Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:26][CH2:25][C:24]([NH:23][CH:20]1[CH2:19][CH2:18][N:17]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:22][CH2:21]1)=[O:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A chloroform (0.4 mL) solution of benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of 1-benzyl-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was shaken at room temperature for 12 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added to the mixture. The obtained mixture was shaken at room temperature for 12 hours. The resulting reaction mixture was filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and washings were combined, and dichloromethane (4 mL) was added. The solution was washed with a 2 M aqueous solution of NaOH (0.5 mL) to provide 4-(N-benzoylglycyl)amino-1-benzylpiperidine (Compd. No. 386) (11.3 mg, 64%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 352.0 (M++H, C21H25N3O2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([OH:33])[CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:28]=[C:27]([C:26]([F:34])([F:25])[F:35])[CH:32]=[CH:31][N:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cc(C(F)(F)F)ccn1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cc(C(F)(F)F)ccn2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 30.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-trifluoromethyl-pyridin-2-ol (43 mg, 0.26 mmol) to give the title compound (20 mg, 30%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[CH2:16]([C:18]([CH2:23][OH:24])([CH2:21][OH:22])[CH2:19][CH3:20])[OH:17].[CH:25]1[CH2:29][CH:28]=[CH:27][CH:26]=1>>[CH:18]12[CH2:21][CH:3]([CH:2]([C:1]([OH:5])=[O:4])[CH2:16]1)[CH:20]=[CH:19]2.[CH:26]12[CH2:25][CH:29]([CH:7]([C:6]([OH:10])=[O:9])[CH2:8]1)[CH:28]=[CH:27]2.[CH:18]12[CH2:21][CH:13]([CH:12]([C:11]([OH:15])=[O:14])[CH2:16]1)[CH:20]=[CH:19]2.[CH2:16]([C:18]([CH2:23][OH:24])([CH2:21][OH:22])[CH2:19][CH3:20])[OH:17]
Reactant: C1=CCC=C1
Reactant: C=CC(=O)O
Agent: CCC(CO)(CO)CO
Product: O=C(O)C1CC2C=CC1C2
Temperature: 40 °C

Procedure:
Trimethylolpropane triacrylate (338 g, 1.0 mol) was stirred under nitrogen in a 1000 ml, four-necked, round-bottomed flask equipped with a Freidrichs condenser, a thermometer, a constant pressure addition funnel, and mechanical stirring at 40° C. Freshly cracked cyclopentadiene monomer (217 g, 3.3 mol) was added at such a rate that the temperature of the reaction slowly climbs to about 90° C. by the end of the addition. The reaction mixture was stirred at this temperature for two hours. The extent of reaction as monitored by the decrease in the infrared absorption band at 1636 cm-1. When the reaction was judged to be complete (no change in the infrared absorption), excess cyclopentadiene was removed by vacuum concentration of the resin. The yield of resin is 534 g.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:30](=[O:31])[C:29]3[CH:32]=[C:33]([CH3:35])[S:34][C:28]=3[NH:27][C:26]2=S)[CH2:19][CH2:18]1.[OH-].[K+].C([OH:41])C.OO>O>[OH2:1].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:30](=[O:31])[C:29]3[CH:32]=[C:33]([CH3:35])[S:34][C:28]=3[NH:27][C:26]2=[O:41])[CH2:19][CH2:18]1
Reactant: Cc1cc2c(=O)n(CCN3CCC(Cc4nc5cccnc5n4Cc4ccco4)CC3)c(=S)[nH]c2s1
Reactant: CCO
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(=O)n(CCN3CCC(Cc4nc5cccnc5n4Cc4ccco4)CC3)c(=O)[nH]c2s1
Reaction time: 8 h
Yield: 58 %

