Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>ClCCCl.CC(C)=O>[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([C:29]4[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(C)=O
Solvent: CCS
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN3CCCCC3)cc2)n1
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
The AlCl3 (1.2 g, 9 mmol) was stirred in 30 mL of DCE at 0° C., ethanethiol (1 mL, 14 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-methylpyridine (0.5 g, 1.2 mmol) in 20 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 25 mL THF at 0° C., followed by 25 mL 1N HCl and worked up. The free base gave a very clean NMR, but the elemental analysis was low for carbon and hydrogen, so it was taken up in 50 mL hot acetone, citric acid H2O (0.2 g, 0.9 mmol) was added, then heated 10 min, concentrated, triturated with Et2O, filtered, and dried in vacuo to give 0.38 g (72 % yield) of product as the citrate salt: mp 90°-100° C.; 1H NMR (CDCl3) (free base) d 1.34-1.66 (comp, 6H, piperidine), 2.42-2.65 (comp, 7H, pyr-CH3 and piperidine), 2.70-2.79 (m, 2H, CH2 N), 3.95-4.10 (m, 2H, OCH2), 6.50-6.59 (m, 4H, ArH), 6.76-6.85 (d, 2H, J=8 Hz, ArH), 6.98-7.05 (d, 1H, J=8 Hz, ArH), 7.10-7.21 (m, 2H, ArH), 7.41-7.50 (d, 1H, J=8 Hz, ArH); MS(FAB) 398 [M+i]+Anal. Calcd for C25H28N2O2 ·C6H8O7 : C, 64.13; H, 6.25; N, 4.82. Found: C, 63.99; H, 6.36; N, 4.58.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:12]=1[CH2:13][N:14]1[C:19]([CH3:20])=[C:18]([C:21](OCC)=[O:22])[C:17](=[O:26])[C:16]([Br:27])=[C:15]1[CH3:28].CO>C1COCC1.C(Cl)Cl>[F:10][C:11]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:12]=1[CH2:13][N:14]1[C:19]([CH3:20])=[C:18]([CH:21]=[O:22])[C:17](=[O:26])[C:16]([Br:27])=[C:15]1[CH3:28]
Reactant: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)c(Br)c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Br)c(=O)c(C=O)c(C)n1Cc1c(F)cccc1F
Reaction time: 1 h
Yield: 64.3 %

Procedure:
DIBAL (5.3 mmol, 5.3 mL of a 1.0 M solution in hexanes) was added dropwise via syringe to a stirred solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone (1.40 g, 3.5 mmol) in THF/DCM (60 mL/20 mL), at −78° C. under N2. A suspension was formed at the end of the addition. After 1 hour, an additional aliquot of DIBAL (3.0 mmol, 3.0 mL of a 1.0 M solution in hexanes) was added. The reaction was deemed complete after 1 hour at −78° C. MeOH (5 mL) was carefully added to quench any unreacted DIBAL and the mixture was partitioned between EtOAc and 1 M HCl. The organic layer was separated and washed with brine, dried over anhydrous MgSO4 and filtered. Upon removal of the solvents in vacuum, the crude solid residue was triturated with Et2O. The product was obtained as a beige solid (0.80 g, 2.25 mmol, 64%). 1H NMR (CDCl3, 300 MHz): 10.55 (s, 1H), 7.40-7.33 (m, 1H), 7.00-6.93 (m, 2H), 5.38 (s, 2H), 2.78 (s, 3H), 2.69 (s, 3H); LRMS m/z 356.0 (M+−1), 358.0 (M++1).
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[C:5](/[C:14](/I)=[CH:15]/[C:16](=O)[C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2>C1COCC1.[Cu]I>[F:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[C:16]([C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[CH:15][C:14]=2[CH3:1]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: [Li]C
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of copper(I) iodide (Aldrich, 190 mg, 1.0 mmol) in dry THF (2 mL) was added methyllithium (Aldrich, 1.4 M solution in ether, 1.42 mL, 2.0 mmol), under argon, at 0° C. and the reaction mixture was stirred for 15 minutes. To the colorless solution obtained was added dropwise a solution of (Z)-5-fluoro-4-[l -iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (39.6 mg, 0.1 mmol) in THF (2 mL). After stirring at 0° C. for another 45 minutes, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product (28.5 mg) which was further purified by preparative TLC (silica gel, 20% ethyl acetate in hexanes) to afford 6-fluoro-5-methyl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 12.6 mg, 47.4%).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>Cl>[Cl:26][C:21]1[CH:20]=[C:19]([S:18][C:12]2[N:11]([CH2:27][C:28]([OH:31])([CH3:29])[CH3:30])[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(CC(C)(C)O)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CO)n(CC(C)(C)O)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 52.8 %

