Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[CH3:15])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Br)nc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-3-pyridinol (0.31 g, 1.78 mmol), (±)-phenylmethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.73 g, 2.14 mmol) and K2CO3 (0.50 g, 3.57 mmol) in DMF (12 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight, then heated at 100° C. for 27 h. The mixture was cooled to ambient temperature and poured into water, and extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude (±)-phenylmethyl 4-{1-[(6-bromo-3-pyridinyl)oxy]ethyl}-1-piperidinecarboxylate as a brown oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:10](=[N:18][OH:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].[H-].[Na+].O>CN(C=O)C.Cl.C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:19][N:18]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: CC(=NO)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=NOc1ncc(F)c(N)n1)c1ccccc1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N2 atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH2Cl2 (5 mL), and neutralized with a few drops of 2N HCl. The phases were separated and the organic extract was dried over MgSO4, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:9]([NH2:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:22]>C(O)(=O)C.CCOCC>[NH2:1][C@@H:2]([C:9]([NH2:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:22]
Reactant: NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=O)[C@H](N)c1ccccc1
Yield: 87.5 %

Procedure:
20.0 g (70 mmoles) of Z-D-Phg-NH2, prepared as described in Step 1, are dissolved in 40 ml of acetic acid, and 70 ml of a 8 n HBr solution in acetic acid are poured to the solution. After 1 hour the reaction mixture is diluted with ether and the hydrobromide is filtered off. The salt, containing a great excess of HBr, is recrystallized from a tenfold amount of ethanol. 14.15 g (87.5%) of H-D-Phg-NH2.HBr are obtained; m.p.: 263.0°-263.5° C. (determined on a Koffler apparatus). Rf8 (HBr): 0.25; Rf8 base: 0.40. [α]D =-75.6° (c=1.0, in dimethyl formamide).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]#[N:22])[C:14]=3[CH2:13][CH2:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(SSC2C=CC=CC=2)C=CC=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]#[N:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCc1cccc2c1CCN=C2c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(SSc2ccccc2)cc1
Product: N#CCc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12

Procedure:
Six (6) grams of 1-(4-nitrophenyl)-3,4-dihydroisoquinoline-5-acetonitrile and 5 g of diphenyl disulfide were reacted for 6 hours over an oil bath at 165° C. After the reaction, the reaction mixture was extracted with chloroform, chromatographed, and recrystallized from acetone-n-hexane to afford 2.5 g of 1-(4-nitrophenyl)-isoquinoline-5-acetonitrile having a melting point of 218.9° to 219.3° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[O:22]1[CH2:25][CH:24]([CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29])[CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([CH2:27][CH2:26][CH:24]2[CH2:25][O:22][CH2:23]2)(=[O:30])=[O:29])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)CCC1COC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)CCC2COC2)c2n(c1=O)CCO2
Yield: 5.4 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Example 7A, 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.2 g, 0.673 mmol) was reacted with 2-(oxetan-3-yl)ethanesulfonyl chloride (0.18 g, 1.009 mmol) in dry pyridine (3 mL) to afford the crude product. Purification by preparative HPLC, followed by flash column chromatography (3% methanol in chloroform) afforded 20 mg of the compound (17A) (9% yield) and 3 mg of the hydrolyzed by-product (compound (17B).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1>C(Cl)(Cl)Cl.C(#N)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:32])=[O:31])=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(C(F)(F)F)c1
Reactant: CNCCOCC(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N(C)CCOCC(=O)O)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A suspension is prepared of 8 g (60 mM) of 2-(2-methylaminoethoxy)acetic acid in 100 ml of chloroform and 20 ml of acetonitrile, and, at ambient temperature, 17 ml (120 mM) of triethylamine are added, then, dropwise, 7.63 ml (60 mM) of chlorotrimethylsilane. The mixture is agitated at 60° C. for 2 hours and then cooled to ambient temperature and 17 ml (120 mM) of triethylamine and then 16.48 g (60 mM) of 4-methoxy-2-(trifluoromethyl)benzenesulphonyl chloride in solution in 60 ml of chloroform, are added slowly. The reaction mixture is kept under agitation at 5° C. for 16 hours, and then concentrated under reduced pressure. The residue is taken up into 150 ml of dichloromethane and is treated with 40 ml of an N solution of hydrochloric acid. The organic phase is separated, washed with water, and then extracted with twice 120 ml of N sodium hydroxide. The basic aqueous phase is separated, washed with 100 ml of dichloromethane and then acidified with a 5N solution of hydrochloric acid. The precipitate formed is extracted with twice 80 ml of dichloromethane; the organic phase obtained is washed with water and then dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is crystallised in isopropyl ether, separated off and dried. 6.32 g of the compound sought after are thus obtained as a white solid (yield=28%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][N:38]2[CH:42]=[C:41]([Si](C)(C)C)[N:40]=[N:39]2)[NH:33][CH2:32]1)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)[NH:33][CH2:32]1)=[O:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](Cn2cc([Si](C)(C)C)nn2)CO1)C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](Cn2ccnn2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of Nα-(methoxycarbonyl)-β-phenyl-N-(2-{2-[(2R,5R)-5-{[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]methyl}morpholin-2-yl]ethyl}phenyl)-L-phenylalaninamide (1 eq.) in tetrahydrofuran (0.03M) was added TBAF (2.7 eq.). The reaction mixture was then heated to 50° C. for 16 hrs. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and concentrated. The evaporation residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 30% of MeOH/EtOAc.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][Si](C)(C)C)=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[CH:11])=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C#C[Si](C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(OCC)cn1
Yield: 93.6 %

