Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1.Cl>C1COCC1.CCOC(C)=O.O>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:20]2[C:25]([C:26]3[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)[CH2:43][C:44]4[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=4)[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(Cl)nc3)n2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
1.0 M LHMDS in THF (600 μL, 0.600 mmol) was added to a solution of 5-amino-2-chloropyridine (49 mg, 0.381 mmol) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (80 mg, 0.180 mmol) in THF (4 mL) under nitrogen at rt. A dark orange mixture formed. After 1.5 h, the mixture was heated to about 50° C. After overnight, more 5-amino-2-chloropyridine (49 mg, 0.381 mmol) and LHMDS (600 μL, 0.600 mmol) were added. The reaction mixture was heated for another 2 h and cooled to rt. The mixture was neutralized with HCl (5 N, 0.3 mL) and diluted with EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with DCM twice and the combined organic was dried over Na2SO4 and concentrated. The residue was purified on silica (10-80% EtOAc in hexane) to give a yellow oil (70 mg). LCMS (ES, pos.): calcd for C30H28FN7O2: 553.2. found: 554.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 12.19 (s, 1H); 8.84 (dd, J=7.83, 1.76 Hz, 1H); 8.47 (d, J=2.74 Hz, 1H); 8.33 (dd, J=4.70, 1.76 Hz, 1H); 8.26 (dd, J=8.71, 2.84 Hz, 1H); 7.16-7.24 (m, 5H); 6.80-6.91 (m, 5H); 4.84 (s, 4H); 3.80 (d, J=5.87 Hz, 6H); 2.59 (s, 3H).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C[N+]1([O-])CCOCC1.C(OCC)(=O)C>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:14]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[CH2:12][C:11](=[O:13])[CH2:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 24 h
Yield: 36.9 %

Procedure:
1-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 Å molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0° C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5% triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave 1-(diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37% yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, 1H), 4.01 (s, 4H); MS (EI) for C16H15NO: 238 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.FC1C=CC(C2C=C3C(=CC=2)N=CN=C3O)=CC=1>>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(OCC2CC2)c2cc(Br)ccc2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Product: Nc1nc(OCC2CC2)c2cc(-c3ccc(F)cc3)ccc2n1
Yield: 97 %

Procedure:
This compound, prepared from 2-amino-6-bromo-4-(cyclopropylmethoxy)-quinazoline and 4-fluorophenylboronic acid in 97% yield, using the procedure described for the synthesis of 6-(4-fluorophenyl)-4-hydroxy-quinazoline, was characterized by its mass spectrum as follows: MS (m/z): 310 ([M+H]+, 100).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([NH2:10])=[N:8][CH:9]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:3][C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([N:10]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:8][CH:9]=1
Reactant: Nc1ncc(Br)nc1-c1ccccc1Cl
Reactant: ClCCCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc(Br)cnc1N1CCCC1
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Sodium hydride (0.55 g) is added at room temperature to a solution of 5-bromo-3-(2-chloro-phenyl)-pyrazin-2-ylamine (0.23 g) in DMF (10 mL). Subsequently 1-bromo-4-chlorobutane (0.21 g) is added and the mixture is stirred for 3 h. Citric acid (10%, 20 mL) is added and the mixture is extracted with ethyl acetate (3×50 mL). Organic phases were pooled, washed with sodium bicarbonate and brine, dried with Na2SO4 and the solvent was evaporated. The residue was purified by chromatography on silica gel with heptane/ethyl acetate 2:1 to yield 0.27 g of the title compound as a yellow oil, MS (ISP) 338.1, 340.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.O.O.[Sn](Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: O=[N+]([O-])c1cc(Cl)cc(F)c1F
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-chloro-1,2-difluoro-3-nitrobenzene (1.62 g, 8.4 mmol) in acetic acid (30 mL) was added tin(II) dichloride dihydrate (11.4 g, 50.4 mmol). The mixture was stirred for 1.25 h at rt, and then the acetic acid was removed in vacuo. The residue was transferred to a 500-mL Erlenmeyer flask in a minimal amount of ethyl acetate. The resulting suspension was then diluted with approximately 200 mL of ether, and then the flask was placed into an ice bath. To the vigorously stirring mixture was added 50% aqueous sodium hydroxide (10 mL), and a pale yellow solid formed. Celite and sodium sulfate were added to adsorb and dry the precipitate. All the solids were removed by filtration, rinsed with ethyl acetate, and discarded. The filtrate was concentrated, and the residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate). The desired 5-chloro-2,3-difluoroaniline was isolated as an orange oil (913 mg, 5.6 mmol, 66% yield). 1H NMR (400 MHz, CDCl3): 6.57-6.52 (m, 2H), 3.91 (br s, 2H); GCMS for C6H4ClF2N: 163 (M+).
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1ccc(CCCNCn2nnc3ccccc32)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.6 %