Procedure:
In 2 ml of concentrated hydrochloric acid was dissolved 350 mg (0.73 mmol) of the benzyl compound (140b) and the solution was stirred under heating at 110° C. for 3 hours. To this reaction mixture was added a saturated aqueous solution of NaHCO3 and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was then distilled off and the residue was purified by silica gel column chromatography (ethyl acetate) to provide 150 mg (yield 53%) of Compound I-153 as crystals. mp 181-182° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].N.Cl.[CH3:12][N:13](C)C(=O)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[C:12]([C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9])#[N:13]
Reactant: CC(=O)N(C)C
Reactant: Oc1cnc(Cl)c(F)c1
Agent: [Fe+2]
Agent: Cl
Agent: N
Product: N#Cc1ncc(O)cc1F
Temperature: 140 °C
Reaction time: 5 h

Procedure:
A mixture of 2.94 g (20 mmol) of 6-chloro-5-fluoro-3-pyridinol, 360 mg (0.4 mmol) of tris(benzylideneacetone)dipalladium(0), 440 mg (0.8 mmol) 1,1′-bis(diphenylphosphino)ferrocene, 156 mg (2.4 mmol) of zinc powder and 1.4 g (12 mmol) of zinc cyanide in 40 ml of N,N-dimethylacetamide is prepared and the reaction mixture is then stirred at 140° C. for 5 hours. It is left to stand overnight at room temperature. 40 ml of 2 N aqueous ammonia are added slowly and the pH is then adjusted to about 4.5 with 5 N hydrochloric acid. The mixture is extracted 3 times with 100 ml of ethyl acetate and the organic phase obtained is dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a methylcyclohexane/ethyl acetate mixture (in a gradient of 8/2 to 5/5; v/v) as the eluent to give 1.8 g of the expected compound in the form of an orange oil (yield=67%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.[Na]>ClC(Cl)C>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: COc1ccc(CN)cc1
Agent: [Na]
Solvent: CC(Cl)Cl
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNCc2ccc(OC)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 79 mg (0.184 mmol) of (SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (racemate of Example 19, Step A) and 4-methoxybenzylamine (35.7 μL, 0.275 mmol) in 1.8 mL of dichloroethane was added sodium triacetoxyborohydrate (117 mg, 0.551 mmol)at 0° C. in several portions. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM) and the combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (0% to 3% MeOH/DCM with 1% aq. NH4OH) provided the title compound as a yellow film.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:23]([CH2:25][CH3:26])[CH3:24])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](O)=[O:12])[C:6]1=[O:22])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][O:61][C:62]1[CH:91]=[CH:90][C:65]([CH2:66][N:67]2[C@@H:76]([C@@H:77]([OH:89])[C@@H:78]([NH2:88])[CH2:79][C:80]3[CH:85]=[C:84]([F:86])[CH:83]=[C:82]([F:87])[CH:81]=3)[CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68]2)=[CH:64][CH:63]=1>ClCCl>[CH3:60][O:61][C:62]1[CH:63]=[CH:64][C:65]([CH2:66][N:67]2[C@@H:76]([C@@H:77]([OH:89])[C@@H:78]([NH:88][C:11](=[O:12])[C@@H:10]([N:7]3[CH2:8][CH2:9][C@:5]([NH:4][C:1](=[O:3])[CH3:2])([C@@H:23]([CH2:25][CH3:26])[CH3:24])[C:6]3=[O:22])[CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:79][C:80]3[CH:85]=[C:84]([F:86])[CH:83]=[C:82]([F:87])[CH:81]=3)[CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68]2)=[CH:90][CH:91]=1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Reactant: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2Cc3ccccc3CN2Cc2ccc(OC)cc2)C1=O
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation B, 25 mg, 0.069 mmol) in dichloromethane (1 mL) was added Hunig's base (27 mg, 0.21 mmol) to make a clear solution and HATU (34 mg, 0.090 mmol) was then added. After stirring for 1 h, to the reaction mixture was added (1S,2S)-1-((R)-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation A, 33.5 mg, 0.076 mmol) and the reaction mixture was stirred at rt overnight. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 50 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ 0.68 (3H, d, J=5 Hz), 0.94-1.08 (4H, m), 1.61-1.66 (2H, m), 1.94 (3H, s), 2.01-2.20 (4H, m), 2.46 (1H, m), 2.60-2.69 (2H, m), 2.76-2.94 (2H, m), 3.00 (1H, m), 3.07 (1H, dd, J=5, 15 Hz), 3.22 (1H, m), 3.46 (1H, dt, J=5, 10 Hz), 3.62-3.69 (3H, m), 3.74 (3H, s), 3.82 (1H, m), 4.02 (1H, d, J=15 Hz), 4.14 (1H, dd, J=5, 10 Hz), 4.72 (1H, m), 6.70 (1H, m), 6.81 (2H, d, J=10 Hz), 6.87 (2H, d, J=10 Hz), 6.96 (1H, d, J=5 Hz), 7.08-7.13 (6H, m), 7.17-7.20 (2H, m), 7.24 (2H, d, J=5 Hz). MS (ESI)(M+H)+ 781.39.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:28][CH2:27][CH2:25][OH:26])=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(NCCO)nc2)o1
Yield: 59 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) was converted using ethanolamine instead of morpholine to the title compound (126 mg, 59%) which was obtained as an off-white solid. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31]OS(C)(=O)=O)[C:6]=2[CH:37]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:42]3[C:38](=[O:48])[C:39]4=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]4[C:41]3=[O:43])[C:6]=2[CH:37]=1
Reactant: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCC(CCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 103.1 %

