Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]([C:15]3[N:16]=[C:17]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]4)[S:18][CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:16]=[C:17]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]4)[S:18][CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cnn(Cc2nc(-c3cccc(/C=C/c4ccccc4)c3)cs2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(CCc4ccccc4)c3)cs2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.8 %

Procedure:
The compound (40 mg, 0.10 mmol) obtained in Example 27 was dissolved in ethanol (2 mL), Pd—C (10% wet., ca. 1 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hr. After confirmation of the termination of the reaction by TLC, Pd—C was removed. The solvent was evaporated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to give the title compound (12 mg, 29%) as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64]C)[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C:7]([C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])=[O:64])[CH2:4][CH2:3]1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CO[C@@H]1C[C@H](C[C@@H](C)[C@@H]2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C\C=CC=C(C)C(=O)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)CC[C@H]1O
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1C[C@H](C[C@@H](C)[C@@H]2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C(C)C(=O)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)CC[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of rapamycin (5 mg, 0.055 mmol) in dichloromethane (0.1 mL) was added water (0.02 mL) followed by DDQ (2.4 mg, 0.011 mmol), and the resulting dark brown suspension was stirred at room temperature for 45 min. The mixture was filtered through celite and then partitioned between dichloromethane and brine; the organic extracts were dried over anhydrous magnesium sulfate and the resulting crude material was purified by prep TLC. The desired product was isolated as a colorless oil (1.2 mg). 1 H NMR (CDCl3, 400 MHz, 3:1 mixture of trans:cis amide rotamers; data for the trans-rotamer): -- 7.145 (d, J=10.4 Hz, 1H), 6.635 (dd, J=14.9, 10.6 Hz, 1H), 6.57-6.48 (m, 2H), 6.224 (dd, J=15.1, 10.6 Hz, 1H), 5.662 (dd, J=15.1, 8.6 Hz, 1H), 5.447 (d, J=11.2 Hz, 1H), 4.305 (br d, J=5.4 Hz, 1H), 3.983 (d, J=5.4 Hz, 1H), 3.385 (s, 3H), 3.346 (s, 3H),; MS (ESl+/NH4OAc) m/z 920 (M+Na+), 915 (M+NH4+), 898, 880; UV (MeOH) max 318 nm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:40][C:41]([O-:44])([CH3:43])[CH3:42].[K+]>C(OC(C)(C)C)(=O)C.C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:44][C:41]([CH3:43])([CH3:42])[CH3:40])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Agent: [K+]
Solvent: CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1

Procedure:
To a stirring solution of methyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (38A) (14 g, 24.1 mmol) in t-butyl acetate (200 mL) was added 2 mL of t-BuOK in THF (2M) under vacuum. 3×2 mL t-BuOK were added to the stirring solution under vacuum to drive the reaction to complete. The mixture was then acidified to neutrality and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 3.5 g of the desired product 38B: 1H NMR (300 MHz, CDCl3) δ ppm 8.29 (1H, m), 7.71 (1H, d), 7.62 (2H, m), 7.49 (2H, t), 7.34 (3H, m), 6.02 (2H, s), 5.20 (2H, s), 4.02 (2H, m), 3.71 (3H, m), 3.08 (2H, m), 1.59 (9H, t), 0.97 (2H, m), −0.09 (9H, m). MS (ESI(+)): m/z 623.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1([C:33](=[O:35])[CH3:34])C=CC=N1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH:14]([C:33](=[O:35])[CH3:34])[C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Reactant: CC(=O)n1cccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1C(=O)CC2COCC1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (482 mg, 2 mmol) in THF (5 mL) was added LiHMDS (3 mL, 3 mmol) slowly at −78° C. After 15 mins, 1-pyrazol-1-yl-ethanone (264 mg, 2.4 mmol) was added, and the resulting mixture was stirred at −78° C. for 1 hour and then at room temperature for 1 hour. The reaction mixture was quenched with water, and then extracted with EA (20 mL×2). The organic layer was concentrated in vacuo. The residue was purified by flash chromatography (EA in PE 0%˜70%) to afford 6-acetyl-7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (compound AL) as light yellow oil (56 mg, 20%). LC/MS: calc'd 284 (MH+), exp 284 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccoc1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.061 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].Br[C:36]1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3(C)CC3CO2)=CC=1)(=O)=O.C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3([CH3:36])[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:34]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21C
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 40, starting from methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 49) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>O1CCCC1>[CH2:24]([NH:28][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CN
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CNC(=O)c1ccc(N2CCN(C)CC2)c(S(=O)(=O)N(C)C)c1

