Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C@H:16]2[CH2:24][OH:25])(=[O:14])=[O:13])=[C:7]([CH3:26])[CH:6]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH3:26])[C:8]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C@H:16]2[CH2:24][O:25][CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:35])(=[O:13])=[O:14])=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2CO)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
35% sodium hydroxide solution (10 ml) was added to a cooled (0° C.) solution of (S)-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)indolin-2-yl)methanol (3.3 mmol, 1.0 eq) and tetra-n-butylammonium chloride (1.1 mmol, 0.33 eq) in toluene (20 ml). tert-Butylbromoacetate (1.5 eq) was added slowly to this mixture and the mixture was stirred for 2 h at room temperature. The organic phase was separated off and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over Na2SO4 and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 50%
Reaction SMILES: OS(O)(=O)=O.CC([N:15]1[N:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([NH:52][C:53](=[O:64])[C@H:54]([C@H:60]([CH2:62][CH3:63])[CH3:61])[NH:55][C:56]([O:58][CH3:59])=[O:57])[CH2:28][C@H:29]([OH:51])[C@@H:30]([NH:38][C:39](=[O:50])[C@H:40]([C:46]([CH3:49])([CH3:48])[CH3:47])[NH:41][C:42]([O:44][CH3:45])=[O:43])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:22][CH:21]=2)=[N:16]1)(C1C=CC=CC=1)C>>[NH:18]1[C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][N:27]([NH:52][C:53](=[O:64])[C@H:54]([C@H:60]([CH2:62][CH3:63])[CH3:61])[NH:55][C:56]([O:58][CH3:59])=[O:57])[CH2:28][C@H:29]([OH:51])[C@@H:30]([NH:38][C:39](=[O:50])[C@H:40]([C:46]([CH3:48])([CH3:49])[CH3:47])[NH:41][C:42]([O:44][CH3:45])=[O:43])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24][CH:25]=2)=[N:16][N:15]=[N:19]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Agent: O=S(=O)(O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn[nH]2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reaction time: 1.25 h

Procedure:
35 ml of an 80% aqueous H2SO4 solution are added to 354 mg (0.435 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane, with ice-cooling. After stirring for 75 min, the mixture is worked up analogously to Example 26 to yield the title compound: HPLC20-100: tRet=12.6; FAB MS (M+H)+=696.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6]>[Fe]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([NH:2][CH3:1])[C:4]=1[C:5]#[N:6]
Reactant: CNc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Product: CNc1cccc(N)c1C#N

Procedure:
2-Amino-6-methylaminobenzonitrile is prepared by iron reduction of 2-methylamino-6-nitrobenzonitrile as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:28]3[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]3)[S:8][C:7]=2[CH:35]=1.[BH4-].[Na+].O>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:28]3[CH2:29][CH2:30][CH:31]([OH:34])[CH2:32][CH2:33]3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCC(=O)CC3)sc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCC(O)CC3)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
50 mg of [6-methoxy-2-(4-oxocyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 4 ml of methanol and 0.5 ml of THF, followed by ice cooling, 6 mg of sodium borohydride was added, and the mixture was stirred at 0° C. for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resultant crude product was purified by TLC (developing solvent, chloroform:methanol=19:1) to obtain 32 mg of [6-methoxy-2-(4-hydroxycyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:42])([C:18]3[N:19]=[CH:20][N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=3)[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:43]([NH:45][CH3:46])=[O:44])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:42])([C:18]3[N:19]=[CH:20][NH:21][CH:22]=3)[CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:43]([NH:45][CH3:46])=[O:44])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc(F)c(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(F)c(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 54.1 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 6-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide (1.64 g) and pyridine hydrochloride (559 mg), the colorless amorphous title compound (535 mg) was obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>CN(C)C=O.CS(C)=O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[O:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:18][CH:17]=1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: c1cnn(Cc2ccc(OCCOc3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 110 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous dimethylsulfoxide (5 ml) solution of 500 mg of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 1 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 488 mg of 2-bromothiazole was added dropwise over 10 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 280 mg of 4-(1-pyrazolyl)methylphenyl 2-(2-thiazolyloxy)ethyl ether (compound 5). Yield, 41%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C-:5]#[N:6].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=O)[CH2:15][CH2:14][CH2:13]2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.[N+](C1C=CC=CC=1)([O-])=O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:5]#[N:6])=[CH:15][CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2c(c1)CCC=C2C#N
Reaction time: 2 h