Procedure:
To a solution of 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in dimethylformamide (30 ml) is added potassium phthalimide (0.58 g), and the mixture is stirred at 110° C. for 3 hours. The mixture is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) as colorless amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([CH2:19][N:12]2[C:13](=[O:14])[CH:9]([CH2:8][C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][C:11]2=[O:15])[CH:21]=1
Reactant: CNC(=O)c1cccc(CCl)c1
Reactant: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(CN2C(=O)NC(Cc3ccc([N+](=O)[O-])cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.2 %

Procedure:
The product from step (a) (4.0 g), the product from step (b) (3.3 g) and anhy. K2CO3 (2.55 g) were taken up in DMF (25 ml) and stirred at room temperature for 60 hours. The mixture was poured with vigorous stirring into ice-water (175 ml) to give an oily precipitate. Ethyl acetate was added and stirring continued for 1 hour to solidify the precipitate. The latter was filtered off, washed with water, ethyl acetate and ether, and dried to give the desired product as a peach-coloured solid (4.5 g).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C.B([O-])([O-])OC.[NH4+].[Cl-]>C1COCC1>[N:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:2]([B:21]([OH:24])[OH:22])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: COB(OC)OC
Agent: COB([O-])[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCN2CCCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-[2-(4-bromophenoxy)ethyl]-pyrrolidine (2.70 g, 10 mmol) in THF (40 mL) was added n-butyl lithium (6.9 mL 1.6 M in hexanes, 11 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 15 min and then at 0° C. for 15 min. Trimethyl borate (2.5 mL, 22 mmol) was then added to the reaction mixture at 0° C. The mixture was gradually warmed to room temperature overnight. Methyl borate in the reaction mixture was hydrolyzed by reacting with saturated NH4Cl aqueous solution (100 mL) at room temperature for 30 min. The upper organic layer was collected. The aqueous layer was extracted with CHCl3 (2×100 mL). The organic layers were combined, washed with brine (2×100 mL) and dried with MgSO4. The solvent was evaporated, resulting in a dense oil which was purified by column chromatograph (10% MeOH/CHCl3 and 1% Et3N) to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][OH:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][OH:25])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C(CO)CCl
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6][N:5]1[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19]
Reactant: [H][H]
Reactant: COCC1CN(Cc2ccccc2)CCN1C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COCC1CNCCN1C(=O)C(F)(F)F
Yield: 92 %

