Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]([F:28])([CH3:27])[CH3:26])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]([F:28])([CH3:26])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-:34])=[CH:15][C:14]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2cnc3cccnc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c[n+]([O-])c3cccnc3c21
Reaction time: 2 h
Yield: 99.9 %

Procedure:
2-[2-(Benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.89 g, 5.0 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (1.50 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 50 mL of 2% Na2CO3 solution and the layers were separated. The aqueous portion was extracted with an additional 25 mL of CH2Cl2. The combined organic layers were washed successively with 2% Na2CO3, H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1.97 g of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide as an off-white solid.
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C([O:26][C@@H:27]4[CH2:31][CH2:30][N:29](C)[CH2:28]4)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.N1CCC(O)C1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52]([O:26][CH:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[N:51]=2)=[CH:36][CH:35]=1
Reactant: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Agent: OC1CCNC1
Product: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(OC3CCNC3)n2)cc1

Procedure:
The title compound was prepared according to the experimental for compound 183 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and pyrrolidin-3-ol. M/e+ 406 for C22H21ClN5O (M+H)−; 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, J=6.9 Hz, 1H), 7.91 (dd, J=6.6, 1.8 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.62 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (m, 1H), 6.79 (td, J=6.9, 1.1 Hz, 1H), 4.59 (s, 1H), 4.35 (s, 2H), 3.54 (m, 3H), 2.09 (m, 2H), 1.55 (s, 1H) ppm
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].Cl>O1CCOCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([N:7]3[C:8](=[O:10])[CH2:9][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]3)=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 52 °C
Yield: 51.2 %

Procedure:
A solution of 1.27 g (3.7 mmol) of (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 77 ml of dioxane is treated with 8.64 ml of hydrochloric acid (37%). The mixture is heated at 52° C. for 18 h in a closed flask. For the working-up, the solution is evaporated under reduced pressure to yield the crude acid as a yellowish solid. For purification, the crude acid is triturated at −5° C. in 10 ml of ethyl acetate. The solid is collected on a filter funnel and then dried under high vacuum to yield 0.624 g (51% of theory) of (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a white solid; MS: m/e=330 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CO.CN1C(=O)N(C)CCC1.C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CN1CCNCC1
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Product: CN1CCN(Cc2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)CC1