Procedure:
To a stirred mixture of 3 parts of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-6-methyl-2-thioxothieno[2,3-d]pyrimidin-4(1H)-one, 4.3 parts of potassium hydroxide, 56 parts of ethanol and 5.5 parts of water were added dropwise 45 parts of a hydrogen peroxide solution 3%. The whole was stirred overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.7 parts (58%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-6-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione monohydrate; mp. 135.4° C. (496).
Reaction SMILES: N[C:2]1[C:3]2[C:11](=O)[CH:10]=[CH:9][N:8]([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl[Si](C(C)C)(C(C)C)O[Si](Cl)(C(C)C)C(C)C.O>N1C=CC=CC=1>[N:5]1[C:4]2[N:8]=[CH:9][CH:10]=[CH:11][C:3]=2[CH:2]=[N:7][CH:6]=1
Reactant: Nc1ncnc2c1c(=O)ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: O
Product: c1cnc2ncncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A reaction mixture of 4-amino-5-oxo-8-(β-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1.8 g, 6.20 mmol) and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (2.15 mL, 6.73 mmol) in anhydrous pyridine (25 mL) was stirred at room temperature for 20 h and cooled with ice. Water (0.5 mL) was added, and the mixture stirred at ambient temperature for 30 min and concentrated. The residue was dissolved in ethyl acetate, washed with diluted sodium bicarbonate, dried over Na2SO4, and concentrated. Chromatography on silica (EtOAc-hexanes 3:2) gave 2.0 g of 4-amino-5-oxo-8-[3,5-O-(1,1,3,3-tetraisopropyldisiloxy)-β-D-ribofuranosyl)]pyrido[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH2:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(F)cc1)C2=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(Cl)c2c(c1)CN(Cc1ccc(F)cc1)C2=O
Yield: 49.7 %

Procedure:
A mixture of 7-chloro-5-ethenyl-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol 1-one (0.134 g, 0.45 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.068 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.68 (q, 2H), 4.19 (s, 2H), 4.74 (s, 2H), 6.98-7.32 (m, 6H). GC-MS: m/z 303 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:46])([CH3:45])[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([CH3:46])([CH3:45])[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])=[CH:33][CH:34]=2)[S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)S(=O)(=O)c2cccnc2)c1
Reaction time: 1 h

Procedure:
The title compound was prepared by alkylation of {3-[(pyridine-3-sulfonylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (122 mg, 0.322 mmol) with [2-(4-bromomethyl-phenyl)-2-methyl-propoxy]-tert-butyl-dimethyl-silane (121 mg, 0.339 mmol) following the procedure described for Example 1, Step A. The reaction time was 1 h. The crude product (238 mg) was used in the next step without purification. MS 655 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:13]2[CH2:14][N:10]([C:11](=[O:23])[N:12]2[O:15]CC2C=CC=CC=2)[CH:9]([C:24]([NH2:26])=[O:25])[CH:8]=1)(=[O:3])[CH3:2].C(NCCC1[C@@H]2CN(C(=O)N2OCC2C=CC=CC=2)[C@H](C(N)=O)C=1)(=O)C>CCOC(C)=O.C(O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C@@H:13]2[CH2:14][N:10]([C:11](=[O:23])[N:12]2[OH:15])[C@H:9]([C:24]([NH2:26])=[O:25])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC1=CC(C(N)=O)N2CC1N(OCc1ccccc1)C2=O
Agent: [Pd]
Agent: CC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OCc1ccccc1)C2=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(O)C2=O
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of 4-(2-acetamidoethyl)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 247, 0.120 g, 0.33 mmol) in EtOAc (20 mL) and ethanol (6.67 mL) was added Pd/C (0.036 g, 0.33 mmol). The reaction mixture was stirred under hydrogen at 1 atm for 1 hour, then filtered through celite and concentrated to dryness to afford the title compound as a white solid (0.09 g, 100%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: COCCN
Product: COCCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) was dissolved in 2-methoxyethylamine (15 ml) and heated under reflux for 6 hours. Evaporation of the solvent and chromatographic purification of the residue on a column of silica gel with elution by chloroform and then with chloroform/methanol (20:1) yielded the title compound as a pale yellow oil (2.7 g).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:29]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:30]([C:41]([OH:43])=O)[C@H:31]([CH3:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH:51]1[C:59]2[C:58]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:57]=3[O:56][C:55]=2[CH:54]=[CH:53][C:52]=1[NH2:65]>>[CH2:33]([O:32][C@H:31]([CH3:40])[C@@H:30]([NH:29][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]([NH:65][C:52]1[CH:53]=[CH:54][C:55]2[O:56][C:57]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][C:58]=3[C:59]=2[CH:51]=1)=[O:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 18.6 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-D-Thr(Bzl)-OH (0.42 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl {(1R,2R)-2-(benzyloxy)-1-[(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)carbonyl]propyl}carbamate (0.11 g). MS (ESI) m/z 493 ([M+H]+); MS (ESI) m/z 491 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH2:9]O)=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([F:21])[CH:17]=[CH:16][CH:15]=3)[CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([CH3:11])[CH2:9][N:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[C:18]([F:21])[C:19]=4[CH:20]=[C:12]3[C:4]=2[CH:3]=1
Reactant: CC(CO)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1Cn2c(cc3c(F)cccc32)-c2cc(Cl)ncc21
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a suspension of 2-(6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propan-1-ol (60 mg, 0.21 mmol) and DEAD (111 mg, 0.63 mmol) in THF (4 mL) was added PPh3 (156 mg, 0.63 mmol) at 0° C. under N2, and the mixture was stirred for 12 hours. Then the mixture was diluted with H2O and extracted with EA. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated to give 2-chloro-11-fluoro-5-methyl-5,6-dihydroindolo[2,1-a][2,6]naphthyridine (30 mg, yield: 56%). 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.54 (s, 1H), 7.05˜7.15 (m, 3H), 6.73˜6.77 (m, 1H), 4.16˜4.20 (m, 1H), 4.00˜4.04 (m, 1H), 3.31˜3.35 (m, 1H), 1.30 (d, J=8.0 Hz, 3H). MS (M+H)+: 287/289.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Yield: 88.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XLVI) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2Cl2 (927 mg, 5 mmol %) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give 5-nitro-3,3′-bipyridin-4-amine (XLVII) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 400 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: Br[Mg]c1ccccc1
Product: COc1ccc2cc(-c3ccccc3)ccc2c1