Procedure:
To a solution of 5-ethoxy-2-[(trimethylsilyl)ethynyl]pyridine (2.74 g) in methanol (40 mL) was added 8M aqueous sodium hydroxide solution (3.73 mL) at room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-brown powder (1.72 g).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:25])[NH:22][C:23]=2[CH3:24])=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:26].C(O)C>C(O)(=O)C>[BrH:26].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:25])[NH:22][C:23]=2[CH3:24])=[CH:16][CH:17]=1
Reactant: Cc1[nH]c(=O)cnc1-c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]c(=O)cnc1-c1ccc(N)cc1

Procedure:
5-(4-Benzyloxycarbonylaminophenyl)-6-methyl-2(1H)-pyrazinone (0.5 g) was treated with hydrogen bromide in acetic acid in a manner similar to that described in Example 20 to give the title compound as its hydrobromide salt (340 mg) which after digestion with hot ethanol had m.p.>300° C.; δ(D2O) inter alia 2.39 (3H, d, CH3), 8.03 (1H, q, pyrazinone ring 3-H); ν(KBr) 1705, 1750 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:22]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20]O)[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].CS(OS(C)(=O)=O)(=O)=O.[Br-:32].[Li+].N1C(C)=CC=CC=1C>C1COCC1.O>[Br:32][CH2:20][C:18]1[CH:17]=[CH:16][C:10]2/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:22][C:6]=3[O:7][CH2:8][C:9]=2[CH:19]=1
Reactant: C/C(C#N)=C1/c2ccc(CO)cc2COc2cc(F)ccc21
Reactant: [Br-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.1 %

Procedure:
[step 6] (E)-2-[3-fluoro-8-(hydroxymethyl)dibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (13.3 g, 45.0 mmol) obtained in step 5 was dissolved in THF (450 mL), methanesulfonic anhydride (19.6 g, 112.6 mmol), lithium bromide (23.5 g, 270.2 mmol) and 2,6-lutidine (31.5 mL, 270.2 mmol) were added, and the mixture was stirred at room temperature for 13 hr. To the mixture was added water (200 mL), and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with 1 mol/L hydrochloric acid (100 mL), saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-97/3 v/v) to give the title compound (13.4 g, 83%).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[O-:12][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+]>CC(C)=O.CC(C)=O.O>[C:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ccc(C=O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)n1ccc(C(=O)O)c1
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 1-tert-butyl-1H-pyrrole-3-carbaldehyde (0.339 g, 2.24 mmol) in acetone (40 mL) was added, over a 2 h period, a solution of KMnO4 (0.708 g, 4.48 mmol) in Acetone/H2O (1:1, 60 mL). After 3 h, the reaction was poured into a solution of 10% NaHSO3/1N HCl (120 mL) and the solution was extracted with DCM (3×60 mL). The combined extracts were washed with H2O (2×60 mL) and 5% NaHCO3 (3×60 mL). The bicarbonate washes were carefully acidified to pH 3 and extracted with DCM (3×60 mL). The combined organic layers were washed with brine (1×), dried (MgSO4) and concentrated afford 1-tert-butyl-1H-pyrrole-3-carboxylic acid (0.270 g, 72% yield) as a white solid. MS (ESI) m/z: 168.1 (M+H+).
Reaction SMILES: [S:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].CO>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:18]([O:4][C@H:3]1[C@H:5]([O:6][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:7]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:9]([CH3:11])[O:10][C@@H:2]1[S:1][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A suspension of compound of example 9 (50 g) and tetrabutylammonium hydrogen sulphate (19.9 g) in DCM is warmed until a homogenous solution is obtained. To this solution benzyl chloride (101 ml) followed by 250 ml of 50% (w/w) NaOH-solution are added. The thick emulsion is refluxed under vigorous stirring. After 1.5 h 12 ml of MeOH is added and the reaction mixture is additionally refluxed for overnight. After cooling it is diluted with 200 ml of DCM and washed with water (400 ml) and brine (100 ml). DCM is evaporated to give a yellow oil (˜150 g) to which 230 ml of MeOH is slowly added. The resulting suspension is stirred overnight at 4° C., the precipitate is filtered, washed with 200 ml of n-heptane and dried i.v. to yield 68 g of white powder. Physical characteristics are in good agreement with those reported [7].
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](N)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CC[N:18](CC)CC>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]=1[NH2:18]
Reactant: Nc1ccc2c(c1)Cc1cc(N)ccc1-2
Reactant: CCN(CC)CC
Product: Nc1ccc2c(c1N)Cc1ccccc1-2
Yield: 70 %

