9]3[CH:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[CH:23]=[CH:24][C:8]=3[S:7][C:6]=2[CH:28]=1
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(CCO)CC1)Cc1ccc(F)cc1S2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)OCCN2CCN(C3Cc4ccc(F)cc4Sc4ccc(C(C)C)cc43)CC2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
A solution of 5.7 g of 3-fluoro-10-[4-(2-hydroxyethyl)piperazino]-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin (Example 2) in 20 ml of chloroform was treated with 5.2 g of 3,4,5-trimethoxybenzoyl chloride and after its dissolution, the mixture left overnight at room temperature. It was then decomposed with water and then diluted with chloroform and washed with an ice-cold 5% sodium hydroxide solution, dried with potassium carbonate and the chloroform evaporated. The remaining oil (8.4 g, 100%) was the crude ester which was neutralized with oxalic acid in ethanol to yield an oxalate crystallizing from aqueous ethanol and melting at 188°-192° C. with decomposition. The compound is identical with the product obtained by a different way according to Example 16.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[N:22]([CH2:37][CH2:38][CH3:39])[C:23](=[O:36])[C:24]2[NH:25][C:26]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:27][C:28]=2[N:29]=1.[Cl-].[NH4+]>O>[CH:30]1([C:26]2[NH:25][C:24]3[C:23](=[O:36])[N:22]([CH2:37][CH2:38][CH3:39])[C:21]([NH:1][CH:2]([CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=4)[C:3]([OH:5])=[O:4])=[N:29][C:28]=3[N:27]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCCn1c(Cl)nc2nc(C3CCCCC3)[nH]c2c1=O
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCCn1c(NC(Cc2cccc(F)c2)C(=O)O)nc2nc(C3CCCCC3)[nH]c2c1=O
Yield: 1.8 %

Procedure:
To a solution of 2-Amino-3-(3-fluoro-phenyl)-propionic acid (112 mg, 0.612 mmol) and K2CO3 (140 mg, 1.02 mmol) in water (5 ml) was added 2-Chloro-8-cyclohexyl-1-propyl-1,7-dihydro-purin-6-one (150 mg, 0.51 mmol). The reaction mixture was stirred at refluxing temperature for overnight. Aqueous ammonium chloride was added to the reaction mixture. The solid obtained was filtered and dried. The crude product was purified by preparative HPLC to obtain 4 mg (˜2%) of pure product as pink solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18](O)[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:18]1[N:19]=[N:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[N:15]=2)[CH:17]=1
Reactant: C[C@H](Nc1nccc(-c2cc(O)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](Nc1nccc(-c2cc(Cl)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 90 °C

Procedure:
Compound 9 (3.5 g, 7.96 mmol) and phosphorus oxychloride (20 mL) were combined under argon then heated at 90° C. for 0.5 h. The solution was cooled and poured onto ice. The resulting suspension was made basic with 2N sodium hydroxide and extracted several times with methylene chloride. The combined organic extracts were washed with brine and dried with anhydrous sodium sulfate. Evaporation of the solvent in vacuo gave an oil which was purified by flash column chromatography (hexane ethyl acetate 80:20) to give Compound 10 as a foam: 2.9 g (6.4 mmol, 80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)c1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(C(C)C)cc4)cc3)c2cc1OC
Yield: 90 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (3 ml) with heat, 4-isopropylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 26 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 70 mg of the title compound (yield: 90%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:54][C:55]([C:57]3[S:58][C:59]([C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:60][CH:61]=3)=[O:56])[C:42]([NH:44][C@@H:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH3:46])=[O:43])=[CH:36][CH:35]=2)=[N:32][CH:33]=1.C1COCC1>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].O.CC#N>[C:62]([C:59]1[S:58][C:57]([C:55]([NH:54][C@@H:41]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:31]3[N:30]=[CH:29][C:28]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[CH:33][N:32]=3)=[CH:35][CH:36]=2)[C:42]([NH:44][C@@H:45]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[CH3:46])=[O:43])=[O:56])=[CH:61][CH:60]=1)([CH3:63])([CH3:64])[CH3:65]
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 46 %

Procedure:
To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (224.6 mg, 1.6 mmol), sodium carbonate decahydrate (96.0 mg, 1.6 mmol), tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninate (500.0 mg, 1.6 mmol), Pd(dppf)Cl2 (58.5 mg, 0.08 mmol), THF (2.0 mL), CH3CN (2.0 ml) and water (1.0 mL). The solution was degassed using N2 bubbling for 10 min. The reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was dried under reduced pressure to remove the solvent and diluted in DCM (20 mL). The mixture was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 462.3 mg (91%) of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-36 as a solid. LCMS-ESI (m/z) calculated for C35H40N4O5S: 628.3. found 629.3 [M+H]+, tR=3.447 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 9.12 (s, 2H), 8.55 (t, J=16.2 Hz, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.1 Hz, 2H), 7.69 (t, J=7.5 Hz, 3H), 7.50 (dd, J=15.4, 8.3 Hz, 2H), 7.00-6.85 (m, 2H), 6.75 (t, J=9.9 Hz, 1H), 4.80 (td, J=9.7, 4.7 Hz, 1H), 4.15 (p, J=7.2 Hz, 1H), 3.10 (ddd, J=39.3, 19.4, 11.8 Hz, 2H), 1.40 (d, J=6.6 Hz, 9H), 1.31 (s, 9H), 1.23 (t, J=11.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]2([CH2:39][OH:40])[CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:40][CH2:39][C:34]1([NH:33][S:30]([C:26]2[CH:25]=[C:24]([NH:23][C:20]([C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]5[CH2:16][CH2:15]5)=[CH:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][C:10]=34)=[O:22])[CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-(1-hydroxymethyl-cyclopentyl)-benzenesulfonamide (example B.13) according to general procedure II. Pale-yellow solid. MS (ISP) 566.3 [(M+H)+]; mp 255-257° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccccc1O
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (5.20 g, 27.6 mmol) in DMF (50 mL) was treated with 2-tert-butylphenol (4.9 mL, 31.7 mmol) and cesium carbonate (27.0 g, 82.8 mmol). The mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to rt, the mixture was poured into water (500 mL) with stirring. The brown precipitate formed was filtered and washed with water, and recrystallized twice from ethanol to afford 2a as brown crystals (6.66 g, 80%). [M+H]+=303.2.