Procedure:
The title compound was prepared by reacting 2-bromo-6-methoxynaphthalene (1.97 g, 8.31 mmol) with phenylmagnesium bromide according to the method used to prepare intermedite 10 to yield 1.59 g (82%) of a white solid: mp 122-126° C.; 1H NMR (CDCl3): δ 3.94 (3H, s), 7.16-7.18 (2H, m), 7.34-7.37 (1H, m), 7.46-7.49 (2H, m), 7.69-7.72 (2H, m), 7.78-7.82 (2H, m), 7.97 (1H, s); MS (EI) m/z 234.2 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>CN(C)C=O>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])=[CH:21][C:17]=1[C:18]([N:10]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])=[O:19]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1Br)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-nitrophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-bromo-5-(2-nitro-4-bromophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-bromo-5-(2-nitro-4-bromophenoxy)benzoyl]-4-nitrophthalimide.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[CH:19][C:18]=1[CH3:28]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([O:16][CH3:15])=[C:18]([CH3:28])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccc(C=CC(=O)O)cc1C
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3)nc2n(CC)c1=O
Yield: 38.1 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.00 g (13.9 mmol) of 4-methoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 1.70 g (yield 36%) of Compound 174 as white flocculent precipitates.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[N:11]=[N:12][NH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1)=O.[CH:17]1([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.CO>[CH:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH:27][CH2:1][C:3]3[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]4[N:11]=[N:12][NH:13][N:14]=4)=[O:8])=[CH:5][CH:4]=3)=[CH:28][CH:29]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 70 °C
Yield: 83.4 %