Procedure:
2″,7″-[Bis-(4′-O-demethylA4β-N-4-desoxypodophyllotoxin)] diamino flourene (8b) was prepared according to the procedure described for the earlier compounds, employing 2,7-diamino flourene (135 mg, 0.5 mmol), Bu4N+I−(185 mg, 0.5 mmol), Et3N (150 mg, 1.5 mmol) and 4′-O-demethyl-4β-bromo podophyllotoxin (462 mg, 1.0 mmol) to give the product in 70% yield. Spectral data: 1H NMR (CDCl3); 7.39-7.45 (d, 2H), 6.78 (S, 2H), 6.66 (S, 2H), 6.50 (S, 2H), 6.43-6.48 (d, 2H), 6.30 (S, 4H), 5.92-6.00 (ABq, 4H), 5.33 (S, 2H), 4.70 (br, 2H), 4.55-4.61 (d, 2H), 4.334.45 (t, 2H), 3.97-4.10(t,2H), 3.79 (S, 6H), 3.08-3.20 (dd, 2H), 2.90-3.08 (m, 2H); FAB MS: m/z 960 (M+); mp. 240-243° C.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13](=[O:37])[NH:14][C:15]1[N:16]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:17]=[C:18]([C:20]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:19]=1)[CH3:12])C1C=CC=CC=1>CCO.[Pd]>[NH2:10][CH:11]([CH3:12])[C:13]([NH:14][C:15]1[N:16]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:17]=[C:18]([C:20]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH:19]=1)=[O:37]
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(N)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reaction time: 16 h

Procedure:
A suspension of 0.36 g (0.7 mmol) of {1-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-ylcarbamoyl]ethyl}carbamic acid benzyl ester and 0.36 g of 10% Pd/C in 5.0 mL of absolute EtOH was agitated under 30 psi H2 for 16 h. The reaction mixture was filtered through Celite and 0.36 g of fresh 10% Pd/C was added to the filtrate which was again agitated under 30 psi H2 for 16 h. This process was repeated once more and, after a final filtration, the filtrate was concentrated. Purification on silica gel using 4% Et3N-MeOH as eluant afforded 2-amino-N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]propionamide.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:23]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]([NH:41][C@H:42]([C:48](OC2C=CC([N+]([O-])=O)=CC=2)=[O:49])[CH2:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:40])=[CH:33][CH:32]=1>CN(C)C=O.CCOCC>[NH:41]([C:39]([O:38][CH2:37][C:34]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1)=[O:40])[C@H:42]([C:48]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:23]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:49])[CH2:43][CH2:44][C:45](=[O:46])[NH2:47]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g of the H-Thr(tBu)-Ala-Ile-Gly-OMe described under 28), in 30 ml of dimethylformamide, are mixed with 3.5 g of Z-Gln-ONP and stirred at room temperature until the mixture becomes solid. After allowing to stand overnight the mixture is diluted with ether and the precipitate is filtered off and washed with ether until free of nitrophenol. The protected pentapeptide shows Rf =0.14 in the system chloroform-methanol (95.5 ) in a thin layer chromatogram on silica gel. Melting point: >250°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:36])[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:28][N:29]([CH3:36])[CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:34]
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CN(C)CCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)CCCN(C)C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 4-(dimethylamino)butanoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H) 1.27-1.38 (m, J=7.45, 7.45, 7.45, 7.45 Hz, 2H) 1.90-1.99 (m, 2H) 2.21 (m, 2H) 2.44-2.49 (m, 2H) 2.81 (d, J=4.80 Hz, 6H) 3.07-3.15 (m, 2H) 6.76 (s, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.69 (d, J=8.34 Hz, 2H) 7.79-7.90 (m, 4H) 8.09 (d, J=8.34 Hz, 1H) 9.43 (s, 1H) 10.40 (s, 1H); ESI-MS: m/z calc'd for C27H31N5O2S 489.63. found 490.3 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].N12CCCN=C1CCCCC2>ClCCl>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]([OH:9])[CH2:19][N+:16]([O-:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])CC(O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Fifty grams (254.78 mmol) of diphenylacetaldehyde (Aldrich) and 18.66 g (305.73 mmol) of nitromethane was dissolved in 635 mL of dichloromethane. The stirred solution was treated with 35 g of 3Å molecular sieves followed by 11.64 g (76.43 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Aldrich) and stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was treated with 700 mL of 2N aqueous HCl. The organic layer was separated and washed with saturated brine solution, dried with sodium sulfate and evaporated in vacuo. The residue was treated with 600 mL of hexane and stirred overnight whereupon crystallization occurred. After isolation there was obtained 38.22 g (58%) of 3,3-diphenyl-2-hydroxy-l-nitropropane as a pale yellow solid which was used directly in the following step.