Procedure:
136.4 mg (0.50 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d] pyrimidine and 67 μl of N-methylpiperazine in 5 ml of methanol, 15 ml of DMPU and 63 μl of acetic acid are hydrogenated at 50° C. in the presence of 30 mg of Raney nickel. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in ethyl acetate and satd NaHCO3 solution. The aqueous phase separated off is extracted twice with ethyl acetate; the organic phases are washed with satd NaHCO3 solution, 4 times with water and brine, dried over Na2SO4 and evaporated. Column chromatography (SiO2, CH2Cl2/methanol=7:2) and stirring in diethyl ether yields 4-(3-chloroanilino)-6-[(4-methylpiperazin-1-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=7.4; TLC-Rf=0.16 (CH2Cl2/methanol=7:3); FAB-MS: (M+H)+=357.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O1CCCC1>[CH:15]1([C:5]2[C:4]([C:1](=[O:3])[CH2:2][C:29](=[O:32])[CH2:30][CH3:31])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:14])[CH:6]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1cc(C(C)=O)c(C2CCC2)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)c1cc(C(=O)OC)c(C)cc1C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (compound 238.1, 500 mg, 2.03 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at 0° C. was added dropwise a solution of LiHMDS (680 mg, 4.06 mmol, 2.00 equiv) in tetrahydrofuran (5 mL). After 30 min of stirring at 0° C., a solution of propanoyl chloride (280 mg, 3.03 mmol, 1.50 equiv) in tetrahydrofuran (5 mL) was added dropwise. The resulting mixture was stirred for 3 h at 15° C., and then concentrated under reduced pressure. The residue was diluted with 40 mL of ethyl acetate, washed with of brine (3×40 mL), dried (Na2SO4), and concentrated under reduced pressure. This resulted in 500 mg (crude) of the title compound as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16]C(=O)C(C)(C)C)[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:16][C:11]1[NH:10][C:9](=[O:23])[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:30][C:29]4[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccc3ccc(CNc4ccc(F)cc4)cc3c2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.97 g, 2.5 mmole) and 4-fluoroaniline (0.56 g, 5 mmole) (Aldrich) were dissolved in dimethylformamide (15 ml). The reaction was stirred for 30 minutes at 100° C., sodium bicarbonate (0.42 g, 5 mmole) added and the suspension stirred for a further 30 minutes. The dimethylformamide was removed in vacuo, the residue washed with methylene chloride and filtered. The filtrate was evaporated, and the residue was subjected to chromatography on a Waters Prep 500 instrument (silica cartridge, elution with ethyl acetate/methylene chloride (1:19)). Fractions containing product were concentrated in vacuo, the residue dissolved in a minimum amount of ethyl acetate, and the solution diluted with hexane until precipitate formed. The solid was collected by filtration and dried under high vacuum to give the title compound as a beige solid (0.305 g, 29%). 1H NMR (DMSO-d6, 200 MHz) δ: 1.25 (s, 9H, t-butyl); 4.42 (d, J= 6 Hz, 2H, CH2); 6.33 (t,J=6 Hz, 1H, NH); 6.53-6.60 (m, 2H, Ar); 6.85 (t, J=8 Hz, 2H, Ar); 7.50 (d, J=10 Hz, 1H, Ar); 7.60 (dd, J=8, 2 Hz, 1H, Ar); 7.96 (d, J=8 Hz, 1H, Ar); 8.19 (d, J=8 Hz, 1H, Ar); 9.72 (s, 1H, Ar); 11.23 (s, 1H, NH); 12.28 (s, 1H, NH).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>O1CCCC1.O>[CH2:13]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([I:3])=[N:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Ic1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Ic1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.49 g of 95% pure sodium hydride (59.0 mmol) were added in portions to a solution of 12.0 g (49.2 mmol) of 3-iodoindazole in 100 ml of anhydrous tetrahydrofuran under argon. After the mixture had been stirred at room temperature for 45 minutes, 7.02 ml (59.0 mmol) of benzyl bromide were added dropwise. The mixture was stirred overnight at room temperature, and diethyl ether and water were then added. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. The excess benzyl bromide was separated off by bulb tube distillation. The distillation residue gave a product in the form of an oil which gradually crystallized.
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>N1C=CC=CC=1.CCOC(C)=O>[OH:22][CH2:21][CH2:20][O:23][C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Reactant: OCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
K-t-BuO (1.24 g, 11 mmol) was added to a mixture of the product obtained in Step 1 (1.98 g, 6.5 mmol) and ethylene glycol (2.54 ml, 45.5 mmol) in pyridine (15 ml). The reaction mixture was stirred at 100° C. for 6 h and at room temperature overnight. The solution was then poured into ice-water and diluted with EtOAc. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by chromatography on silica gel eluting hexane/EtOAc (1:1) to give 1.71 g (65%) of title product as an orange oil. MS m/z 331 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:37][C:38]1[CH:63]=[CH:62][C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([NH:52][C:53]3([C:59]([OH:61])=O)[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)(=[O:51])=[O:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1.Cl.[CH2:65]([O:72][NH2:73])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C)C=O>[CH2:65]([O:72][NH:73][C:59]([C:53]1([NH:52][S:49]([C:46]2[CH:45]=[CH:44][C:43]([O:42][C:41]3[CH:62]=[CH:63][C:38]([F:37])=[CH:39][CH:40]=3)=[CH:48][CH:47]=2)(=[O:50])=[O:51])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:61])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NOCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropyl ethylamine (3.89 grams, 0.030 mole) and (benzotriazol-1-yloxy)tris-(dimethylamino)-phosphonium hexafluorophosphate (13.27 grams, 0.030 mole) were added sequentially to a solution of 4-[4-(4-fluorophenoxy)-benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (11.22 grams, 0.028 mole) in anhydrous N,N-dimethylformamide (140 mL). The resulting solution was stirred at room temperature for 16 hours. Additional diisopropyl ethylamine (4.0 mL, 0.051 mole) and O-benzyl hydroxylamine hydrochloride (5.46 grams, 0.034 mole) were then added and the resulting mixture was stirred at 60° C. for 18 hours. After concentration under vacuum, the residue was treated with 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate solution, water, and brine. The solution was dried over magnesium sulfate, filtered and concentrated to one fourth original volume. Addition of an equal volume of hexane precipitated 4-[4-(4-fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid N-benzyloxyamide (11.595 g, 81.6%) as a white crystalline solid (mp 175-176° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[C:25]([O-])([O-])=[O:26].[K+].[K+].C=O.O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:25][OH:26])[C:9]2=[O:21])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-II; prepared as described in U.S. Pat. No. 5,808,095) (60.0 g, 0.167 mol) and K2CO3 (27.7 g, 0.20 mol) in THF (600 mL) was added formaldehyde (37% solution in H2O, 240 mL, 3.2 mol) followed by H2O (300 mL). The lightly turbid mixture was stirred at room temperature for 3 hours, and diluted with diethyl ether (1000 mL). The organic layer was separated. The aqueous layer was washed with ether (200 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. Evaporation of solvents provided the title compound as a white dry foam (64.5 g, 99% yield). LC/MS m/e: 390 (MH+), 96% purity. 1H NMR (CDCl3): δ 7.79 (dd, J=1.0, 3.0 Hz, 1H) 7.34 (m, 3H), 7.24 (m, 1H), 6.75 (dd, J=1.5, 6.5 Hz, 1H), 5.45 (m, 1H), 5.28 (m, 1H), 3.50 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[C:18]1(B(O)O)[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1.CO[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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.C1(C)C=CC=CC=1.C(O)CCC>[C:18]1([C:2]2[C:10]3[C:6](=[N:7][N:8]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)[N:9]=3)[C:5]([C:39]3[C:44]4[C:43]5=[C:32]6[C:31](=[CH:30][CH:29]=4)[CH:18]=[CH:19][CH:20]=[C:21]6[CH:22]=[CH:23][C:42]5=[CH:41][CH:40]=3)=[CH:4][CH:3]=2)[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: c1cc2ccc3ccc(-c4ccc(-c5ccc6ccc7cccc8ccc5c6c78)c5nn(-c6ccncc6)nc45)c4ccc(c1)c2c34
Temperature: 110 °C
Yield: 40.9 %