Procedure:
To a mixture of 3.44 g (0.056 g-atom) of zinc powder (−325 mesh) and 60 mL of anhydrous tetrahydrofuran was added 5.0 mL (0.039 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 5.1 mL (0.039 mole) of ethyl bromodifluoroacetate in 5 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 7 g (0.026 mole) of benzotriazol-1-ylmethyl-(3-phenyl-propyl)-amine in 30 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 1.1 g of 2,2-difluoro-3-(3-phenyl-propylamino)-propionic acid ethyl ester as a oil.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][CH2:7][CH2:8][C@@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[S:21][C:20]=3[NH:19][C:18]3[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:17]=3[N:16]=2)[CH2:10]1>C(O)C>[ClH:4].[ClH:4].[CH3:5][O:6][CH2:7][CH2:8][C@@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[S:21][C:20]=3[NH:19][C:18]3[CH:29]=[CH:30][C:31]([C:33]([F:35])([F:36])[F:34])=[CH:32][C:17]=3[N:16]=2)[CH2:10]1
Reactant: CC(=O)Cl
Agent: COCC[C@H]1CN(C2=Nc3cc(C(F)(F)F)ccc3Nc3sc4ccccc4c32)CCN1
Solvent: CCO
Product: Cl

Procedure:
Add a solution of acetyl chloride (0.078 mL, 1.1 mmol) in absolute ethanol to a solution of (S)-5-[3-(2-methoxy-ethyl)-piperazin-1-yl]-8-trifluoromethyl-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.10 g, 0.22 mmol) in absolute ethanol and isolate the precipitated solid by suction filtration. Dry the solid under reduced pressure to give the title compound (0.095 g). Exact mass spectrum (ES+, m/e, C23H23F3N4OS.2HCl): calc. 461.1623 (M+1-2HCl), found 461.1613.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2nc(N)sc2c1
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: CN(C)C=O
Product: COc1ccc2nc(NC(=O)c3nnn(Cc4ccc(Cl)c(Cl)c4)c3C)sc2c1
Temperature: 45 °C
Reaction time: 72 h
Yield: 9.6 %

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) (0.1 g, 0.35 mmol), 2-amino-6-methoxybenzothiazole (0.062 g, 0.35 mmol), HATU (0.082 g, 0.45 mmol) and DIPEA (85 μL, 0.45 mmol) in DMF (5 mL) was stirred at 45° C. for 3 days. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM/MeOH (99/1) to give after trituration in diisopropyl ether, the title compound as a white solid (15 mg, 10%). HRMS calculated for C19H15Cl2N5O2S (M+H)+ 448.0402, found: 448.0403, Rt: 3.31 min. MP: 225° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.Cl[CH2:34][C:35]1[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=1.O>CN(C)C=O>[CH3:41][C:36]1[C:35]([CH2:34][O:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[C:9]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH:8]=[CH:7]3)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: Cc1ncccc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4C)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
Sodium hydride (60%, oily, 80.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (799 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (283 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(2-methyl-3-pyridylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (959 mg, yield: 95%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([Li])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C#CCCCC.C([Li])CCC.[C:19]1([B:25](OC(C)C)[O:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C=C(C)C>C(OCC)C>[C:6]1([B:25]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:26][CH:27]([CH3:28])[CH3:29])[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CC(C)OB(OC(C)C)c1ccccc1
Reactant: [Li]C#CCCCC
Agent: C#CCCCC
Agent: C=C(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCCC#CB(OC(C)C)c1ccccc1

