Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([F:12])([CH2:8][CH:9]([F:11])[F:10])[C:4](Cl)([F:6])[F:5].[F:15]C(F)=C>>[F:1][C:2]([F:14])([F:13])[C:3]([F:12])([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:15])([F:6])[F:5]
Reactant: FC(F)CC(F)(C(F)(F)F)C(F)(F)Cl
Reactant: C=C(F)F
Product: FC(F)CC(F)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1-chloro-1,1,2,4,4-pentafluorobutane may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be chlorinated to form 2-trifluoromethyl-1-chloro-1,1,2,4,4-pentafluorobutane.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]#[C:14][OH:15]>>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[NH:13][C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CO
Reactant: O=C(O)CNCc1ccccc1
Product: O=C1CN(Cc2ccccc2)C(=O)N1

Procedure:
The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH:9]([C:20](O)=[O:21])[NH:8][CH:7]=1)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([C:20]([CH:9]2[NH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1=CNC(C(=O)O)Cc2c1[nH]c1ccccc21
Solvent: ClCCl
Product: CCOC(=O)C1=CNC(C(=O)N2CCCCC2)Cc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,2,3,6-tetrahydroazepino[4,5-b]indole-2,5-dicarboxylic acid 5-ethyl ester (45 mg, 0.15 mmol) in DCM (3 mL) was added CDl (27 mg, 1.1 equiv.). After stirring for 1 hour at 20° C., piperidine (23 μL, 1.5 equiv.) was added. The mixture was stirred overnight at 20° C. and a clear solution was obtained. Evaporation of solvent gave a crude product, which was purified by trituration with MeOH to afford the title compound (22 mg); 1H-NMR (CDCl3): δ 10.44 (1H, br s), 7.95 (1H, d), 7.38 (2H, d), 7.05-7.13 (2H, m), 6.69 (1H, d), 4.29 (2H, q), 3.98 (1H, dd), 3.65-3.73 (2H, m), 3.46 (1H, m), 3.31 (1H, m), 2.71 (1H, dd), 1.58-1.76 (6H, m), 1.36 (3H, t); MS (ES): 368 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][C:28]#[N:29])/[C:9]1=[O:30])=O)(C)(C)C.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:47])=[C:36]([CH:38]=[N:39][C:40]([O:42][Si](C)(C)C)=[CH2:41])[CH:37]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:30])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][C:28]#[N:29])[CH2:41][C:40](=[O:42])[NH:39][CH:38]3[C:36]3[CH:37]=[C:32]([F:31])[CH:33]=[CH:34][C:35]=3[CH3:47])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC#N)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC#N)C12C(=O)Nc1cc(Cl)ccc12
Yield: 1.7 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro-2-cyanomethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 11 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (44 mmol) in toluene to give the title compound as a white solid (100 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]1[NH:12][CH:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:10]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[S:9]1)[C:5]([OH:7])=[O:6].[C:34](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.P(=O)(O)(O)O>ClCCl>[CH2:16]([O:15][C:13]([CH:11]1[C:10]2([CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)[S:9][CH:8]([CH:4]([NH:3][C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:5]([OH:7])=[O:6])[NH:12]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(C(=O)O)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
9.1 g (0.0177 mole) of alpha-amino-4-benzyloxycarbonyl-8-phenyl-1-thia-3,8-diazaspiro[4.5]decane-2-acetic acid dihydrochloride (obtained in 5.3) are suspended in 150 ml of dichloromethane. After cooling to -20° C., 18,6 g (0.0668 mole) of trityl chloride are added all at once. While maintaining the temperature at about -20° C., the suspension is slowly treated over the course of 1 hour with 17.6 g (0.17 mole) of triethylamine in 100 ml of dichloromethane. The reaction mixture is stirred for 1 hour at a temperature of from -10 to -20° C. and then left to stand overnight in a refrigerator, whereafter it is poured onto an ice-water mixture (pH about 11) and neutralized to about pH 6 by the addition of 85% phosphoric acid. The aqueous phase is extracted three times with 100 ml of dichloromethane. The combined extracts are washed with water and dried over anhydrous sodium sulfate, followed by evaporation to dryness under high vacuum on a waterbath at a temperature of from 20° to 25° C. The 4-benzyloxycarbonyl-8-phenyl-alpha-tritylamino-1-thia-3,8-diazaspiro[4.5]-decane-2-acetic acid thus obtained is used, without further purification, in step 7.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(OCc2ccccc2)ccn1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccnc(Nc3ccccn3)c2)cc1
