Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:36])[C@@H:10]([NH:24][C:25]1[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:28]([C:34]#[N:35])=[CH:27][CH:26]=1)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:13]2[O:12][C:11]([C@H:10]([NH:24][C:25]3[C:33]4[CH:32]=[CH:31][S:30][C:29]=4[C:28]([C:34]#[N:35])=[CH:27][CH:26]=3)[C@@H:9]([OH:8])[CH3:36])=[N:15][N:14]=2)=[CH:17][CH:18]=1)#[N:23]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (355 mg, 0.69 mmol) in THF (33 mL) was added TBAF (0.70 mL, 0.70 mmol, 1 M solution in THF) at −50° C. After addition, the reaction mixture was stirred between −30° C. to −50° C. for 2 h, then quenched by adding saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried over Na2SO4. The solvent was removed to provide a residue, which was subjected to flash chromatography purification to give the title compound 4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (173 mg, 63%) and some dehydration product 4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (70 mg, 27%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.16 (d, J=8.8 Hz, 2H), 7.95 (d, J=8.8 Hz, 2H), 7.87 (d, J=5.7 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.6 Hz, 1H), 5.25 (dd, J=4.3, 8.6 Hz, 1H), 4.79 (b, 1H), 4.66 (m, 1H), 1.42 (d, J=6.3 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.25 (d, J=8.2 Hz, 2H), 8.01 (d, J=8.2 Hz, 2H), 7.96 (d, J=5.5 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.09 (q, J=7.0 Hz, 1H), 6.58 (d, J=8.2 Hz, 1H), 1.95 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[C:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH:31][C:28]1[CH:29]=[N:30][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][CH:27]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: Nc1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2ccccc2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (1.096 g, 4.38 mmol, 1.50 equiv) in dichloromethane (20 mL), 2-phenylpyrimidin-5-amine (500 mg, 2.92 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (838 mg, 4.39 mmol, 1.50 equiv), and 4-dimethylaminopyridine (713 mg, 5.84 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The reaction was diluted with 100 mL of water and the resulting mixture was extracted with 3×50 mL of dichloromethane. The organic layers were combined, washed with 1×100 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE:EA:CH2Cl2 (20:1:0-3:1:1). The product was obtained as 150 mg (11%) of a yellow solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.O.[NH2:38][NH2:39].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:39][N:38]=2)=[CH:26][CH:27]=1
Reactant: NN
Reactant: O=C(Cc1ccc(OC(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(OC(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of 4-hydroxy-3-(4-trifluoromethoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (307 mg, 0.60 mmol) produced in Synthesis Example 19 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 120 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(4-trifluoromethoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (190 mg, yield 63%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:26][C:27](=[O:41])[C@@H:28]([NH:30][C:31]1[N:36]=[C:35](Cl)[N:34]=[C:33]([C:38]([NH2:40])=[O:39])[CH:32]=1)[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:26][C:27](=[O:41])[CH:28]([NH:30][C:31]1[N:36]=[C:35]([C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[CH:16][CH:15]=2)[N:34]=[C:33]([C:38]([NH2:40])=[O:39])[CH:32]=1)[CH3:29].[NH2:26][C:27](=[O:41])[C@@H:28]([NH:30][C:31]1[N:36]=[C:35]([C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[CH:16][CH:15]=2)[N:34]=[C:33]([C:38]([NH2:40])=[O:39])[CH:32]=1)[CH3:29]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: CC1(C)OB(c2ccc(Oc3ccc4c(c3)OCO4)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc4c(c3)OCO4)cc2)n1)C(N)=O
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc4c(c3)OCO4)cc2)n1)C(N)=O
Temperature: 100 °C
Yield: 87.2 %

Procedure:
A 50-mL vial with a screw-top septum was charged with 200 mg of 2-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 1 equivalent of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (1.53 mg, 0.59 mmol), 1.5 mL 2M aqueous Na2CO3, 0.07 equivalents of PdCl2(PPh3)2 (28 mg, 0.04 mmol), and 8 mL dioxane. The vial was purged with nitrogen and heated to 100° C. for 6 h, at which time the reaction was complete. The mixture was diluted with 100 mL EtOAc and washed two times with 100 mL water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed by combiflash using a 40-gram silica column with a gradient EtOAc (100% max) in hexane to provide 108 mg (43% yield) of S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)pyrimidine-4-carboxamide as a white solid. m/z 421, 1H NMR (CD3OD): 8.51-8.41 (m, 2H), 7.14-7.07 (s, 1H), 7.01-6.93 (m, 2H), 6.86-6.78 (m, 1H), 6.64-6.60 (m, 1H), 6.57-6.50 (m, 1H), 6.01-5.95 (s, 2H), 4.61-4.49 (m, 1H), 1.56-1.48 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[O:5].[C:12](OC)(OC)(OC)[O:13][CH3:14]>CO>[CH3:12][O:13][C:14]1[N:6]([OH:7])[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)NO
Reactant: COC(OC)(OC)OC
Solvent: CO
Product: COc1nc2ccccc2c(=O)n1O
Temperature: 5 °C
Yield: 59 %

