Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[N:13]=1>O.C(#N)C>[O:22]([C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 51.7 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3-bromobenzoic acid (6 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (5.9 g). The product obtained by precipitation in water (9.8 g; m.p. 188°-192° C.) is dissolved in acetonitrile (300 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-bromobenzamide (5.4 g), m.p. 194° C., is obtained.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([NH:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Reactant: Cc1ccc(OCCN)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(OCCNc2nc(C(C)(C)C)cn3c(=O)[nH]nc23)cc1
Temperature: 80 °C

Procedure:
To a solution of 60 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 100 mg of 2-p-tolyloxy-ethylamine hydrochloride in DMF (2.0 mL) was added 60 mg of TEA. The mixture was heated to 80° C. for three h and then was cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was washed with sat. sodium chloride solution and then dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford the title compound as a white solid. MS (M+H+)=342.5.
Reaction SMILES: [CH3:1][C:2]1([C:5](=[O:12])[CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)(=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:6]([N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:12])=[CH:16][CH:15]=1
Reactant: CC1(C(=O)Cn2cncn2)CC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC1(C(=O)C(=Cc2ccc(Cl)cc2)n2cncn2)CC1
Temperature: 100 °C

Procedure:
1-(1-Methylcyclopropyl)-2-(1,2,4-triazole-1-yl)ethane-1-one (10 g, 0.06 mole), 4-chlorobenzaldehyde (9 g, 0.06 mole), anhydrous potassium carbonate (8 g, 0.06 mole) and acetic anhydride (100 ml) were mixed, and the mixture was heated to 100° C. for 6 hours with stirring. Precipitates in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain an oily product. The oily product was extracted with chloroform (300 ml), and the extract was washed with a sodium hydrogen carbonate-saturated water (300 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. One drop of the residue was dissolved in acetone, and the acetone solution was gas-chromatographed under the conditions described below. Then, a peak corresponding to the II-A isomer was found at a retention time of 250 sec, and that corresponding to the II-B isomer at a retention time of 300 sec. The ratio of the both isomers was 19.1/63.5, i.e. about 1/3, as calculated from the percentage of each area.
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:38][CH2:37][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:35])=[C:21]([F:34])[C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[C:3]=1[CH3:50].[C:51](O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)[CH3:52]>>[C:46]([O:45][C@@H:40]([C:4]1[C:3]([CH3:50])=[C:2]([CH:51]=[CH2:52])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:38][CH2:37][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([F:34])[C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:49])[CH3:47]
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Product: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1c(ccc(F)c1F)O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 52.5 %

Procedure:
Prepared in 52.5% yield from methyl(2S)-2-[(22S)-5-bromo-16,17-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 702.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:32]([C:27]3[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:34])=[O:33])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of [4-(4-Amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and 2-Methyl-benzenesulfonyl chloride (113 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum. The residue was diluted with water (10 mL) and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-30% ethyl acetate in hexanes, to afford {6-chloro-3-methyl-4-[4-(toluene-2-sulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 62.1%) as a white foam. HRMS calcd. for C27H23ClFNO4S [(M−H)−] 492.1042, obsd. 492.1042.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=1)([O-:3])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1c([N+](=O)[O-])cn2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cccc2[nH]cc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl [3-nitro-1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step C (730 mg, 1.75 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 5.25 mL, 5.25 mmol) and the reaction mixture was stirred at ambient temperature for 10 min, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and extracted with CHCl3 (15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:EtOAc—90:10 to 50:50, to give the title compound. MS: m/z=221 (M−C4H7).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][O:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[N:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:23][O:24][C:25]=3[C:26]([F:29])([F:28])[F:27])=[N:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 529 μL, 1.1 mmol) was added dropwise (exothermic) to a solution of cyclopropanemethylamine (75 mg, 91 μL, 1.1 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 6 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (92 mg, 83%) which was obtained as an off white solid. MS: m/e=418.3 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C:23]([OH:25])=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.Cl.[CH3:27][NH:28][O:29][CH3:30]>ClCCl>[CH3:27][N:28]([O:29][CH3:30])[C:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:25]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Portions of 1,1′-carbonyldiimidazole (2.06 g, 12.7 mmol) are added to a stirred mixture of isoquinoline-1-carboxylic acid (2.00 g, 11.6 mmol) in dichloromethane (25 ml). N,O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol) is added and the mixture is stirred at ambient temperature overnight. The reaction mixture is diluted with dichloromethane and then washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. The organic solution is dried with sodium sulfate, filtered, and concentrated to give 2.5 g of N-methyl N-methoxy isoquinoline-1-carboxamide, which is used in the next step without further purification: mass spectrum (ion spray): m/z=217.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(Oc3ccccc3)cc2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Yield: 94.8 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one (2.5 g, 6.88 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (4.30 ml, 34.4 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (2.2 g, 95%).
Reaction SMILES: C[O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][C@@H:18]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:17]4)[S:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Br>>[N:21]1([C@@H:18]2[CH2:19][CH2:20][N:16]([C:14]3[S:15][C:11]4[CH:10]=[C:9]([C:6]5[N:7]=[N:8][C:3]([OH:2])=[CH:4][CH:5]=5)[CH:28]=[CH:27][C:12]=4[N:13]=3)[CH2:17]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1ccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nn1
Agent: Br
Product: Oc1ccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nn1