Yield: 72.7 %

Procedure:
Compound I (2.325 mg, 8.80 mmol), 2-aminopyridine (911 mg, 9.68 mmol), tBuOK (1.481 g, 13.20 mmol), (±)-BINAP (219 mg, 0.35 mmol) and Pd2(dba)3 (201 mg, 0.22 mmol) were stirred in toluene (35 mL) at 90° C. under Ar(g) for 17 h. The reaction mixture was then diluted with CH2Cl2 (20 mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40 then 50:50) to furnish II as a yellow oil (1.773 g, 73%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:39])=[O:38]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of cholesterol (19.3 g, 50.0 mmol) in anhydrous CH2Cl2 (250 mL) was cooled to 4° C. by ice-water bath. To this solution, triethylamine (13.9 mL, 100.0 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.3 mL, 55 mmol) in anhydrous CH2Cl2 (50 mL). The reaction was maintained at 4° C. and stirred for 3 h. When the cholesterol was consumed as analyzed by TLC (hexanes/ethyl acetate, 5:1), the solvent was removed in vacuo. The resulting residue was redissolved in CH2Cl2 (15 mL), the product was precipitated by addition of MeOH (150 mL), and the product collected by vacuum filtration. The solid was washed with MeOH (30 mL) and dried under vacuum to yield the product (23.0 g, 99.0%) as a white solid, mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 5.41 (s, 1H), 4.56-4.45 (m, 1H), 3.00 (s, 3H), 2.57-2.43 (m, 2H), 2.04-0.81 (m, 38H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6, 123.7, 81.9, 56.5, 56.0, 49.9, 42.2, 39.6, 39.4, 39.1, 38.7, 36.8, 36.3, 36.1, 35.7, 31.8, 31.7, 28.9, 28.1, 27.9, 24.2, 23.8, 22.8, 22.5, 20.9, 19.1, 18.6, 11.8; IR (film) ν max 3029, 2944, 2908, 2861, 1468, 1440, 1415, 1353, 1330, 1173 cm−1; ESI+ m/z ((MNa)+ 487.3237, C28H48O3SNa requires 487.3222).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Nc1n[nH]cc1-c1ccccn1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccccn4)c3n2)ccc1Cl
Yield: 69.4 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (270 mg, 69%). MS (ISP) 389.2 [(M+H)+]; mp 183° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>O.CCCCC>[N:1]([CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)=[N+:2]=[N-:3]
Reactant: C/C(=C\CCl)COC1CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Product: C/C(=C\CN=[N+]=[N-])COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A solution of 11.43 g (175.86 mmol) of sodium azide (NaN3) and 2.20 g (6.45 mmol) of tetrabutylammonium hydrogenosulfate in 60 ml of water was added to a solution of 12.0 g (58.62 mmol) of (E)-2-(4-Chloro-2-methylbut-2-en yloxy)tetrahydro-2H-pyran in 300 ml of pentane. The reaction mixture was stirred at room temperature overnight. The organic phase was separated and the aqueous phase was extracted with 3×150 ml of Et2O. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 11.21 g (53.06 mmol, 90% yield) of a mixture of azides isomers. No purification was done as infeasible separation was observed on silica gel. The product was used without further purification for the next step.
Reaction SMILES: C1(C)C=CC=CC=1.C[Al](C)C.C1C[O:15][CH2:14]C1.Cl.CNOC.C([C@@H]1CO[C:31](=O)[N:30]1[C:35](=[O:42])[C@H:36]([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH3:39])C1C=CC=CC=1>ClCCl.C1COCC1.ClCCl>[OH:40][C@@H:37]([CH2:38][CH3:39])[C@@H:36]([CH3:41])[C:35]([N:30]([O:15][CH3:14])[CH3:31])=[O:42]
Reactant: C1CCOC1
Reactant: CC[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[C@H](O)[C@@H](C)C(=O)N(C)OC
Temperature: 0 °C

Procedure:
2M trimethylaluminum toluene solution (90 ml, 180 mmol) was added to a THF (180 ml) solution of N,O-dimethylhydroxyamine hydrochloride (18.3 g, 187.6 mmol) at −10° C. under stirring. After the reaction solution was warmed to 0° C. and stirred for 10 minutes, it was warmed to room temperature and further stirred for 30 minutes. The reaction solution was cooled to −10° C. again, and a THF-dichloromethane solution (4:5, 180 ml) of (4R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2-methylpentanoyl]-1,3-oxazolidin-2-one (21.85 g, 75 mmol) was added dropwise to the reaction solution. After the reaction solution was warmed to 0° C. and stirred for two hours, a mixed solution of dichloromethane −0.5N hydrochloric acid (1:1, 80 ml) was added slowly, and the mixture was stirred for one hour at 0° C. The reaction solution was filtered through celite and the filtrate was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60; heptane:ethyl acetate=1.5:1) to obtain (2R,3S)-3-hydroxy-N-methoxy-N,2-dimethylpentanamide (13.0 g) as a colorless oil.
