Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:14][CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[CH3:12]
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)nc2ccc(CBr)cc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 2-chloro-4,6-dimethylquinoline (1.31 g) in chloroform (20 mL) was added N-bromosuccinimide (1.24 g) at room temperature. The reaction solution was heated at 70° C., and benzoyl peroxide (0.25 g) was divided into 5 portions and added at intervals of a few tens of min. The mixture was stirred at the same temperature for 1 h. The reaction solution was cooled to room temperature and diluted with ethyl acetate, then the organic layer was washed with a mixed solution of saturated aqueous sodium thiosulfate and saturated brine and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=10:1) to obtain 6-bromomethyl-2-chloro-4-methylquinoline (0.79 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9]O.C(N(CC)CC)C.F.F.F.C(N(CC)CC)C.[F:29]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:29][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(CO)c1ccccc1F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CF)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-hydroxyethanone [CAS 218771-68-7; WO9857925, ex. 16) (2.77 g, 18.0 mmol) in dichloromethane (42 ml) was treated consecutively at 0° C. with triethylamine (6.36 g, 62.8 mmol), triethylamine trihydrofluoride (3.05 g, 18.0 mmol) and nonafluoro-n-butanesulfonyl fluoride (8.48 g, 26.9 mmol). The tube was sealed and the reaction mixture stirred overnight at room temperature. For the workup, the dark red solution was poured on a saturated solution of sodium hydrogencarbonate and ice, then extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel (Telos Flash Silica) using dichloromethane as the eluent to give the 2-fluoro-1-(2-fluoro-phenyl)-ethanone (1.23 g, 61% yield) as a yellow semisolid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:11](=[O:10])[CH2:15][CH2:14][CH2:13][NH:12][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Brc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A thoroughly dried three-necked round-bottom flask was equipped with reflux condenser, addition funnel and argon inlet. Then magnesium powder (7.5 g, 311 mmol, activated by iodine) and dry THF (300 mL) were placed into this apparatus. A solution of 1,4-dibromobenzene (73.5 g, 311 mmol) in dry THF (200 mL) was slowly added at such a rate that the mixture maintained at reflux. When the addition was completed the mixture was refluxed for additional 2 hrs. After cooling to room temperature, the solution was added into a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (48 g, 260 mmol) in THF (320 mL) at −78° C. and the mixture was stirred at −78° C. for 2 hrs. The solution was warmed to ambient temperature and stirred for another 10 hrs before quenching with water. Hydrochloric acid (1 N, 100 mL) was added and the mixture was stirred at ambient temperature for 10 minutes. The mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo to afforded the crude product, which was purified by column chromatography (EtOAc: DCM:hexane=1:1:15) to give the title compound as a white solid (53 g, yield 60%). LC-MS (ESI) m/z: 342 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[S:46]([CH3:45])(=[O:48])=[O:47]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)S(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([N:14]3[CH2:23][C@H:22]4[N:18]([CH2:19][CH2:20][CH2:21]4)[C:17]4[N:24]=[C:25]([S:28][CH3:29])[N:26]=[CH:27][C:16]=4[C:15]3=[O:30])[CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1)#[N:2].[OH-:31].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:29][S:28][C:25]1[N:26]=[CH:27][C:16]2[C:15](=[O:30])[N:14]([C:10]3[CH:9]=[C:8]([C:6]4[O:7][C:3]([C:1]([NH2:2])=[O:31])=[CH:4][N:5]=4)[CH:13]=[CH:12][CH:11]=3)[CH2:23][C@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:24]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncc(C#N)o3)c1)C2=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncc(C(N)=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