Procedure:
A mixture of Intermediate A (1.41 g, 4 mmol), pyrene-1-boronic acid (1.23 g, 5.0 mmol), 4-methoxyphenylboronic acid (0.76 g, 5.0 mmol), sodium carbonate (2.12 g, 20 mmol) in water (10 mL), tetrakis(triphenylphosphine)palladium (0) (0.50 g, 0.43 mmol), n-butanol (30 mL), and toluene (20 mL) was heated under argon at 110° C. for 4 hours. Thin layer chromatography (TLC) of the reaction mixture indicated no starting material left. The reaction mixture was poured into water (200 mL) and extracted with dichloromethane (3×200 mL). The extract was dried over anhydrous sodium carbonate, and the volatiles were removed under reduced pressure. The residue was chromatographed (silica gel, dichloromethane/ethyl acetate 95:5). The first fraction gave 4,7-di(pyren-1-yl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 4) (610 mg, 25%) as orange crystals. 1H NMR (400 MHz, CDCl3): δ 8.60 (m, 2H, pyridine), 8.38 (m, 4H, pyrene), 8.22-8.29 (m, 6H, pyrene), 8.20 (m, 4H, pyrene), 8.05-8.10 (m, 6H, pyrene and pyridine), 7.90 (s, 2H, benzotriazole). UV-vis spectrum (dichloromethane): λmax=381 nm. Fluorimetry (dichloromethane): λmax=524 nm.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH2:3]1.[CH3:31][C:32]([CH3:34])=O.[C:35]([BH3-])#N.[Na+].C=O>C(Cl)Cl>[CH:32]([N:1]([CH3:35])[C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH2:3]1)([CH3:34])[CH3:31]
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The entirety of benzyl (S)-1-((1S,2R,4R)-4-amino-2-(ethylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate prepared in Step 1 (1 eq) was dissolved in CH2Cl2 (20 mL). The resultant solution was charged with acetone (10 eq) and stirred at RT for 10 min before sodium cyanoborohydride (2 eq) was added in one portion. The reaction was stirred at RT for 10 h and then charged successively with formaldehyde (10 eq in 37 wt % aq soln) and sodium cyanoborohydride (2 eq). The reaction was stirred for another 9 h at RT and then quenched with sat. NaHCO3. The aqueous mixture was extracted with EtOAc (200 mL, then 2×75 mL). The organic extracts were combined, washed with brine (30 mL), dried (MgSO4), filtered, and, concentrated in vacuo. After the resulting oil stood, some paraformaldehyde-related products solidified; these were removed by dissolving the mixture in a minimal volume of EtOAc and filtering. Subsequent concentration provided benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate. MS found: (M+H)+=494.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=O)OCC)=[CH:4][CH:3]=1.[C:25]1([NH:35][NH2:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:13]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[N:35]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[N:36]=2)=[CH:4][CH:3]=1
Reactant: NNc1cccc2ccccc12
Reactant: CCOC(=NC(=O)c1cccc2ccccc12)c1ccc(Br)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccc(-c2nc(-c3cccc4ccccc34)n(-c3cccc4ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The compound obtained in step A) (1.0 g, 0.026 mol) and 1-naphthyl hydrazine (0.45 g, 0.028 mol) is dissolved in CCl4 (15 ml) and stirred for 10 hours at 25° C. under a nitrogen atmosphere. The reaction mixture is stirred for 12 hours and filtered to remove traces of insoluble particles. The CCl4 solution is then concentrated and a few drops of methanol are added to the residue, wherein a brownish solid is obtained (Yield=0.7 g (56%)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:22])[CH2:19][C:20]#[N:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:22])[CH:19]([C:10](=[O:11])[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:20]#[N:21]
Reactant: Cn1cccc1C(=O)CC#N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To the filtered solution of 4.4 g of 2,6-dichlorophenylisocyanate in 30 ml of toluene is added 2.5 g of 1-methyl-β-oxo-2-pyrrolpropionitrile and 2.1 g of triethylamine while stirring. The mixture is allowed to stand overnight at room temperature, whereupon it is filtered. The solids are washed with toluene and diethyl ether, taken up in 50 ml of methanol and the solution poured into the mixture of 6 ml of 5 N hydrochloric acid and 300 ml of water. The crystals formed are collected, washed with water, dried, triturated with ethanol, and recrystallized from methanol, to yield the 1-methyl-β-oxo-α-(2,6-dichlorophenylcarbamoyl)-2-pyrrolpropionitrile melting at 196°-199°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1C(=O)N([Br:27])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][Br:27])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Agent: c1ccc(COOCc2ccccc2)cc1
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 50.1 %

