Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:49][CH2:48][CH2:47][C:46]([OH:50])=[O:45])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)NCCC(=O)O)c2)cc1

Procedure:
The product from Example 116B and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.90 (t, 1 H), 7.14-7.36 (m, 8 H), 6.85-7.12 (m, 5 H), 6.67 (ddd, 1 H), 6.48 (m, 2 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.90 (t, 2 H), 3.80 (br.s, 1 H), 3.22 (dd, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.35 (t, 2 H), 2.19 (t, 2 H), 1.76-1.98 (m, 2 H); MS (APCI) m/z 646 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][O:11][C:4]1[N:3]=[C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(Br)n1
Product: COc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 93.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-6-methoxy-3-nitropyridine (116 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow solid (112 mg, 94%). mp 114-116° C. 1H NMR (DMSO) δ 2.56 (s, 3 H), 3.76 (s, 3 H), 6.85 (d, J=8.6 Hz, 1 H), 7.53-7.68 (m, 5 H), 8.12 (d, J=8.6 Hz, 1 H). 13C NMR δ 13.8, 53.4, 107.7, 122.9, 127.0, 128.0, 128.4, 129.2, 132.6, 144.1, 150.3, 161.1. HRMS (FAB): cal. for C14H14N3O [M-FH+]: 240.1237; found: 240.1234.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[N:17]=[N:18][NH:19][C:20]=1[Si](C)(C)C.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[N:17]=[N:18][NH:19][CH:20]=1
Reactant: C[Si](C)(C)c1[nH]nnc1-c1ccncc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cc(I)ccc1Nc1cnccc1-c1c[nH]nn1
Yield: 68.6 %

Procedure:
N-(2-fluoro-4-iodophenyl)-4-[5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl]pyridin-3-amine (20 mg, 0.044 mmol) was added into a solution of NaOH (3.5 mg, 0.088 mmol) in THF (0.5 mL) for 5 days. The mixture was diluted with MeOH and neutralized to pH7 with acidic resin (Dowex). After filtration and the filtrate was concentrated to give pure product (11.5 mg, 69%). LC/MS [Method A: rt: 0.40 min; m/z: 381 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][S:6][CH2:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19].[N:24]1([CH2:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)O)[CH:28]=[CH:27][N:26]=[CH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][S:6][CH2:7][C:8]1[C:17]([O:18][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19]
Reactant: O=C1CCCc2c1ccc(O)c2CSCc1ccc(Cl)c(Cl)c1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CSCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
5-(3,4-Dichloro-benzylsulfanylmethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (256 mg, 0.69 mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (144 mg, 0.75 mmol), and triphenylphosphine resin (1.46 g, loading 1.41 mmol/g) were combined in dry tetrahydrofuran (10 mL) and treated with diisopropyl azodicarboxylate (271 μL, 2.0 mmol). The resulting orange-brown heterogeneous mixture was allowed to stir at ambient temperature overnight. The spent triphenylphosphine resin was removed by filtration, washing sequentially with ethyl acetate, methanol, and chloroform. The filtrate was concentrated in vacuo and the crude material was purified by silica gel chromatography (hexanes/ethyl acetate/triethylamine 28:70:2) to give 280 mg (75%) of the desired product as a colorless solid: (LC-MS, APCI) m/z 553/555 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[C:15]([NH:25][C:26]3[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=3)[N:14]=[C:13]2[O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(NC(C)=O)cc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 404(MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>O>[N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2OC2C1
Reactant: C1CCNC1
Solvent: O
Product: O[C@H]1CCCC[C@@H]1N1CCCC1
Yield: 87.4 %

Procedure:
Pyrrolidine (10.5 g, 148 mmol), cyclohexene oxide (15 mL, 148 mmol) and water (5 mL) were refluxed under nitrogen for 7 h. The cooled, orange mixture was partitioned between saturated sodium hydroxide aq (150 mL) and diethyl ether (150 mL). The aqueous layer was back-washed with diethyl ether (75 mL) and the combined diethyl ether layers were dried over sodium sulfate. The diethyl ether was removed in vacuo the residual oil was vacuum distilled (bp 51° C. at full vacuum) to give (1R,2R)/(1S,2S)-2-(Pyrrolidinyl)cyclohexan-1-ol (21.9 g, 87%). 13C NMR (50 MHz, APT, CDCl3) δ 70.47 (−), 64.82 (−), 47.44 (+), 33.15 (+), 25.11 (+), 24.23 (+), 24.00 (+), 21.12 (+).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][N:13](COCC[Si](C)(C)C)[C:9]=2[C:8]([C:22]#[N:23])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](=[O:38])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][C:26]=2[O:39][CH3:40])[N:6]=1.O.C(=O)(O)[O-:48].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[C:8]([C:22]([NH2:23])=[O:48])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](=[O:38])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][C:26]=2[O:39][CH3:40])[N:6]=1
Reactant: COc1cc(CC(=O)N2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(CC(=O)N2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O
Temperature: 85 °C