Procedure:
A mixture of 22.8 g (0.15 mol) of o-amino-benzhydroxamic acid, 50 ml of methanol and 27.2 g (0.2 mol) of tetramethyl orthocarbonate is boiled under reflux for 2 hours and then cooled to 5° C. The product which crystallizes out is filtered off under suction. In this manner, 17 g (60% of theory) of 2-methoxy-3-hydroxy-3,4-dihydro-4-oxo-quinazoline are obtained in the form of colorless crystals of melting point 220° C. ##STR18##
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[F:43])(=[O:35])=[O:34])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4S(C3C=CC=CC=3)(=O)=O)=[N:12][CH:11]=2)[CH2:3]1.[OH-].[Na+]>C(O)(C)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[F:43])(=[O:34])=[O:35])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][NH:19]4)=[N:12][CH:11]=2)[CH2:3]1
Reactant: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (105 mg, 0.140 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.699 ml, 1.399 mmol) added. The reaction mixture was stirred at RT for 2 h, the solvent removed under a stream of nitrogen and the residue dissolved in water (1 ml) and acidified to pH˜6 by the addition of 2M hydrogen chloride (aq)(a black precipitate formed). The suspension was extracted with dichloromethane (3×2 ml) and the combined organics dried to give a brown solid. This was combined with the black precipitate which remained insoluble in the extraction, dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (20 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:7][C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][S:5][CH:6]=1.[Cl:18]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C(O)(=O)C>[ClH:1].[Cl:18][C:4]1[S:5][CH:6]=[C:2]([Cl:1])[C:3]=1[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc2[nH]c(Nc3cscc3Cl)nc2c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cl
Product: Fc1ccc2[nH]c(Nc3c(Cl)csc3Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(4-Chloro-thiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine (85 mg) was dissolved in acetic acid (4 ml) and under vigorous stirring at room temperature a solution of N-chlorosuccinimide (42 mg) in acetic acid (4 ml) was added. After stirring for 45 min. at room temperature, stirring was continued for 5 h at 50° C. After the addition of further N-chlorosuccinimide (4 mg) stirring was continued for one hour at 50° C. Then the reaction mixture was treated with toluene (20 ml) and solvent mixture distilled off. The residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by preparative HPLC, the product containing fractions were combined, the acetonitrile was removed, the aqueous residue made basic and extracted three times with ethyl acetate. The organic layers were combined, dried (MgSO4) and filtered. After removal of the solvent water and 2 N HCl were added to the residue. After freeze drying the desired product (17 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH:37]([NH2:39])[CH3:38]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH:37]([CH3:38])[CH2:36][N:35]([CH3:40])[CH3:34])=[O:23])(=[O:15])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CC(N)CN(C)C
Product: CC(CN(C)C)NC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0333 cm3 of 1-(dimethylamino)-2-propylamine. 49 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide are thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.13 (d, J=6.5 Hz, 3H), from 2.10 to 2.25 (mt, 1H), 2.15 (s, 6H), 2.38 (dd, J=13 and 8 Hz, 1H), 2.98 (s, 3H), 3.80 (mt, 2H), 4.14 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.46 (d, J=8 Hz, 4H), 7.83 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.16 (broad d, J=8 Hz, 1H)].
Reaction SMILES: [ClH:1].Cl.C(N(CC)[C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([CH2:13][CH3:14])[CH:7]=1)C.[S-2:17].[Na+].[Na+].[Cl-].[Na+]>O.[Fe](Cl)(Cl)Cl>[Cl-:1].[CH2:13]([CH:8]([C:9]1[SH+:17][C:11]([CH2:10][CH3:9])=[CH:6][CH:7]=[CH:8][CH:6]=[CH:11][CH:10]=1)[CH3:7])[CH3:14]
Reactant: CCc1cc(N(CC)CC)ccc1N
Reactant: [S-2]
Reactant: Cl
Agent: Cl[Fe](Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCc1ccccccc(C(C)CC)[sH+]1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 6.2 %