Procedure:
To a solution of 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-methylpyrazole (4.0 g, 14.9 mmol) in CCl14 (75 mL) was added NBS (5.3 g, 29.7 mmol) and benzylperoxide (0.2 g, 1.49 mmol). The reaction was brought to reflux overnight. The next day the CCl4 was evaporated and the residue was partitioned between ethyl acetate and sodium bicarbonate (sat.). The organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-bromomethylpyrazole (2.6 g, 50% yield) as pure compound: MS (CI): 348 (M+H)+ (100%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([NH:25][C:26]5[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)[CH3:34])=[CH:28][CH:27]=5)=[O:24])=[CH:18][C:17]=4[CH:41]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:42][I:43]>CN(C)C=O>[I-:43].[CH3:34][N+:33]([CH3:42])([CH2:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:19]2[CH2:20][CH2:21][CH2:22][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=4)=[CH:41][C:17]=3[CH:18]=2)=[O:24])=[CH:31][CH:30]=1)[CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: CI
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3CCC2)cc1)C1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3CCC2)cc1)C1CCOCC1
Product: [I-]

Procedure:
A solution of 2-(4-piperidinophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-6,7-dihydro-5 H-benzocycloheptene-8-carboxamide (0.2 g) and methyl iodide (0.025 ml) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (chloroform/methanol) to give crude crystals, which were recrystallized from ethanol-hexane to give dimethyl-(N-(2-(4-piperidinophenyl)-6,7-dihydro-5 H-benzocycloheptene-8-carbonyl)-4-aminobenzyl)-4-tetrahydropyranylammonium iodide (Compound 225) (0.15 g) as pale brown crystals.