Procedure:
The product of Example 30E (80 mg, 0.12 mmol) was dissolved in concentrated sulfuric acid (3 mL) and water (0.5 mL) was added and the solution was heated at 85° C. for 0.5 hours. After cooling to ambient temperature, the mixture was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 14.11 (s, 1 H), 11.83 (s, 1 H), 9.59 (s, 1 H), 8.59 (s, 1 H), 7.71-7.68 (m, 2 H), 7.60-7.58 (m, 2 H), 7.44 (t, J=7.8 Hz, 1 H), 6.77 (s, 1 H), 6.31 (d, J=8.1 Hz, 1 H), 4.79 (s, 2 H), 3.81 (s, 3 H), 3.51 (s, 2 H), 3.46 (t, J=6.6 Hz, 2 H), 3.33 (t, J=6.3 Hz, 2 H), 1.93-1.78 (m, 4 H). MS: 553 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=O)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:26]([NH:27][C:17]([C:13]1[C:14]([OH:16])=[N:15][C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][CH:12]=1)=[O:19])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc(COCc2ccccc2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of step D product (2-e) (20.0 g, 76.9 mmol), diphenylmethanamine (15.5 g, 84.6 mmol), HATU (43.8 g, 115.0 mmol), and TEA (23.3 g, 230 mmol) in DMF (100 mL) were combined and stirred at the ambient temperature overnight. Ice-water (40 mL) was added to the reaction mixture and extracted with DCM (30 mL×2). The organic phase was concentrated to give a residue, which was purified by silica gel chromatography (eluented with PE/EA=3:1˜1:1) to a afford the product, 2-f, (31.0 g, 96%). 1H NMR (300 MHz, CD3OD): δ4.29 (s, 2H), 4.52 (s, 2H), 6.22 (s, 1H), 7.21-7.23 (m, 15H), 8.60 (s, 1H). LC-MS: (M+H)+ 426.
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=O.C(=O)([O-])O.[Na+]>>[CH2:46]([O:5][C:6](=[O:27])[NH:7][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:12][CH2:13]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCN(NC(=O)OCc3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A mixture of tert-butyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 493-(150 mg, 0.39 mmol) and trifluoroacetic acid (4 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (4 ml) and neutralized with triethylamine (4 ml, 28.7 mmol). Subsequently, to the solution, benzyl chloroformate (100 mg, 0.59 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added. The mixture was extracted with methylene chloride. The extract was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=1/1) to afford benzyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate (6.5 mg, yield 4%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[C:32]1([S:38]([CH2:41][CH2:42][C:43](O)=[O:44])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][CH2:41][S:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:40])=[O:39]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)CCS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCS(=O)(=O)c1ccccc1)O[C@@H](Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 68.6 %

Procedure:
((S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide) (150 mg, 0.357 mmol), EDC (103 mg, 0.535 mmol), 3-(phenylsulfonyl)propanoic acid (84 mg, 0.393 mmol), and DMAP (65.4 mg, 0.535 mmol) in DCM (30 ml) were stirred at RT for 4 hours. The reaction mixture was washed with HCl 1N (2×) and NaHCO3 sat. sol. (2×); the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by trituration with iPr2O (10 ml). Further triturations with petroleum ether (15 ml) and Et2O (20 ml) were performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)ethyl)pyridine
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.N1CCOCC1>O1CCCC1>[OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:14]
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and HBTU (25.1 g, 66.3 mmol, N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in tetrahydrofuran was added 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 h, morpholine (5.8 mL, 66.3 mmol) was added to the mixture at room temperature. After 12 h, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the crude was purified by silica gel column chromatography to provide the title compound (5.8 g, 48%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C(C2C=CC([C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=3)=CC=2)CC(OC)O1>>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=3)=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Yield: 48 %