(S)-5-[3-(5-Cyano-1,3-oxazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (140 mg, 0.334 mmol) obtained in Step 3 of Example 125 was dissolved in ethanol (5 mL), and the mixture was stirred at room temperature for 2 hours after adding a 2 mol/L aqueous sodium hydroxide solution (1.67 mL, 3.34 mmol). The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-5-carboxamide (50.3 mg, 34%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(C(CC(=O)O)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Wang resin (Advanced Chemtech, 2.5 g, 0.8 mmol/g, 2 mmol equivalent) in a mixture of DMF (20 ml) and DCM (20 ml) was treated with 3-(9-fluorenylmethoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid (2.6 g, 6 mmol), 4-dimethylaminopyridine (244 mg, 2 mmol) and 1,3-diisopropylcarbodiimide (940 μl, 6 mmol) and the mixture agitated under nitrogen at room temperature for 24 h. The resin was filtered and washed with DMF and DCM. The resin was treated with a 1M solution of stannous chloride dihydrate in DMF (50 ml) at room temperature for 8 h then washed as before to give the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:17]>>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[S:17])[N:11]=1
Reactant: NC(N)=S
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Product: CN(C)c1nc(=S)[nH]c2ccccc12

Procedure:
Prepared as in Example 46 from 2-chloro-N,N-dimethylquinazolin-4-amine (Example 40) and thiourea. 1H NMR (400 MHz, DMSO-d6) δ 3.31 (s, 6H), 7.24-7.19 (m, 1H), 7.40-7.38 (m, 1H), 7.65-7.61 (m, 1H), 8.00 (d, J=8.0 Hz, 1H), 12.35(s, 1H). MS 206 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C@@H:12]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C@H:11]([CH3:30])[O:10][C:9]1=[O:31])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C@@H:12]([O:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C@H:11]([CH3:30])[O:10][C:9]1=[O:31]
Reactant: Cc1ccc(C[C@H]2COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(C[C@H]2COC[C@H](N)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl((3S,7S,8R,9S)-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-2-oxo-1,5-dioxonan-3-yl)carbamate (0.03 g, 0.07 mmol) in CH2Cl2 (0.7 mL) was added a 4 M solution of HCl in dioxane (0.33 mL, 1.34 mmol), and the resulting colorless solution was stirred at room temperature for 1.5 h. The solvent was evaporated under a positive stream of N2 and the residue was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried by passing through a phase separator cartridge, and concentrated to give (3S,7S,8R,9S)-3-amino-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-1,5-dioxonan-2-one (0.021 g, 90%) as a white solid: mp 81-84° C.; 1H NMR (400 MHz, CDCl3) δ 7.08 (t, J=2.7 Hz, 4H), 4.91 (dq, J=9.2, 6.4 Hz, 1H), 3.84 (dd, J=11.6, 7.5 Hz, 1H), 3.74 (m, 2H), 3.64 (m, 1H), 3.47 (dd, J=8.3, 6.4 Hz, 1H), 3.41 (dd, J=10.7, 6.1 Hz, 1H), 3.31 (m, 2H), 3.07 (m, 3H), 2.31 (s, 3H), 1.87 (m, 2H), 1.59 (m, 1H), 1.47 (d, J=6.4 Hz, 3H), 0.95 (dd, J=6.7, 1.6 Hz, 6H); ESIMS m/z 351 ([M+H]+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CC1(C)C2CC[C@@]1(CS([O:23][CH2:24][CH2:25][CH2:26][C@@:27]1([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1)(=O)=O)C(=O)C2.[C:42]1([C:48](Cl)=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[Cl:40][C:35]1[CH:34]=[C:33]([C:27]2([CH2:26][CH2:25][CH2:24][OH:23])[CH2:32][CH2:31][CH2:30][N:29]([C:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:49])[CH2:28]2)[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)OCCC[C@@]1(c3ccc(Cl)c(Cl)c3)CCCNC1)C(=O)C2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCC(CCCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Diisopropylethylamine(5.7 mL, 3.27 mmol, 5.0 eq) was added to a mixture of camphorsulfonate salt (9) (3.4 g, 6.53 mmol) in CH2Cl2 (21 mL, 0.3 M) and followed by dropwise addition of PhCOCl (0.83 mL, 7.19 mmol, 1.1 eq). The solution was stirred at room temperature for 1 hour. The reacting mixture was diluted with CH2Cl2 (200 mL) and washed with brine, 1 M KHSO4, and saturated NaHCO3 then dried over MgSO4. The concentrated crude oil was purified by flash chromatography (CH2Cl2-MeOH/95:5) to give white solid (2.30 g, 89.8%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(Cl)Cl.