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were introduced portionwise, while stirring, into a solution of 30 g of isobutylamine in 0.4 l of tetrahydrofurane. The mixture, whose temperature rose to about 50° C., was subsequently heated for another 10 minutes under reflux and was then concentrated to half its volume.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:16]1([O:15][C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=[C:6]3[C:5]=2[NH:4][C:1](=[O:3])[CH:2]=[C:7]3[OH:8])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(O)cc(=O)[nH]c2c1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (6.42 g, 20.9 mmol) and anhydrous THF (60 mL) was added via syringe pump (1 mL/min) to a solution of KHMDS (150 mL, 0.5M PhMe, 75 mmol) at −78° C. under N2. The reaction was allowed to slowly warm to rt as the bath expired overnight. After 17 h, the reaction was poured into ice/water (250 mL), let stir for 10 min, and the layers were separated. The aqueous was washed with ether (150 mL), acidified with conc. HCl (7 mL), and filtered to give 8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one: MS (ESI): 276.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:18][CH:19]=1
Reactant: c1ccc(COc2ccccc2-c2coc(-c3ccccc3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccccc1-c1coc(-c2ccccc2)n1

Procedure:
0.7 g of 4-(2-benzyloxyphenyl)-2-phenyl-1,3-oxazole according to step (d) are hydrogenated in 30 ml of tetrahydrofuran in the presence of 0.1 g of Pd/C catalyst at 20-60° C. (5 bar). After the catalyst has been separated off the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (dioxane:hexane 1:5). Yield: 0.5 g (99%);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C([Cl:15])=O.[C:18]1([CH:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:15].[ClH:15].[ClH:15].[C:37]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:29][CH2:30]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)C=Cc1cccnc1
Product: Cl
Product: O=C(C=Cc1cccnc1)NCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Batch size: 6.0 g (40 mmol) 3-(3-pyridyl)-acrylic acid, 9.4 ml (110 mmol) oxalyl chloride and 12.4 g (36.5 mmol) 2-[2-(4-diphenylmethyl-piperazin-1-yl)-ethoxy]-ethylamine. The crude product is chromatographically pre-purified over silica gel with CHCl3/CH3OH (98/2 to 95/5). After removal of the solvent, the residue is dissolved in isopropanol and mixed with isopropanolic HCl solution. The mixture is rotated in and the HCl salt is cyrstallized from 50 ml methanol/6 drops diisopropyl ether: Colorless crystals of MP. 157-159° C.; yield 0.6 g (3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([CH3:16])[O:17][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](Cc1ccc(-c2ccc(Br)cc2)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
(2S)-1-(4′-Bromobiphenyl-4-yl)propan-2-ol (0.23 g, 0.79 mmol) and imidazole (0.11 g, 1.6 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.24 g, 1.6 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Diethyl ether was added to the reaction solution, followed by sequential washing with water and hydrochloric acid (1 M). After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.80 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.25 g, 0.62 mmol) as a white solid (yield 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]Br.[N+]([O-])(O)=O>S(=O)(=O)(O)O.C(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 30 %

Procedure:
To 1-fluoro-2,4-dinitrobenzene (13.0 g, 69.85 mmol, 1 equiv) dissolved in sulfuric acid (190 mL) at room temperature was added bromine (4.30 mL, 83.82 mmol, 1.2 equiv) dropwise followed by the slow dropwise addition of nitric acid (70%, d=1.500; 3.25 mL, 76.84 mmol, 1.1 equiv). The reaction vessel was fitted with a refluxing condenser, and the reaction mixture was heated at 80° C. for 10 hours. LCMS indicated a reactant:product ratio of 1:1. After allowing to cool to room temperature, the mixture was poured into ice and diluted with DCM. The aqueous and organic layers were partitioned, and the aqueous extracted with DCM (2×300 mL). The combined organic extracts were washed with saturated Na2S2O3 (2×200 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified using a pad of silica gel and eluted with EtOAc/hexanes (25-35% EtOAc in increments of 5% EtOAc) to give the product 1-bromo-2-fluoro-3,5-dinitrobenzene (5.55 g, 30%) as a light-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[CH:21]=1>>[F:28][CH:27]([F:29])[O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: FC(F)Oc1cccc(CBr)c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(OC(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-3-(difluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.05 min.; [M+H]+: 392.75 g/mol.
Reaction SMILES: [CH:1]([N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]=[C:25]1[O:29][C:27](=[O:28])[CH2:26]1>>[C:27]([O:23][CH2:22][CH2:21][N:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1)(=[O:28])[CH2:26][C:25]([CH3:24])=[O:29]
Reactant: C=C1CC(=O)O1
Reactant: OCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Product: CC(=O)CC(=O)OCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 81.8 %