Procedure:
N,N-Diethyl-m-ethyl-p-phenylenediamine dihydrochloride (2 g, 7.5 mmol) was dissolved in water (75 cm3) and the solution adjusted to pH 1.6. The pink solution then had sodium sulphide (>60%) (1.35 g, 10.4 mmol) added portion-wise. To the suspension was added an aqueous solution of iron (III) chloride (4.22 g, 15.6 mmol in 35 cm3 of water) where there was an immediate colour change to purple. The solution was then aerated for 1 hour before a second portion of iron (III) chloride (4.22 g, 15.6 mmol in 35 cm3 of water) solution was added. The solution was cooled to 5° C. before filtering and washing the precipitate with water. The precipitate was also washed with ethanol and the ethanol concentrated to give a sticky purple solid. To the aqueous filtrate was added sodium chloride (50 g) and the solution was stirred for 10 minutes whereby the colour changed to red/purple as the product was salted out. The suspension was filtered and the solid dissolved in dichloromethane (100 cm3) and methanol (10 cm3) before drying over magnesium sulphate. Filtering and concentration with the ethanol soluble product gave the title compound (0.06 g, 3%) as a purple solid. dH (250 MHz; D2O): 6.73 (2H, s, ArH), 6.48 (2H, s, ArH), 3.45 (8H, brdq, NCH2), 2.46 (4H, q, 7.5, CH2), 1.17 (12H, brdt, CH3), 0.93 (6H, t, 7.5, CH3); m/z (ESI) 396.2 (100%, [M-Cl]+). Optionally, flash column chromatography was performed to remove iron chloride residues, with 10% methanol: 90% dichloromethane as eluent and using silica 40-63μ 60?.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([CH:16]=1)[OH:15])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:18][C:19]1([CH3:34])[CH:24]2[CH2:25][CH:20]1[CH:21]=[CH:22][C:23]2(OC(=O)C)[O:26]C(=O)C>>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([OH:17])[C:13]([CH:21]2[CH:20]3[CH2:25][CH:24]([C:19]3([CH3:34])[CH3:18])[C:23](=[O:26])[CH2:22]2)=[C:14]([OH:15])[CH:16]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OC1(OC(C)=O)C=CC2CC1C2(C)C
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Product: CCCCCCC(C)(C)c1cc(O)c(C2CC(=O)C3CC2C3(C)C)c(O)c1

Procedure:
Following the same procedure, 1.18 g. of 5-(1,1-dimethylheptyl)resorcinol and 1.19 g. of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene were reacted to afford (+)-4-[4-(1,1-dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone having the identical physical properties as that obtained as described in Example 3.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([NH2:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28].P>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[N:19][P:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(N)=Nc2ccccc2C(C)C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: P
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2ccccc2C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
N2-(2-isopropylphenyl)-4-methylbenzamidine (1.26 g, 5.0 mmol) was dissolved in 25 mL of diethylether and cooled to 0° C. Butyllithium (2.50 mL of 2.0 M solution in pentane, 5.0 mmol) was added dropwise, producing a fluffy white suspended solid. The slurry was warmed to room temperature and stirred for 2 hours. Chlorodiisopropylphosphine (0.80 mL, 5.0 mmol) was added slowly at room temperature. The suspended solid became finer and denser and the solution became slightly yellow upon complete addition of the phosphine. Stirring was continued for 1 hour. The solution was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo. The yellow foamy residue was suspended in 25 mL of pentane, stirred for 2 hours and taken to dryness under vacuum, affording 1.64 g (70%) of yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH2:16][CH2:15][C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:20].[Ce+4].S([O-])([O-])(=O)=O>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH2:16][C:15](=[O:20])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Reactant: O=S(=O)([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2=O
Yield: 29.9 %

Procedure:
To a suspension of 2-Acetylamino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (140 g) in acetic acid (1.5 L) and water (1.5 L) was added gradually cerium (IV) sulfate 4 hydrate (900 g) with vigorously stirring. After the solution was stirred overnight, the solid was removed by filtration and the filtrate was concentrated. The solution was then neutralized with aqueous ammonia and extracted 3 times with ethyl acetate-tetrahydrofuran (=4:1). The organic layers were combined and evaporated in vacuo. The resulting solid was washed with tetrahydrofuran to provide the title compound (44 g) as a pale yellow solid.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([NH2:8])=[O:7].Br[CH2:16][C:17]([O:19]CC)=[O:18]>C(O)C>[C:6]([C:5]1[C:4]([I:14])=[C:3]([C:11]([I:12])=[CH:10][C:9]=1[I:13])[O:2][CH2:16][C:17]([OH:19])=[O:18])(=[O:7])[NH2:8]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1c(I)cc(I)c(O)c1I
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I
Yield: 93.7 %