Reaction SMILES: N.C(O)C.[CH2:5]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14]/[C:15](=[CH:17]\[C:18]#[N:19])/[C:16]=3[C:6]1=2.[H][H]>[Co].C(O)C>[CH2:5]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][C:15](=[CH:17][CH2:18][NH2:19])[C:16]=3[C:6]1=2
Reactant: [H][H]
Reactant: N#C/C=C1\CCc2ccc3c(c21)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Product: NCC=C1CCc2ccc3c(c21)CCO3

Procedure:
A saturated ammonia/ethanol solution (150 ml) and Raney cobalt (8.4 g) were added to an ethanol (150 ml) solution of (E)-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]-furan-8-ylidene)acetonitrile (2.6 g, 13.2 mmol), and the reaction mixture was stirred at room temperature in a hydrogen atmosphere (5 kgf/cm2) for 3 hours. The Raney cobalt was filtered off and the solvent was distilled off under reduced pressure to give 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine. To this residue was added a saturated hydrogen chloride/ethanol solution (100 ml), followed by 1 hour of heating under reflux. The reaction solution was concentrated and the residue obtained was recrystallized from ethanol to give 2.75 g (yield: 88%) of the target compound.
Reaction SMILES: [N+](C1C=CC(C2SC=CC=2)=CC=1NC(=O)C1C=CC(C2NN=NN=2)=CC=1)([O-])=O.[C:29]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](=[O:60])[NH:45][C:46]3[CH:51]=[C:50]([C:52]4[S:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=[CH:48][C:47]=3[N+:57]([O-])=O)=[CH:43][C:38]=2[N:37]=[C:36]1[CH3:61])(=[O:31])[CH3:30].CO>C(OCC)(=O)C>[C:29]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](=[O:60])[NH:45][C:46]3[CH:51]=[C:50]([C:52]4[S:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=[CH:48][C:47]=3[NH2:57])=[CH:43][C:38]=2[N:37]=[C:36]1[CH3:61])(=[O:31])[CH3:30]
Reactant: CC(=O)OCCn1c(C)nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3[N+](=O)[O-])ccc21
Agent: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OCCn1c(C)nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3N)ccc21
Yield: 96 %

Procedure:
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 307 and using ethyl acetate as a solvent instead of methanol, the title compound 308 was obtained in 96% yield. 1H NMR: (DMSO) δ (ppm): 9.70 (s, 1H), 8.23 (s, 1H), 7.87 (dd; J=1.0, 8.4 Hz; 1H); 7.62 (d, J=8.4 Hz; 1H), 7.48 (d; J=2.0 Hz; 1H); 7.34 (dd; J=0.8, 4.8 Hz; 1H); 7.28 (dd; J=2.0, 8.0 Hz; 1H); 7.23 (dd; J=0.8, 3.6 Hz; 1H); 7.03 (dd; J=1.2, 4.8 Hz; 1H); 6.81 (d; J=8.0 Hz; 1H); 5.15 (bs, 2H); 4.52 (t; J=4.8 Hz; 2H); 4.35 (t; J=4.8 Hz; 2H); 2.60 (s, 3H); 1.91 (s, 3H). MS: calc: 434.5; found: 435.2 (M+H)
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6]/[C:7](=[CH:11]\[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])/[CH2:8][CH2:9][OH:10]>O.CC(C)=O.O.O.O.[Cr]>[CH3:6][C:7](=[CH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][C:9]([OH:2])=[O:10]
Reactant: C/C(=C\CCC(C)C)CCO
Reactant: O=S(=O)(O)O
Agent: [Cr]
Solvent: CC(C)=O
Solvent: O
Product: CC(=CCCC(C)C)CC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.84 g (88.4 mmol, 3 eq) of chromium VI oxide in 25 mL of water in the presence of 8.2 mL of 95% sulphuric acid is added to a solution of 4.6 g (29.5 mmol, 1 eq) of (E)-3,7-dimethyloct-3-enol in 250 mL of acetone, at 0° C., while maintaining the temperature at 0° C. After addition, the reaction mixture is stirred for 15 minutes at 0° C. and the reaction is then quenched by adding 250 mL of water. The reaction medium is extracted with 2×250 mL of diethyl ether. The organic phases are combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate, and the residue is then filtered through silica gel: eluent (95/5→75/25 Cy/EtOAc).