Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.OC[NH:68][C:69](=[NH:71])[CH3:70]>CN(C=O)C.O>[CH3:70][C:69]1[N:71]=[C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[O:21][N:68]=1
Reactant: CC(=N)NCO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)n1
Temperature: 140 °C
Yield: 69.1 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol), N-ethyldiisopropylamine (1.04 g, 2.0 mmol) and 1-hydroxybenzotriazole hydrate (40 mg, 0.3 mmol) in DMF (16 mL) at ambient temperature and under argon was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (517 mg, 1.6 mmol) followed by N-hydroxymethylacetamidine (149 mg, 2.0 mmol). After 14 h the mixture was diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined extracts were washed with 10% aqueous LiCl solution (2×10 mL) then dried over sodium sulfate, filtered and concentrated. The residue was then dissolved in DMF (16 mL) and heated at 140° C. for 3 h then cooled, diluted with EtOAc (60 mL), washed with 10% aqueous LiCl (3×100 mL), then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 0:1) afforded the title compound (385 mg, 69%) as a yellow solid. MS: m/e=349.4 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]([C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[S:22][C:23](=[O:25])[CH3:24])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>CC#N>[C:23]([S:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:8]([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:7][C:6]([OH:27])=[O:5])=[O:26])(=[O:25])[CH3:24]
Reactant: CC(=O)Sc1c(Cl)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Sc1c(Cl)cccc1C(=O)N(CC(=O)O)C1CCCC1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
N-(2-Acetylthio-3-chlorobenzoyl)-N-cyclopentylglycine t-butyl ester (20.6 g, 0.05 mole) was dissolved in 150 ml CH3CN. Sodium iodide (11.3 g, 0.075 m) was then added. The resulting slurry was covered with nitrogen and warmed to 55° C. Chlorotrimethylsilane (8.15 g, 0.075 m) was then added in one portion. The reaction was stirred 30 minutes at 55° C. under nitrogen atmosphere. The heat source was removed and the reaction cooled to room temperature in an ice bath. Water (60 ml) and CH2Cl2 (100 ml) were then added. The aqueous layer was quickly withdrawn and the organic layer washed 2×75 ml H2O, 2×75 ml Na2S2O3 and 2×75 ml brine. The organic layer was then dried (MgSO4), filtered and concentrated to yield a dark yellow oil.
Reaction SMILES: C(OC([C:6]1[C:11](=[O:12])[NH:10][C:9]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:8]=2[C:7]=1[NH2:22])=O)C>[OH-].[Na+].O>[NH2:22][C:7]1[C:8]2[CH:15]=[N:14][N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[NH:10][C:11](=[O:12])[CH:6]=1
Reactant: CCOC(=O)c1c(N)c2cnn(-c3ccccc3)c2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(=O)[nH]c2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
4-Amino-6,7-dihydro-6-oxo-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.68 g, 2.28 mmol) was heated at reflux in sodium hydroxide solution (12 ml of a 15 wt. % solution in water). After 6 h, the mixture was allowed to cool to room temperature and was then transferred to a fridge and kept there for 19 h. The white precipitate was filtered off and the filtrate set aside. The solid was dissolved in water and acidified to pH 5 by dropwise addition of concentrated hydrochloric acid. The product was extracted into ethyl acetate (×2) and the combined organic layers washed with brine before being dried (MgSO4) and concentrated. 4-Amino-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (324 mg, 63%) was obtained as a white solid. The filtrate which had been set aside was acidified to pH 5 and extracted with ethyl acetate (×2). The combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate solution and then brine before being dried (MgSO4) and concentrated. This afforded a second crop of the product (145 mg, total yield 91%), m.p. 223-225° C. δH (400 MHz; DMSO) 5.58 (1H, s), 6.76 (2H, br s), 7.23-7.27 (1H, m), 7.46-7.50 (2H, m), 8.16 (1H, s), 8.21-8.24 (2H; m), 11.16 (1H, br s); m/z (ES+) 227 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNCCC(=O)OC(C)(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 3-aminopropanoate hydrochloride (Bachem, 227.1 mg; 1.24 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylbenzylamino)propanoate which was used directly without any further purification. The residue was taken up into DCM (4.5 ml) and TFA (0.5 ml) added. After stirring at RT for 2 hours the solvent was removed in vacuo. The residue was taken up into dilute HCl and precipitated by basification to pH 3-4. The solid was removed by filtration, washed with water and dried to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:30]5[CH2:31][CH2:32][O:28][C:29]5=[O:33])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Product: O=C(c1ccc(N2CCOC2=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 26.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (641 mg) described in Preparation Example 112 and oxazolidin-2-one (200 mg), the title compound (172 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.C.C[OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:28])=[N:9][N:8]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Reactant: CO