Procedure:
According to the procedure as described in Example 1(c) for N-(1,7-diaza-4-oxa-8-oxo-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)-sucinnamic acid benzyl ester, crude 3(R)-amino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(b)) and 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (prepared as described in Example 4(a)) were condensed to give 84 mg (48%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester as a yellow solid, mp 120° C. 1H NMR (CDCl3): δ 7.72 (s, 4H), 7.59 (s, 4H), 7.32-7.28 (m, 2H), 7.26 (s, 3H), 7.12 (t, 1H, J=2.1 Hz), 6.82 (t, 1H, J=2.7 Hz), 6.61 (dd, 1H, J=1.8, 3.0 Hz), 6.27 (d, 1H, J=9.0 Hz), 5.58 (m, 1H), 5.13 (s, 2H), 5.12 (m, 1H), 4.01 (d, 2H, 8.7 Hz), 3.41 (dd, 1H, J=5.8, 16.7 Hz), 3.11 (dd, 1H, 8.7, 16.8 Hz), 2.78 (d, 3H, J 5.0 Hz), 0.87 (s, 9H). IR (KBr): 2960, 2221, 1736, 1685, 1654, 1562, 1542 cm−1. HRFABMS: Calculated for C35H37N4O4 (M+H+): 577.2815. Found: 577.2832. Anal. Calculated for C35H36N4O4•0.2 DMF 0.5 H2O: C, 71.23; H, 6.45; N, 9.80. Found: C, 71.14, H, 6.23; N, 10.19.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nccc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nccc(N2CCN(C(=O)c3ccccc3)CC2)n1
Yield: 31.6 %

Procedure:
1 g of 2-methyl-4-piperazino-pyrimidine was dissolved in 50 ml of acetone, and 2 g of potassium carbonate and 0.8 g of benzoyl chloride were added. The suspension was refluxed for 6 h until starting compound was no longer detectable. After filtration, the filtrate was concentrated in vacuo, and the residue was recrystallized from dichloromethane/petroleum ether. 0.5 g of 2-methyl-4-(4-benzoyl-piperazino)-pyrimidine was obtained. (Melting point: 147° C.)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([O:8][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1c(Br)cnc(O)c1C
Product: Cc1c(Br)cnc(OCCC(C)(C)O)c1C
Yield: 49.1 %

Procedure:
According to the method of (Example 36) <Step 1>, from 5-bromo-3,4-dimethylpyridin-2-ol (3.0 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (4.2 g), the subject compound (2.1 g) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].O.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[N:20]=[CH:31][O:22][N:21]=2)[C:3]=1[S:23]([C:26]([F:28])([F:29])[F:27])(=[O:24])=[O:25]
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: Nc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 658.2 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfonyl-3-pyrazolecarboxamide oxime (0.51 g, 1.87 mmol) was dissolved in 12 ml of trimethyl orthoformate and p-toluenesulfonic acid monohydrate (0.05 g) was added, and then the mixture was heated under reflux for 1 hour. Trimethyl orthoformate was distilled off and 80 ml of ethyl acetate was added to the residue. The ethyl acetate layer was washed twice with 50 ml of an aqueous saturated sodium hydrogencarbonate solution, and then washed once with 50 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a colorless crystal. This crystal was washed with a hexane-chloroform mixed solvent (volume ratio=2:1) to obtain 0.86 g (1.73 mmol) of the title compound as a colorless crystal. Yield 93%.
Reaction SMILES: [F:1][C:2]1([F:14])[C:4]2([CH2:7][C:6]([CH3:13])([C:8]([O:10]CC)=[O:9])[CH2:5]2)[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1([F:14])[C:4]2([CH2:5][C:6]([CH3:13])([C:8]([OH:10])=[O:9])[CH2:7]2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CC2(C1)CC2(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC2(C1)CC2(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 326A (0.5 g, 2.448 mmol) in THF (10 mL) and water (5 mL) was added NaOH (0.245 g, 6.12 mmol) and the reaction mixture was stirred at RT for 16 h. The volatiles were removed from the reaction mixture and the pH of the resulting residue was adjusted to ˜3 using a 1.0 N aq. solution of HCl. The aqueous layer was extracted with EtOAc (3×10 mL) The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 326B (0.35 g, 81%, a mixture of cis and trans isomers) as a yellow liquid used directly in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.39 (br. s., 1H), 2.55-2.63 (m, 2H), 1.89-2.02 (m, 2H), 1.34-1.45 (m, 3H), 1.14-1.23 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn](CCCC)(CCCC)[C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCCCC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 36.7 %

Procedure:
1.9 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 3.5 g of 1-tributylstannyl-hex-1-ine and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 8 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 30 ml of hexane, and the resulting solid is recrystallised from cyclohexane. 0.7 g of ethyl 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate is obtained (36% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].CCN(CC)CC.[CH:18]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:9][NH:10][C:22](=[O:23])[CH2:21][CH:18]2[CH2:20][CH2:19]2)=[N:4][CH:5]=[CH:6][C:7]=1[I:8]
Reactant: NNc1nccc(I)c1Cl
Reactant: O=C(Cl)CC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC1CC1)NNc1nccc(I)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To a solution of D2 (0.73 g, 2.709 mmol) in dry DCM (8 ml), cooled at 0° C., were added Et3N (0.562 ml, 4.064 mmol) and cyclopropyl-acetyl chloride (0.385 g, 3.251 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. To this mixture was then added NaHCO3 (aqueous sat. solution). The resulting solution was then extracted with DCM. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield intermediate compound D3 (0.94 g, 99%).