[OH-].[Na+]>O>[CH2:8]1[CH2:9][CH2:10][N:5]([C:1]([N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:2])[CH2:6][CH2:7]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCCCC1)N1CCCCC1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Phosgene was passed for 17 minutes, at the rate of 3 grams per minute, through a mixture of 84 grams (1 mole) of piperidine, 500 ml. of methylene chloride and 100 ml. of water. The pH was maintained in the range of 8-11 by the addition of 50% aqueous sodium hydroxide solution during the latter portion of the phosgene passage. An exothermic reaction occurred which caused refluxing of the mixture. After phosgenation was complete, additional base was added until the pH remained constant at 11 for 5 minutes, after which 200 ml. of water was added and the organic layer was removed, washed twice with aqueous hydrochloric acid solution and filtered. Upon vacuum stripping, the desired bis(pentamethylene)urea was obtained in 96% yield. Its structure was confirmed by proton nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:36])(=[O:35])[NH2:34])[CH:28]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:23][N:37]=[C:26]([C:27]4[CH:28]=[C:29]([S:33]([NH2:34])(=[O:35])=[O:36])[CH:30]=[CH:31][CH:32]=4)[N:25]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (175 mg, 70%). MS (ISP) 500.3 [(M+H)+]; mp 326° C.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Clc1ccccc1
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(c1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 40 ml of tetrahydrofuran, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride and 0.14 g (0.001 mol (corresponding to 1% by mol)) of copper(I) bromide were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 13.5 g (0.12 mol) of chlorobenzene and 3.5 g (0.14 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 40 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 110° C. to 112° C. under reduced pressure of 5 Torr were collected. As a result, 19.9 g (purity: 99.0%) of the aimed di-tert-butylphenylphosphine was obtained as a viscous oily substance. The yield was 89.0%.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:22][C:23](O)=[O:24])=[O:20])[CH2:13][C:14]2[N:18]=[CH:17][NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[N:84]1[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=1[CH2:90][CH2:91][NH2:92]>C(Cl)Cl>[CH2:7]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:19](=[O:20])[N:21]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:32]=1)[CH2:22][C:23](=[O:24])[NH:92][CH2:91][CH2:90][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][N:84]=1)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ccccn1
Reactant: O=C(O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)C(Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of the acid from Step 3 (0.33 g, 0.61 mmol) in methylene chloride was added PyBOP (0.67 g, 1.3 mmol) and diisopropylethylamine (0.23 mL, 1.3 mmol) followed by 2-pyridineethaneamine hydrochloride (0.082 g, 0.67 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue taken up in ethyl acetate, which was washed 3 times with saturated NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography gave 0.156 g (37%) of the title compound as a white foam; ES-MS 647 (m+1).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:1]([N:9]1[CH2:10][CH2:11][CH:6]([OH:5])[CH2:7][CH2:8]1)=[O:3]
Reactant: O=N[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add a solution of sodium nitrite (13.8 g, 200 mmol) in water (40 mL) to 4-hydroxy piperidine (10.1 g, 100 mmol) in water (20 mL). Cool the mixture to 0° C. on an ice bath. Add acetic acid (8.6 mL, 150 mmol) dropwise over 20 minutes. After the addition, continue stirring at 0° C. for 30 minutes, slowly warm up to room temperature and stir at room temp for 5 hours. Add sodium carbonate (15.9 g, 150 mmol) in portion to quench the acid. Extract the reaction with ethyl acetate (3×60 mL), combine the organic, dry over sodium sulfate, filter and concentrate to afford the desired product as yellow oil. Yield: 12.9 g, (98%).