Product: O=C(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C

Procedure:
Heating of a mixture of 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine (Example 4 in WO 98/35958) and charcoal in boiling methanol for about 7 days in an open vessel leads to partial oxidation of the methylen-bridge of 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazin. After cooling to RT, unchanged 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine crystallizes out and can be filtered off. Chromatography (SiO2; dichloromethane/methanol 98:2) of the concentrated filtrate then leads to [4-(4-chloranilino)phthalazin-1-yl](pyridin-4-yl)ketone and rac. [4-(4-chloranilino)phthalazin-1-yl](pyridin-4-yl)methanol (see Expl. 78 in WO 98/35958). [4-(4-Chloranilino)phthalazin-1-yl](pyridin-4-yl)ketone: 1H NMR (DMSO-d6) δ 9.88 (bs, 1H, HN), 8.79 (d, 2H, pyridine), 8.71 (d, 1H), 8.63 (d, 1H), 8.07 (m, 2H), 7.97 (d, 2H, chloranilino), 7.77 (d, 2H, pyridine), 7.45 (d, 2H, chloranilino); IR (KBr): 3287, 3139, 3066, 1667 (CO), 1620 cm−1; FAB MS (M+H)+=361.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[CH:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(C(N)=O)cc2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2S,3R,4S,5R)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide (475 mg) was resolved on Berger SFC system under 30° C., 100 Bar, 35% MeOH on a O.D. Column to give two peaks. Peak 1, undesired, 38 mg white solid; Peak 2, desired, 38 mg white solid;
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:21]4[C:16]5[C:17](=[N:18][C:13]([C:3]6[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[Cl:12])=[N:14][CH:15]=5)[NH:19][N:20]=4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=496.0/498.0
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C@@H:9]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:8][C@@H:9]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc([N+](=O)[O-])c3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc([N+](=O)[O-])c3)OC(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
Acetic anhydride (1.67 ml, 17.6 mM) is added to a solution of (S)-2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)-1-(3-nitrophenoxy)propane (1.99 g, 4.4 mM) (Example 27) in CH2Cl2 (4 ml) and pyridine (2 ml). The mixture is maintained in agitation for 21 hours at room temperature. Then it is treated with 1N HCl, followed by a saturated aqueous NaHCO3 solution. The two phases are separated and the organic phase dried over Na2SO4, filtered and the solvent removed under vacuum. An oil is obtained from which the product (S)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]-1-(3-nitrophenoxy)propane is isolated (yield of 69%) by column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate=1:1). [α]D=−10.0 (c 1.04, CHCl3). FT-IR (neat): 3092, 2930, 2850, 1740, 1597, 1576, 1531, 1499, 1458, 1373, 1350, 1329, 1307, 1259, 1234, 1164, 1095, 944, 805, 737 cm−1. 1NMRs (400 MHz CDCl3, δ): 7.82-7.79 (m, 1H, aromatic proton); 7.68-7.65 (m, 3H, aromatic protons); 7.42-7.38 (t, 1H, J=8.2 Hz, aromatic proton); 7.21-7.18 (dd, 1H, J=8.4 Hz, 2.6 and 0.9 Hz, aromatic proton); 7.00-6.97 (m, 2H, aromatic protons); 5.30-5.20 (m, 1H, CHOAc); 4.17-4.13 (dd, 1H, J=10.3 and 3.5 Hz, CH2OAr), 4.12-4.08 (dd, 1H, J=10.3 and 6.4 Hz, CH2OAr); 3.86 (s, 3H, OCH3); 3.10-2.90 (m, 4H, 2 CH2N of piperazine); 2.70-2.50 (m, 6H, 2 CH2N of piperazine and CHOHCH2N); 2.04 (s, 3H, CH3CO). 13C NMRs (100 MHz CDCl3, δ): 170.29, 163.03, 158.88, 149.03, 129.99, 129.81, 126.92, 121.81, 116.15, 114.21, 108.63, 94.40, 68.08, 57.36, 55.56, 52.74, 46.01, 21.04. MS-ESI m/z (%): 494 [M+H]+ (22); 516 [M+Na]+ (100). MS-MS (516): 516 (3), 435 (22), 434 (100), 295 (10), 269 (26), 263 (13). Anal. Calc. for C22H27N3O8S: C, 53.55; H, 5.48; N, 8.52. Found: C, 53.51; H, 5.41; N, 8.69.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.N1(O)C2C=CC=CC=2N=N1.[C:41]([CH2:43][C:44](O)=[O:45])#[N:42].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:44](=[O:45])[CH2:43][C:41]#[N:42])[CH2:3]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCNC4)c3n2)cc(OC)c1OC
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN(C(=O)CC#N)C4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of (3-methyl-piperidin-3-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (11 mg, 0.27 mmol), benzotriazol-1-ol (4.0 mg, 0.03 mmol), 2-cyanoacetic acid (3 mg, 0.04 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrogen chloride (6.0 mg, 0.03 mmol) in anhydrous dichloromethane was treated with triethylamine (0.01 ml, 0.08 mmol) and allowed to stir at room temperature overnight. The reaction mixture was partitioned between dichloromethane/water and the organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 0.25:4.75:95 concentrated aqueous NH4OH: MeOH: dichloromethane as eluant to provide 5 mg (42%) of 3-{3-methyl-3-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-piperidin-1-yl}-3-oxo-propionitrile as a light yellow solid. M+H 578.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2ccc(C(F)(F)F)cc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2ccc(C(F)(F)F)cc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-4-trifluoromethylbenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-4-trifluoromethylbenzyloxy)phenylacetic acid, mp 185°-187° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:17]([CH2:22][CH3:23])([CH2:20]O)[CH2:18]O)[CH3:16]>>[CH2:15]([C:17]1([CH2:22][CH3:23])[CH2:20][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:18]1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CCC(CC)(CO)CO