Procedure:
A solution of (R)-6-(6-methoxypyridazin-3-yl)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 68, 19.8 mg, 0.032 mmol) in hydrobromic acid (48 wt. % in water, 0.25 mL, 2.210 mmol) was heated to 80° C. for 1 hour, concentrated with a stream of nitrogen and chromatographed on silica gel eluting with a gradient of 2 to 10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the desired product, (R)-6-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3-ol. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.57 (m, 2H), 1.61-1.72 (m, 4H), 1.95-2.10 (m, 1H), 2.32-2.43 (m, 1H), 2.46-2.66 (m, 4H), 3.05-3.18 (m, 1H), 3.38-3.47 (m, 1H), 3.52-3.63 (m, 1H), 3.72-3.81 (m, 1H), 3.84-3.92 (m, 1H), 7.05 (d, J=9.8 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.83 (dd, J=8.5, 2.0 Hz, 1H), 8.06 (d, J=9.8 Hz, 1H), 8.21 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[N:6])[CH3:2].[CH2:8]([OH:10])[CH3:9]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[C:5]([O:10][CH2:8][CH3:9])=[NH:6])[CH3:2]
Reactant: CCOC(=O)C#N
Reactant: CCO
Solvent: CCOCC
Product: CCOC(=N)C(=O)OCC
Temperature: 40 °C

Procedure:
Nitriloacetic acid ethyl ester (83 mmol) was dissolved in diethyl ether (water free, 25 ml) and ethanol (water free, 85 mmol) was added and the stirred mixture cooled to 40 ° C. At this temperature, HCl (gaz, dried through concentrated sulfuric acid; 18 g total consumption) was bubbled into the solution over 1 hour. The cooling bath was removed and at 0° C. the reaction mixture warmed up quickly (additional cooling required) and the product precipitated. The solid material was filtered off, washed with diethyl ether and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C@@H:12](O)([CH2:14][CH3:15])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:13][C@@H:12]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:14][CH3:15]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC[C@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC[C@@H](C)Oc1cccc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 3-hydroxybenzoate (5.00 g, 32.9 mmol) in toluene (32.9 ml) was added (S)-(+)-sec-butanol (3.34 ml, 36.1 mmol), triphenylphosphine (9.48 g, 36.1 mmol), and DIAD (7.03 ml, 36.1 mmol). After warming to rt overnight, the reaction mixture was filtered through a fritted funnel and washed with toluene. The filtrate was concentrated. The residue was purified on a silica gel cartridge (0% EtOAc/hexanes to 10% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:18]([CH3:19])=[CH:17][C:15]([NH2:16])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[C:18]([CH3:19])[C:12]([CH3:11])=[CH:13][C:14]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Product: Cc1cc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4,5-dimethyl-2-nitroaniline and was obtained as an orange solid as described in Example 1. 1H NMR (CDCl3): 11.38 (s, 1H), 9.03 (d, J=2.1, 1H), 8.72 (s, 1H), 8.24-8.21 (m, 1H), 8.07 (s, 1H), 7.52 (d, J=8.7, 1H), 2.41 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH2:4]1[CH2:5][CH2:6][CH:1]([N:7]=[C:8]=[N:10][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:2][CH2:3]1
Reactant: NC(=O)NC1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: C(=NC1CCCCC1)=NC1CCCCC1
Reaction time: 5 h