Procedure:
The title compound was prepared following the method of Example 14, using 1-hexynyllithium (64 mmol) prepared from 1-hexyne and n-butyl lithium in ethyl ether (64 mL) and phenyldiisopropoxyborane (11.96 g, 58 mmol) dissolved in ethyl ether (60 mL) and quenched with hydrogen chloride in ethyl ether (18.7 mL, 64 mmol). Yield. 11.2 g (86%), bp 102°-105° C. (0.4 mm Hg); n20D 1.5008; proton NMR (CDCl3)δ7.90 (m, 2H), 7.31 (m, 3H), 4.87 (septet, J=18 Hz, 1H), 2.33 (triplet, J=18 Hz, 2H), 1.23 (d, J=18 Hz, 6H), 0.90 (triplet, 3H); boro NMR (CDCl3)δ+36.5 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 229 (M+H, 10%); IR (thin film) 2195, 1324 cm-1. Anal. Calcd. for C15H 21 BO: C, 78.97; H, 9.28. Found: C, 78.18; H, 9.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Clc1ccccc1I
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccccc4Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-2-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[CH3:19][N:20]([CH3:48])[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:40]4=[CH:41][C:42]5[O:46][CH2:45][O:44][C:43]=5[CH:47]=[C:39]4[O:38][CH2:37]2)[C:30](=[O:36])[NH:31]3)=[CH:23][CH:22]=1>>[CH3:19][N:20]([CH3:48])[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:40]4=[CH:41][C:42]5[O:46][CH2:45][O:44][C:43]=5[CH:47]=[C:39]4[O:38][CH2:37]2)[C:30](=[O:36])[N:31]3[CH2:2][C:3]2[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCO5)C(=O)N3)cn1
Reactant: CC(C)c1nc(CCl)cs1
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(-c4ccc(N(C)C)nc4)cccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 164-165° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.58 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.32 (dd, J=7.8, 7.8 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.82-6.76 (m, 2H), 6.42-6.37 (m, 3H), 5.96 (d, J=19.0 Hz, 2H), 5.11 (d, J=16.0 Hz, 1H), 4.89 (d, J=16.0 Hz, 1H), 4.57 (d, J=9.4 Hz, 1H), 4.42 (d, J=9.4 Hz, 1H), 3.29-3.20 (m, 1H), 2.99 (s, 6H), 1.31 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.9, 157.9, 155.4, 149.9, 148.3, 146.6, 142.6, 141.5, 136.8 (2C), 129.2, 128.8, 125.2, 121.7, 121.1, 115.3, 108.6, 104.3, 102.6, 101.3, 93.2, 77.2, 57.8, 37.6, 32.4, 22.8, 22.7; MS (ES+) m/z 541.3 (M+1).
Reaction SMILES: [CH:1]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH3:19][C@@H:20]1[O:25][C@@H:24]([O:26][C@@H:27]2[C:32]3=[C:33]([OH:50])[C:34]4[C:46](=[O:47])[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][C:44]=5[O:48][CH3:49])[C:38](=[O:39])[C:35]=4[C:36]([OH:37])=[C:31]3[CH2:30][C@@:29]([OH:55])([C:51]([CH2:53][OH:54])=[O:52])[CH2:28]2)[CH2:23][C@H:22]([NH2:56])[C@@H:21]1[OH:57].Cl>CN(C=O)C>[CH:1]1=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1.[CH3:19][C@@H:20]1[O:25][C@@H:24]([O:26][C@@H:27]2[C:32]3=[C:33]([OH:50])[C:34]4[C:46](=[O:47])[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][C:44]=5[O:48][CH3:49])[C:38](=[O:39])[C:35]=4[C:36]([OH:37])=[C:31]3[CH2:30][C@@:29]([OH:55])([C:51]([CH2:53][OH:54])=[O:52])[CH2:28]2)[CH2:23][C@H:22]([NH2:56])[C@@H:21]1[OH:57]
Reactant: OC1C=CCCCCC1
Agent: C1=C/CCCCCC/1
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C1=CCCCCCC1