Procedure:
4-Benzhydrylhomopiperazine-1-ethanol (2.6 g) was reacted with diketene in the same manner as Reference Example 1-(2) to give 2-(4-benzhydrylhomopiperazin-1-yl)ethyl acetoacetate as an oil (2.7 g, 81.8%). IR(Neat): 1735, 1715 cm-1. NMR(CDCl3)δ: 1.6-1.9(2H, m), 2.26(3H, s), 2.5-2.9(10H, m), 3.40(2H, s), 4.20(2H, t, J=6), 4.57(1H, s), 7.1-7.5(10H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][NH2:22]>>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:22][CH2:21][CH2:20][CH2:19][NH2:23])=[N:13][CH:12]=1
Reactant: NCCCN
Reactant: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Product: NCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 52 %

Procedure:
N-(2-amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 6 ml of 1,3-propanediamine were heated to 80° C. for 3 hours. The excess 1,3-propanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (158 mg, 52% yield) as a brown solid. LC-MS (m/z) 304 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH:13]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[N:22]=[CH:21][N:20]=2)[CH:13]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
235 mg (1H-Benzoimidazol-2-yl)-[3-(6-chloro-pyrimidin-4-ylamino)-benzyl]-amine (prepared in Example 63) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (158 mg, 55% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+:10](=[CH2:12])=[N-:11]>C(Cl)Cl>[CH3:12][N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1.[CH3:12][N:10]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[N:11]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: Cn1nc2ccccc2n1
Product: Cn1nnc2ccccc21
Yield: 15 %
Yield: 36 %

Procedure:
Benzotriazole free base (from above; 155 mg, 0.36 mmol) in CH2Cl2 (2.5 mL) was treated while stirring with etheral diazomethane (2-10 eq.). After about 2 h (10-20° C.) the solvent and excess diazomethane were removed in vacuo and the residue was chromatographed on silica (Chromatotron; 1% conc. NH4OH; 1.5% MeOH, 97.5% (CHCl3)) to afford (36%; 57 mg) 2-N-methyl benzotriazole derivative (Example 169) and (15%; 24 mg) 3-N-methyl benzotriazole (Example 168).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[CH:22]1(C(Cl)=O)C[CH2:23]1>>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH:15]3[CH2:23][CH2:22]3)=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Reactant: O=C(Cl)C1CC1
Product: CC1(C)C(=O)NC(=O)c2c1ccc(NC(=O)C1CC1)c2[N+](=O)[O-]

Procedure:
Prepared analogous to Example 1b from 5.8 gm of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione and 6.3 gm of cyclopropane carboxylic acid chloride (heating time: 30 hours).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([Cl:12])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([Cl:11])[N:8]=1
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc(Cl)nc(Cl)c1
Reaction time: 2 h

Procedure:
The above ester was dissolved in dichloromethane (60 ml) and cooled to -20° under nitrogen. Diisobutylaluminium hydride (38 ml) was added dropwise. After 2 hours at 0°, dilute hydrochloric acid was carefully added and the mixture worked up in the usual manner to give 2,6-dichloro-4-hydroxymethylpyridine. NMR 1H: 7.64(2H,s), 4.98(2H,s).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:4]=[CH:3]1.[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:11]([NH:19][C:20](=[O:21])[O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: OCCCc1c[nH]cn1
Agent: Cl
Solvent: CC#N
Product: O=C(NC(=O)c1ccccc1)OCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propanol hydrochloride in 10 ml of acetonitrile are maintained at reflux for 2 h with 5 mmol of benzoyl isocyanate. After evaporation under vacuum, the title compound is stirred in water and filtered.