Procedure:
A mixture of 25.25 g of dry aluminum chloride, 16.7 g of sodium cyanide, 1.7 g of tetrabutylammonium bromide, and 20 drops of concentrated HCl in 170 mL of nitrobenzene was stirred for two hours under a nitrogen atmosphere. Then 30 g of 6-methoxytetralone was added, and the reaction mixture was stirred at 90° C. for six hours to form 6-methoxy-1-cyano-3,4-dihydronaphthalene. A 200-mL portion of 20% NaOH was added, and the reaction mixture became warm and was stirred vigorously at 60° C. for one hour. The phases were allowed to separate. After the nitrobenzene phase had been transferred to another vessel, 35 g of bromine was slowly added and a precipitate formed. The reaction mixture was then heated to remove any HBr, cooled, and worked up to provide 28 g of 6-methoxy-5-bromo-1-cyanonaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[C:22]#[N:23])[CH2:35][CH2:34]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=473.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[C:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2)(O)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:31]=[C:27]1[NH:26][C:21]2([CH2:20][CH2:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:13]([NH:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)=[O:14])[CH:17]=3)[CH2:22]2)[C:29](=[O:30])[NH:28]1
Reactant: NCc1cccc2cccnc12
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1NC(=O)C2(CCc3cc(C(=O)NCc4cccc5cccnc45)ccc3C2)N1

Procedure:
A mixture of 8-(aminomethyl)quinoline (14 mg, 0.088 mmol), (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (15 mg, 0.058 mmol), EDC (22 mg, 0.115 mmol), and HOBT (13 mg, 0.088 mmol) was stirred in DMF (0.8 mL) at ambient temperature for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a tan solid. MS: m/z=401 (M+1). HRMS: m/z=401.1584; calculated m/z=401.1608 for C23H21N4O3.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.C1([Li])C=CC=CC=1.CN(C)[CH:27]=[O:28]>>[CH3:17][O:16][C:10]1[C:11]([O:14][CH3:15])=[CH:12][CH:13]=[C:8]([OH:7])[C:9]=1[CH:27]=[O:28]
Reactant: COc1ccc(OC2CCCCO2)cc1OC
Reactant: CN(C)C=O
Agent: [Li]c1ccccc1
Product: COc1ccc(O)c(C=O)c1OC

Procedure:
3,4-Dimethoxyphenol tetrahydropyranyl ether (47.6 g, 0.2 M) was lithiated with phenyllithium (from 21.02 ml bromobenzene and 2.89 g lithium), formylated by the addition of dry dimethylformamide (15 ml) and subsequently hydrolysed in an analogous manner to that described in example 2(E). The crude product was distilled under high vacuum to give 2,3-dimethoxy-6-hydroxybenzaldehyde as a yellow oil which solidified on standing. After trituration with 40/60 petrol and filtration the product had m.p. 53°-54° C. (Found: C, 59.18; H, 5.54. C9H10O4 requires C, 59.33; H, 5.53%). (C) 5-(2-Formyl-3-hydroxy-4-methoxyphenoxy)pentanoic acid
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[OH:10])[CH3:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.B(F)(F)F.C([O-])(=O)C.[Na+]>>[CH2:1]([C:3]1[C:4]([OH:10])=[CH:5][C:6]([OH:9])=[C:7]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:8]=1)[CH3:2]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CCc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: CCc1cc(C(=O)Cc2ccc(OC)cc2)c(O)cc1O
Temperature: 50 °C

Procedure:
4-Ethylbenzene-1,3-diol (17.5 g, 159 mmol) and 4-methoxyphenylacetic acid (26.4 g, 159 mmol) was heated with boron trifluoride dietherate solution (100.7 ml, 795 mmol) to 90° C. for 3 hours. The mixture was then cooled to 50° C. before it was added to a stirred solution of 10% aqueous sodium acetate (11). The resulting mixture was stirred at room temperature over night at room temperature. The resulting solid was filtered off dissolved in a minimum volume of methanol and pre-absorbed onto silica gel. For the initial purification the crude material was chromatographed, eluting with an increasingly polar mixture of methylene chloride/methanol (95/5 to 90/10). The fractions containing product were grouped into two groups, evaporated under vacuum to give a solid which was triturated with diethyl ether in a further purification step. The title compound was obtained in three portions of varying purity as an off white solid from combined purest fractions (10.78 g, 26.2%) the less pure fractions (7.56 g, 18.4%) and from the combined, evaporated mother liquors after renewed trituration with iso-hexane/diethylether to give the title product (6.32 g, 15.4%). 1H NMR Spectrum (purest solid): δH (300 MHz, CDCl3) 1.22 (3H t, J=7.5 Hz), 1.63 (1H, s), 2.57 (2H q, J=7.5 Hz), 3.79 (3H, s), 4.16 (2H d, J=3.0 Hz), 5.52 (1H, s), 6.30 (1H, s), 6.85-6.90 (2H, m), 7.16-7.21 (2H, m), 7.59 (1H, s), 12.51 (1H, s); Mass Spectrum: (M+H−) 258.20.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]#[N:15]>>[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[Cl:1]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: ClCl
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1N