Procedure:
The polymer bound cyclohexylurea (PS-DCU; 1 g of 1.25 mmol/g) recovered after N-acylation is suspended in dichloromethane (20 ml) in a two-necked round-bottom flask (100 ml) equipped with a silicone rubber septum and a reverse filter funnel under exclusion of moisture and air. Phosphorus oxychloride (POCl3; 0.38 g, 2.5 mmol) is added slowly over a period of 10 minutes to the above suspension of PS-DCU. The mixture is shaken gently for 4-6 hours and supernatant is removed by reverse filtration and replaced by 10% aqueous NaOH (5 ml) and fresh dichloromethane (20 ml). The suspension is shaken for 1 hour and supernatant is removed. The polymer is washed with tetrahydrofuran (2×25 ml) to remove excess of water and base and dried under vacuum to furnish PS-DCC. The process of dehydration is monitored by taking a small amount of POCl3 treated polymer and using it for the conversion of acetic acid to acetic anhydride. The formation of acetic anhydride is monitored by quantitative 1H NMR and GC analysis of the product. The regenerated PS-DCC is found to be stable at room temperature and useful for another round of N-acylation.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:15]2[O:14][N:13]=[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH2:18][CH2:17]3)[C:11]=2[S:10][CH:9]=1>O1CCCC1>[CH3:7][C:8]1[C:15]2[O:14][N:13]=[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18][CH2:17]3)[C:11]=2[S:10][CH:9]=1
Reactant: Cc1csc2c(C3CCN(CCCC#N)CC3)noc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1csc2c(C3CCN(CCCCN)CC3)noc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.3 %

Procedure:
Under inert conditions, add lithium aluminum hydride (3.42 mmol, 3.42 mL, 1.50 equivalents, 1.0 M solution in tetrahydrofuran) to a stirred solution of 4-[4-(6-methyl-thieno[2,3-d]isoxazol-3-yl)-piperidin-1-yl]-butyronitrile (2.28 mmol, 660 mg, 1.00 equivalents) in tetrahydrofuran (dry, 12.86 mL). Stir the resulting solution at room temperature for 2.5 hours. Quench the reaction mixture by adding water (0.16 mL), then sodium hydroxide (aqueous, 0.16 mL, 2 M solution), and then water (0.5 mL). Dilute the resulting suspension with dichloromethane (16 mL) and vigorously stir for 30 minutes. Filter the resulting mixture through a bed of celite®, dry over magnesium sulfate, filter and evaporate to yield the desired product (457 mg) as a brown oil. LC/MS (ESI), m/e 294 (MH+), retention time 0.56 minutes. Condition II.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:31]1([CH2:37][CH2:38]Br)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:38][CH2:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrCCC1CCCCC1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(CCC2CCCCC2)c1=O
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (1.0 g, 7.24 mmoles) and 2-cyclohexylethyl bromide (287 mg, 1.5 mmoles) in dimethylacetamide (8 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from toluene gave the title compound (180 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (br. s., J=5.43, 5.43 Hz, 1 H), 4.63 (t, J=11.62 Hz, 1 H), 4.07-4.19 (m, 2 H), 3.72-3.88 (m, 2 H), 2.18-2.36 (m, 2 H), 1.50-1.87 (m, 10 H), 1.35-1.47 (m, 2 H), 1.04-1.35 (m, 7 H), 0.91 (q, J=11.62 Hz, 2 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:26]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH2:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of compound 4 (1.0 g, 2.4 mmol) in ethanol (20 mL) was added 10% Pd/C (0.3 g) and acetic acid (0.3 mL). The resulting mixture was stirred under an atmosphere of hydrogen for 16 hours and then filtered to remove Pd/C. The filtrate was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (100 g) and eluted with CH2Cl2:MeOH 20:1 to 10:1 (v/v) to afford compound 5 as a oil (0.90 g, 96%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([CH2:36][O:37][CH3:38])[CH2:33][C@H:32]1[C:39]([OH:41])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:38][O:37][CH2:36][C@@H:34]1[CH2:35][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:30])[CH:32]([C:39]([O:41][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:40])[CH2:33]1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC[C@H]1CC(C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.47 g, 20.1 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (5.22 g, 20.1 mmol) were suspended in 2-Me-THF (75 mL) and treated with Cs2CO3 (3.27 g, 10.1 mmol). After stirring 4 h at RT, the reaction mixture was diluted with diluted with DCM. The organic layer was washed with H2O. The aqueous layer was then back extracted 2× with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 50% EtOAc/DCM) to afford (4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.73 g, 70%).