Product: CCC1(CC)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
4-Nitrobenzylphosphonic acid and 2,2-diethyl-1,3-propanediol were treated in the same manner as in Reference Example 20 to yield 5,5-diethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinan-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 159°-160° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5](O)=[O:6].[CH3:12][CH2:13][OH:14]>>[OH:6][C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:13](=[O:14])[CH:12]=1
Reactant: CNc1ccccc1C(=O)O
Reactant: CCO
Product: Cn1c(=O)cc(O)c2ccccc21

Procedure:
This was prepared from N-methyl anthranilic acid (22.04g. 0.146 mole) as described in example 30a., m.p. (EtOH) 270°-273°C. (Found; C, 68.59; H, 5.44; N, 7.73; C10H9NO2 requires; C, 58.56; H, 5.18; N, 8.00%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:14][S:15]([C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:9](=[O:13])[C@@H:10]2[O:12][CH2:11]2)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C@H:14]([S:15]([C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:17])=[O:16])[C@@H:10]([CH2:11][OH:12])[C:9]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(CS(=O)(=O)C(C)(C)C)C(=O)[C@H]2CO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@H](CO)[C@H]2S(=O)(=O)C(C)(C)C)cc1

Procedure:
Analogously to Example 8b, from 1.71 g (5 mmol) of N-p-methoxybenzyl-N-tert.-butylsulphonylmethyl-(R)-glycidic acid amide in THF, by reaction with dehydrated tetra-n-butylammonium fluoride in the presence of activated molecular sieve, there is obtained the title compound in the form of a crude product which is chromatographed over silica gel using toluene/ethyl acetate (4:1) and (2:1). The pure title compound is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[CH:7]=[O:8].CC1(C)C(C)(C)[O:21][B:20](B2OC(C)(C)C(C)(C)O2)[O:19]1.C([O-])(=O)C.[K+]>COCCOC>[CH:7]([C:6]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:4]=[CH:3][C:2]=1[B:20]([OH:21])[OH:19])=[O:8]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1ncc(Br)c1C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1ncc(B(O)O)c1C=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-5-carbaldehyde (2.00 g, 6.55 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.75 g, 6.88 mmol), potassium acetate (1.93 g, 19.7 mmol) and 1,2-dimethoxyethane (40 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.535 g, 0.655 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. overnight. After cooled to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to afford the title compound (571 mg, 25%) as a colorless oil:
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O>C(Cl)Cl.O>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
A solution of 9.0 g (79 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over a 10-minute period to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 31.4 g (64.1 mmol) of ferric sulfate pentahydrate, and 200 ml of dimethyl sulfoxide at a temperature of 20° C. No temperature change is observed as the hydrogen peroxide solution is added. After the addition is complete, the reaction mixture is stirred for 10 minutes. Water (50 ml) is added, and the temperature increases to 45° C. The mixture is diluted with methylene chloride (200 ml) and water (50 ml), and the aqueous layer is extracted with methylene chloride (2×100 ml). The organic layers are concentrated at reduced pressure, and the crude product is purified by flash chromatography on silica gel (4:1 heptane/ethyl acetate) to afford 1.25 g (11% yield) of the title compound, mp 93°-94° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>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].C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([C:29]2[CH:28]=[C:27]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]=[CH:31][CH:30]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Temperature: 150 °C
Yield: 71.7 %

Procedure:
To a mixture of 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one (38 mg, 0.129 mmol), biphenyl-3-ylboronic acid (31 mg, 0.155 mmol), PdCl2(dppf).CH2Cl2 (5.3 mg, 0.006 mmol), under nitrogen, was added THF (1 mL) followed by 1 M aqueous Na2CO3 solution (0.388 mL). The reaction mixture was heated at 150° C. (microwave irradiation) for 25 min, cooled to room temperature and partitioned between water and EtOAc. Layers were separated and the aqueous solution was extracted with CH2Cl2 (2×). Combined organic solutions were dried over Na2SO4 and concentrated. Purification by flash chromatography (24 g silica gel, 3% to 100% EtOAc in hexanes) afforded 34 mg (72%) of 3-(benzyloxy)-5-(biphenyl-3-yl)-1-methylpyridin-2(1H)-one as a white solid. LC/MS (M+H)+ 368.3.