Procedure:
In a similar fashion, from the PNP-derivative 34 derived from the major alcohol 31 (22 mg, 0.0756 mmol) in 7.2 g DMF, after reaction with diisopropylethylamine (80 mg, 0.62 mmol) and doxorubicin hydrochloride (47.7 mg, 0.0822 mmol), followed by removal of the solvent under high vacuum, chromatography and TBME/heptane treatment major-38 was obtained (21 mg, 0.030 mmol, 30%). The filtrate contained an additional amount of product.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C:4]1=[O:5].[CH2:11]([O:18][C:19](N[C@H](C(O)=O)CCC(=O)N)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]([N:6]1[C:7](=[O:10])[CH2:8][CH2:9][CH:3]([NH2:2])[C:4]1=[O:5])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: C1CCOC1
Product: NC1CCC(=O)N(C(=O)OCc2ccccc2)C1=O

Procedure:
α-aminoglutarimide hydrochloride is commercially unavailable internally. It is synthesized from N-benzyloxycarbony-L-glutamine, which reacts with N,N′-carbonyldiimidazole in THF refluxing to yield N-benzyloxycarbony-aminoglutarimide. After that amino protection group is removed and α-aminoglutarimide hydrochloride is yielded by hydrogenation under certain pressure catalyzed with Pd/C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7].C(=O)(O)[O-].[Na+].[CH2:38](Br)[CH3:39]>ClCCl>[CH2:38]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH2:9][N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:6](=[O:7])[C:5]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:39]
Reactant: CCBr
Reactant: COc1cc(C(=O)N(CCC2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCCC1CCN(CC(C)=Cc1ccccc1)C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 3,4,5-trimethoxy-N-(2-methyl-3-phenyl-allyl)-N-(2-pyrrolidin-2-yl-ethyl)-benzamide 0.1 g (2.28 mmol) in dry dichloromethane 5 ml, sodium bicarbonate 0.01 g (2.7 mmol) was added followed by ethyl bromide 0.037 g (3.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 14 hrs. Inorganics were filtered off and filtrate was concentrated. Crude material was subjected to column chromatography on silica gel, elution with chloroform-methanol to yield desired compound as a free amine. This was converted to its hydrochloride salt 42 mg as a yellow semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]2C=CC=[CH:16][C:15]=2F)=[C:10]([O:21][CH3:22])[C:9]([O:23][CH3:24])=[CH:8][C:7]=1[CH3:25])=[O:5].C(OC1C(C(=O)C2C(C)=CC=CC=2C)=C(C)C=C(OC)C=1OC)C1C=CC=CC=1.BrC1C(OC)=CC(OC)=C(C=1C)C(C1C(OC)=C(OC)C=CC=1C)=O>>[CH2:13]([O:12][C:11]1[C:6]([C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[C:7]([CH3:25])[CH:8]=[C:9]([O:23][CH3:24])[C:10]=1[O:21][CH3:22])[CH2:14][CH2:15][CH3:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(OCc2ccccc2F)c1OC
Agent: COc1cc(C)c(C(=O)c2c(C)cccc2C)c(OCc2ccccc2)c1OC
Agent: COc1cc(OC)c(C(=O)c2c(C)ccc(OC)c2OC)c(C)c1Br
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-dichloro-4′,5′-dimethoxy-6′-(2-fluorobenzyloxy)-2′-methylbenzophenone (coded BB-2); 6′-benzyloxy-4′,5′-dimethoxy-2,6-dimethyl-2′-methylbenzophenone (coded BB-3); and [3-bromo-2′,6-dimethyl-2,4′,5′,6′-tetramethoxybenzophenone] 5-bromo-2′,6-dimethyl-2,4,5′,6′-tetramethoxybenzophenone (coded BB-4), most preferred BB-4.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]>CO>[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([O:13][CH3:1])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Yield: 91.4 %

Procedure:
TMSCl (132 g, 1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55° C. under high vacuum to provide 128.8 g (92%) of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (4). HPLC was 97.9 a % (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) δ 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (1H, apparent dd, J 1.9, 7.2, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ −153.6, −129.2. 13C NMR (100 MHz, d6 DMSO) δ 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J 2.7), 128 (CH, d, J 5), 140 (C—F, dd, J 244, 15), 141 (C, dd, J 14, 5), 152 (C—F, dd, J 263, 11), 162 (COO, t, J 3). IR vmax/cm−1 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (−) m/z 231 (M−1) detected.