Procedure:
4-Formyl-N-(2H-tetrazol-5-yl)benzamide (8.94 g, 41.2 mmol) was dissolved in DMF (50 mL) by gentle heating. A solution of 4-cyclohexylaniline (7.20 g, 41.2 mmol) in methanol (100 mL) was added and a turbid suspension was formed. The suspension was heated to 70° C. for 1 hour. Acetic acid (50 mL) and sodium cyanoborohydride (2.0 g, 31.7 mmol) was then added. The turbid suspension was heated to 70° C. for an additional hour, before being cooled to 0° C. on an ice bath. The insoluble material was collected by filtration and washed twice with water, before being dried overnight in a vacuum oven to afford 12.94 g (83.5%) of 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[OH:11].[Br:12]Br>S(=O)(=O)(O)O.C(Cl)(Cl)(Cl)Cl.S([O-])([O-])(=O)=O.[Ag+2]>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[C:2]([OH:11])[CH:3]=[N:4]2
Reactant: Oc1cnc2ccccc2n1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
2-Quinoxalinol (2.9 g, 20 mmol) and silver sulfate (3.1 g, 10 mmol, 0.5 eq.) in sulfuric acid (20 mL) were treated with bromine (1.03 mL, 20 mmol, 1.0 eq.). After stirring at ambient temperature for 18 h, the reaction mixture was diluted with carbon tetrachloride (50 mL), heated to 50° C., and filtered. The filtrate was poured onto ice and the solids collected by filtration and recrystallized from HOAc, giving 6-bromo-2-quinoxalinol (1.8 g, 40%).
Reaction SMILES: [Na].[I-].[C:3]([CH2:5][CH2:6][P+:7](CCC#N)([CH2:12][CH2:13][C:14]#[N:15])[CH2:8][CH2:9][O:10][CH3:11])#[N:4].O.C(Cl)(Cl)Cl>CO>[C:3]([CH2:5][CH2:6][P:7]([CH2:12][CH2:13][C:14]#[N:15])[CH2:8][CH2:9][O:10][CH3:11])#[N:4]
Reactant: COCC[P+](CCC#N)(CCC#N)CCC#N
Agent: [I-]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COCCP(CCC#N)CCC#N

Procedure:
1.55 g of sodium are dissolved in 100 ml of absolute methanol under an atmosphere of argon and then 26 g (0.0685 mole) of tris-(β-cyanoethyl)-2-methoxyethyl-phosphonium iodide are added to this solution. The solution is refluxed for 4 hours. After the mixture has been poured into water, extraction is performed with three 40 ml portions of chloroform. The chloroform solution is dried over magnesium sulphate, the solvent is evaporated and the oily residue distilled in a high vacuum.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[CH2:11]([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([C:14]1[C:20]([OH:21])=[N:5][C:6]2[N:7]([N:8]=[CH:9][CH:10]=2)[C:15]=1[OH:16])[CH:12]=[CH2:13]
Reactant: Nc1cc[nH]n1
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: C=CCc1c(O)nc2ccnn2c1O
Temperature: 25 °C
Yield: 8.1 %

Procedure:
To an ethanolic solution (0.2 L) containing sodium ethoxide (7.8 g, 0.11 mol), 3-aminopyrazole (5.0 g, 0.6 mol) and diethyl allylmalonate (12 mL, 0.61 mol) were added at room temperature. The resultant mixture was heated under reflux for 24 hr. After the mixture was cooled down to room temperature, the solvent was distilled off. The residue was dissolved in water (150 mL) and the aqueous solution was washed with ethyl acetate. This aqueous layer was acidified by adding 6 mol/L hydrochloric acid, and the resultant precipitate was collected by filtration and dried under reduced pressure to obtain 6-allyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine (9.3 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15](O)[CH3:16].S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:15]([O:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)c2ccccc12
Yield: 72 %

Procedure:
4-Fluoro-1-naphthoic acid (190 mg, 1.0 mmol) was transferred to a Pyrex tube and ethanol (0.6 mL) was added followed by conc. sulphuric acid (0.1 mL). The tube was capped and the reaction tube was exposed two times to microwave irradiation (2×120° C., 5 min). The reaction mixture was transferred to a separation funnel with ethyl acetate and washed with 2 M NaOH. The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate. The organic phases were collected, dried over Na2SO4, filtered and concentrated to yield 4-fluoronaphthalene-1-carboxylic acid ethyl ester (154BG85-11, 156 mg, 72%).