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:1])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(C(=O)CBr)cc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Bromine (4.25 ml; 85 mmol) in AcOH: CHCl3 (1:1; 10 ml) was added to a vigorously stirred solution of the compound of example 20b (25.92 g; 80 mmol) in AcOH:CHCl3 (1:1; 110 ml) at 55-60° C. for 15 min. The mixture was stirred at room temperature for 5 min. and poured over crushed ice and NaHCO3 and extracted with EtOAc. The EtOAc layer was washed with water, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound. Yield, 19.34 g, (60%); mp, 84-85° C. (EtOAc-PE 60-80° C.); analysis: C16H19O7Br: requires C, 47.66; H, 4.75; Br, 19.82; found: C, 48.08; H, 4.82; Br, 19.40%.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10][C:9]=2[C:8]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:7][CH:6]=1.O.O.O.C([O-])(=O)C.[Na+].[N+:35]([C:38]1[CH:39]=[C:40]([CH3:47])[CH:41]=[CH:42][C:43]=1[C:44](Cl)=[O:45])([O-:37])=[O:36].C([O-])(=O)C.[Na+].Cl>O.CCOCC>[Na+:1].[Na+:1].[Na+:1].[N+:35]([C:38]1[CH:39]=[C:40]([CH3:47])[CH:41]=[CH:42][C:43]=1[C:44]([NH:4][C:5]1[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10][C:9]=2[C:8]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:7][CH:6]=1)=[O:45])([O-:37])=[O:36]
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: Cc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c([N+](=O)[O-])c1
Yield: 778.9 %

Procedure:
To a stirred solution of 22.5 g of 8-amino-1,3,5-naphthalenetrisulfonic acid trisodium salt in 160 ml of water is added 11.0 g of the preceding product with a small amount of ether. Stirring is continued, and after one hour 1.0 g of sodium acetate trihydrate and 1.0 g of 3-nitro-p-toluoyl chloride are added. The mixture is stirred an additional 3 hours and the above addition of sodium acetate and 3-nitro-p-toluoyl chloride is repeated. The mixture is stirred an additional hour, acidified to Congo Red indicator paper with hydrochloric acid and filtered. The filtrate is neutralized with sodium hydroxide, concentrated, dissolved in 50 ml of water and added to one liter of ethanol with stirring for 16 hours. The solid is filtered and forms a gel on washing with ethanol. The gel is dissolved in water and evaporated. The residue is dissolved in 35 ml of hot water and 320 ml of absolute ethanol is added with stirring. The mixture solidifies and water is added to allow filtration. The solid is washed with ether and dried in vacuo. The filtrate is treated by stirring with one liter of ethanol, the separated solid is collected, washed with ether, and dried to yield a combined total of 23.9 g of 8-(3-nitro-p-toluamido)-1,3,5-naphthalenetrisulfonic acid trisodium salt.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=1)[O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1.[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][C:50]([C:63](O)=[O:64])=[CH:51][CH:52]=2)[N:47]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]2)[C:53]2[C:48](=[CH:49][C:50]([C:63]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=3)[O:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:64])=[CH:51][CH:52]=2)[N:47]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)c1ccc(Oc2cccc(CN)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-[3-(aminomethyl)phenoxy]benzoate-HCl (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-Dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.020 g, 50%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 9.16 (m, 1H), 7.89 (d, 2H), 7.70 (m, 2H), 7.36 (m, 2H), 7.14 (d, 1H), 6.99 (d, 2H), 6.95 (m, 2H), 6.39 (bs, 2H), 4.44 (d, 2H), 3.75 (s, 3H), 3.50 (bs, 4H), 3.29 (s, 4H), 2.18 (s, 3H); Analytical LCMS (M+H)+: m/z=527.0.