Procedure:
0.436 g (19 mmol) of sodium is dissolved in 20 ml of ethanol. Then 9.78 g (19 mmol) of 3-hydroxy-2,4,6-triiodobenzamide and subsequently 3.5 g (21 mmol) of ethyl bromoacetate are added thereto. The mixture is heated for one hour to reflux and, after several hours of stirring in an ice bath, the resultant 3-carbamoyl-2,4,6-triiodophenoxyacetic acid ethyl ester is vacuum-filtered, washed with a small amount of ice-cold ethanol, and suspended in 80 ml of water. The mixture is brought to pH 12 by adding concentrated sodium hydroxide solution, stirred for 30 minutes at 60° C., the solution is treated with 1 g of active carbon, filtered, and brought to pH 1 by the dropwise addition of dilute hydrochloric acid. After several hours of stirring in an ice bath, the thus-formed precipitate is vaccum-filtered, washed with water, and dried, thus obtaining 10.2 g (89% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[C:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)([OH:32])=[O:31]>>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:39]([C:36]3[CH:35]=[CH:34][C:33]([C:30]([OH:32])=[O:31])=[CH:38][CH:37]=3)(=[O:41])=[O:40])=[CH:27][CH:28]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In the same manner as in Example 377, 3-acetyl-2-(4-aminobenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one was reacted with 4-carboxybenzenesulfonyl chloride to give the title compound. yield: 45 mg (26%)
Reaction SMILES: [OH:1][C:2]1([C:15](OC)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.CC(C)([O-])C.[K+].[C:25](=[S:27])=S.ClC(OCC)=O.[C:34]1([NH:40][NH2:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:34]1([NH:40][N:41]2[C:15](=[O:16])[C:2]3([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=4[C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:1][C:25]2=[S:27])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C1(O)c2ccccc2-c2ccccc21
Reactant: S=C=S
Reactant: NNc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N(Nc2ccccc2)C(=S)OC12c1ccccc1-c1ccccc12
Reaction time: 0.05 h

Procedure:
A solution of 9-hydroxy-9-fluorenecarboxylic acid, methyl ester (8.91 g, 0.0371 mole) in tetrahydrofuran (89 ml) was treated with potassium tert.-butoxide (4.16 g, 0.0371 mole). After 6 minutes the solution was cooled in an ice bath and carbon disulfide (2.3 ml, 0.038 mole) was added. After 7 minutes ethyl chloroformate (3.6 ml, 0.038 mole) was added to the cold solution. After 7 minutes 97% phenylhydrazine (3.9 ml, 0.038 mole) was added. After 3 minutes, the mixture was evaporated under reduced pressure to a yellow syrup. The syrup was treated with 1-chlorobutane and water, and the organic layer was washed with saturated sodium bicarbonate solution, water, 1N HCl, and water. The dried (magnesium sulfate) solution was filtered and evaporated under reduced pressure to an oil. The oil was crystallized from carbon tetrachloride/hexane, and the solid product further purified by boiling with isopropanol (without dissolution of all solid), cooling, and filtering. The product was obtained as 3.56 g (27% of theoretical) of analytically-pure white solid, m.p. 187°-189° C.
Reaction SMILES: C=C1OCC2C(OC(C)(C)O2)CO1.Br[CH2:15][CH:16]1[O:25][CH2:24][CH:23]2[CH:19]([O:20][CH:21]([CH2:26][CH3:27])[O:22]2)[CH2:18][O:17]1>>[CH2:15]=[C:16]1[O:17][CH2:18][CH:19]2[CH:23]([O:22][CH:21]([CH2:26][CH3:27])[O:20]2)[CH2:24][O:25]1
Reactant: CCC1OC2COC(CBr)OCC2O1
Agent: C=C1OCC2OC(C)(C)OC2CO1
Product: C=C1OCC2OC(CC)OC2CO1
Yield: 51 %

Procedure:
4-Methylene-9 -ethyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane was prepared in a similar way to 4-methylene-9,9-di methyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane starting from 131 mmol (35 g) of 4-bromomethyl-9-ethyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane, fractional distillation from 65° to 68° C. (0.3 mbar) giving 12.5 g (51% yield).