Procedure:
A mixture of 9.2 parts of 2-(methoxymethyl)-4-(phenylmethyl)-1-(trifluoroacetyl)piperazine and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 6.05 parts (92%) of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine as a residue (intermediate 59).
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.Br[C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[C:30]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:29]=2)[CH:24]=[C:25](Br)[CH:26]=1.[OH-].[Na+]>O1CCCC1.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>[C:1]1([C:21]2[CH:22]=[C:23]([C:28]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[C:30]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:29]=3)[CH:24]=[C:25]([C:8]3[C:7]4[C:16]5=[C:15]6[C:4](=[CH:5][CH:6]=4)[CH:3]=[CH:2][CH:1]=[C:14]6[CH:13]=[CH:12][C:11]5=[CH:10][CH:9]=3)[CH:26]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccc5ccc6cccc7ccc4c5c67)cc(-c4ccc5ccc6cccc7ccc4c5c67)c3)n2)cc1
Yield: 81 %

Procedure:
In a stream of argon, 1.26 g (5.13 mmol) of 1-pyreneboronic acid, 1.00 g (2.14 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 60.1 mg (0.081 mmol) of dichlorobis(triphenylphosphine)palladium were suspended in 75 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 4.01 mL (16.1 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 3 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene to give 1.23 g of the target 2-[3,5-di(1-pyrenyl)-phenyl]-4,6-diphenyl-1,3,5-triazine as grayish white solid (yield: 81%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.N#N.[H-].[Na+].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Reaction time: 0.67 h
Yield: 55.6 %

Procedure:
A 200-mL round-bottom flask was charged with 6-bromo-1H-pyrrolo[2,3-b]pyridine (2.961 g, 15.03 mmol) and THF (30 ml) to give a yellow solution. The flask was fitted with an N2 sweep, then sodium hydride (60% disperion in mineral oil) (0.721 g, 18.03 mmol) was added over 2 min, and the resulting mixture was stirred for 40 min. Triisopropylsilyl chloride (4.02 ml, 18.79 mmol) was added in one portion, and the mixture was stirred for 30 min before being concentrated in vacuo. The residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 10% EtOAc/Heptane) to give 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.952 g, 8.35 mmol, 55.6% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ=7.72 (d, J=8.1 Hz, 1 H), 7.26 (d, J=3.5 Hz, 1 H), 7.18 (d, J=8.1 Hz, 1 H), 6.53 (d, J=3.5 Hz, 1 H), 1.81 (spt, J=7.5 Hz, 3 H), 1.13 (d, J=7.5 Hz, 18 H).
Reaction SMILES: C[O-].[Na+].C(O[O:8][CH:9](OC)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[N:11]=1)(=O)C.Cl>CO>[C:17]([NH:16][C:12]1[N:11]=[C:10]([CH:9]=[O:8])[CH:15]=[CH:14][N:13]=1)(=[O:19])[CH3:18]
Reactant: COC(OOC(C)=O)c1ccnc(NC(C)=O)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1nccc(C=O)n1
Reaction time: 3 h

Procedure:
Sodium methoxide (0.056 g, 1.0 mmol) was added to a solution of 2-acetamidopyrimidine-4-carboxaldehyde monomethyl monoacetoxy acetal (5.0 g, 21 mmol) in MeOH (25 mL) at ambient temperature. After stirring at this temperature for 3 h, the reaction mixture was neutralized by addition of 3N HCl. The resulting solution was concentrated and the residue was treated with CH2Cl2. Remaining solids were removed by filtration and the solvent was evaporated to afford the title compound as a yellow solid; yield 3.2 g (92%).