Reaction SMILES: [Sn].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:4]=12.[Br-:17].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C(Cl)Cl>[Br:17][CH:14]1[CH2:13][CH2:12][N:5]2[C:6]3[C:11]([C:3]([CH3:2])=[C:4]2[C:15]1=[O:16])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: [Br-]
Reactant: Cc1c2n(c3ccccc13)CCCC2=O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Sn]
Solvent: ClCCl
Product: Cc1c2n(c3ccccc13)CCC(Br)C2=O
Temperature: 10 °C
Reaction time: 30 h
Yield: 86.8 %

Procedure:
The reaction was performed in the dark (the flask wrapped in a tin-foil), and with the provision for maintaining a nitrogen atmosphere. To a solution of 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 7, 49.75 g) in methylene chloride (250 mL) was added a solution of trimethylphenylammonium tribromide (94 g) in methylene chloride (1200 mL) as fast as possible (over 2 min); the inside temperature was maintained at 10° C. The reaction mixture was stirred at room temperature for 30 hr, evaporated in vacuo, and the solid residue was partitioned between water (600 mL) and benzene-diethyl ether 1:1 (800 mL, v/v). The separated organic layer was dried (MgSO4), filtered, and the filtrate was evaporated. The crude product was dissolved in chloroform (55 mL), and diethyl ether (600 mL) was added at once, whereby a voluminous, dark-green material precipitated. It was quickly removed by filtration (without suction), and the filtrate was chilled to 0° C. The crystals which formed were collected by filtration; 38 g, mp 126°-128° C. This material was recrystallized from chloroform-diethyl ether (1:8, v/v) to give 35 g of the title compound, mp 131°-133° C.; IR (CHCl3) 1665-1660, and 1535 cm-1 ; UV max (MeOH) 246 and 327 nm, (ε 16000) and (18200) respectively; NMR (CDCl3) δ 2.67 (br s, 3H), overlapping with 2.65 (m, 2H), 4.29 (dd, J1 =7.5 Hz, J2 =4.5 Hz, 2H), 4.67 (t, J=4 Hz, 1H), 7.25-7.7 (m, 4H); Anal. Calcd for C13H12BrNO: C, 56.12% H, 4.35% N, 5.03% and Found: C, 56.20% H, 4.32% N, 5.05%.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]3[C:6](=[C:7]([NH2:22])[N:8]=[C:9]([NH2:21])[N:10]=3)[C:5]=2[CH:4]=[CH:3]1.[H-].[Na+].I[CH3:26].O>CN(C)C=O>[CH3:1][N:2]1[C:14]2[C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]3[C:6](=[C:7]([NH:22][CH3:26])[N:8]=[C:9]([NH2:21])[N:10]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: CI
Reactant: Cc1ccc(-c2cc3nc(N)nc(N)c3c3ccn(C)c23)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(N)nc2cc(-c3ccc(C)s3)c3c(ccn3C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.6 %

Procedure:
A solution of 7-methyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (100 mg, 0.32 mmol) in N,N-dimethylformamide (5.0 mL) at 25° C. was treated with 60% sodium hydride (25 mg, 0.62 mmol) and iodomethane (0.62 mL, 0.35 mmol) and stirred at 25° C. for 15 min. The resulting mixture was poured into water and extracted with a 9/1 methylene chloride/methanol solution. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 9:1 methylene chloride/methanol) afforded 7,N1-dimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (12 mg, 11.5%) as a light yellow solid; EI-HRMS m/e calcd for C17H17N5S (M+H)+ 324.1278, found 324.1280; and 7,N1,N1-trimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (18 mg, 16.5%) as a dark brown solid; EI-HRMS m/e calcd for C18H19N5S (M+H)+ 338.1434, found 338.1437.