Procedure:
Chlorine gas was passed through a stirred solution of 4-amino-3-cyano-trifluoromethylbenzene (5g) in carbon tetachloride (75ml) until the absence of starting material was confirmed by gas liquid chromatography. Flow of the gas was then stopped and evaporation of the solvent under reduced pressure gave 4-amino-3-chloro-5-cyanotrifluoromethylbenzene as an orange solid (5.5g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>C(COC)OC>[S:18]1[CH2:14][CH2:15][N:16]=[C:17]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: S=C=NCCCl
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Cc2ccccc2N1C1=NCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.0 g (0.03 mole) of oxindole in 125 ml dry glyme there is added 1.4 g (0.03 mole) of sodium hydride (50% oil dispersion) and the mixture is stirred at room temperature for 3 hours. Then 3.6 g (0.3 mole) of 2-chloroethyl isothiocyanate in 5 ml of dry glyme is added and the mixture is refluxed overnight. After evaporation of the solvent in vacuo, the residue is chromatographed on an Alumina Act. IV column. Elution with ethyl ether yields the product which is crystallized from ethyl ether to yield 0.6 g, m.p. 97°-99°.
Reaction SMILES: Cl[S:2]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]([F:16])=[CH:14][C:13](/[CH:17]=[C:18](\[CH3:24])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][C:11]=2[F:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42])=[N+:29]=[N-:30].C(N(CC)CC)C.O>C(Cl)Cl>[N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][S:2]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]([F:16])=[CH:14][C:13](/[CH:17]=[C:18](\[CH3:24])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][C:11]=2[F:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)Cl)cc2)c(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a solution of (E)-ethyl 3-(4-(4-(chlorosulfonyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (intermediate 41.3) (250 mg, 0.60 mmol) in DCM (3 mL) was added a solution of 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (157 mg, 0.72 mmol) and triethylamine (72 mg, 0.72 mmol) in DCM (2 mL). After 15 minutes, water (10 mL) was added and the reaction mixture was extracted with DCM (2×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography on silica gel eluting with 50% EtOAc in DCM to give the title compound (169 mg).
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[C:3]([F:24])([F:23])[C:4]([P:7]([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)[OH:8])([F:6])[F:5].C1(P(Cl)(Cl)(Cl)[Cl:37])C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[C:3]([F:24])([F:23])[C:4]([P:7]([Cl:37])([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[O:8])([F:6])[F:5]
Reactant: ClP(Cl)(Cl)(Cl)c1ccccc1
Reactant: O=P(O)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=P(Cl)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.83 h
Yield: 62.2 %

Procedure:
Variant a) 2.49 g (5.0 mmol) of bis(nonafluorobutyl)phosphinic acid are added dropwise at room temperature to a solution of 1.47 g (5.9 mmol) of phenyltetrachlorophosphorane in 3 cm3 of dry chloroform, and the mixture is stirred for a further 50 minutes. Chloroform is separated off by distillation, and bis(nonafluorobutyl)phosphinyl chloride is distilled off at atmospheric pressure, giving 1.62 g of bis(nonafluorobutyl)phosphinyl chloride, which corresponds to a yield of 63%, based on the phosphinic acid employed.
Reaction SMILES: [CH3:1]C1(C)CCCC(C)C1=O.[CH3:11][C:12]1([CH3:21])[CH:17]([CH3:18])[CH2:16][CH2:15][CH:14](C)[CH:13]1[OH:20]>>[CH3:1][C:17]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13](=[O:20])[C:12]1([CH3:11])[CH3:21]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: CC1CCC(C)C(C)(C)C1O
Product: CC1(C)CCCC(=O)C1(C)C

Procedure:
If the procedure of Example 8 is followed but instead of 28 g of 2,2,6-trimethyl-cyclohexanone 31 g of 2,2,3,6-tetramethyl-cyclohexanol are employed, fractional distillation gives 9.6 g of unconverted tetramethyl-cyclohexanone and 21 g (corresponding to 73% of theory, based on ketone converted) of 2,2,3,6-tetramethyl-1-(but-1'-yn-3'-en-1'-yl)-cyclohexanol of boiling point 66°-67° C/0.2 mm Hg and refractive index nD25 = 1.5018. Fragrance note: faintly floral, coniferous, fruity.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[S:4][C:3]=1[CH:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[N:11]=[CH:10][CH:9]=[CH:8]3.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(C)(C)C>[Br:1][C:2]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[S:4][C:3]=1[CH:15]([O:20][C:6]([CH3:7])([CH3:2])[CH3:5])[C:16]([O:18][CH3:19])=[O:17])[N:11]=[CH:10][CH:9]=[CH:8]3
Reactant: COC(=O)C(O)c1sc2ccc3ncccc3c2c1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1sc2ccc3ncccc3c2c1Br
Temperature: -5 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
To a suspension of methyl 2-{1-bromothieno[3,2-f]quinolin-2-yl}-2-hydroxyacetate (16h) (152 mg, 0.43 mmol) in tert-butylacetate (2.3 mL) at −10° C. was added perchloric acid (69.4 μL). The mixture was stirred at −5° C. for 5 hours and then warmed at room temperature for 1 hour more. The mixture was then basified with a saturated aqueous solution of sodium bicarbonate until pH 8. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by 2 preparative TLC (cyclohexane/ethyl acetate 60/40) to afford the desired product (16i) (55 mg, 0.13 mmol, 31%) as beige powder.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18]Br.O>C(O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC#CCOC1CCCCO1
Reactant: Sc1ccccc1
Solvent: CCO
Solvent: O
Product: C(#CCSc1ccccc1)COC1CCCCO1

Procedure:
A stirred solution of sodium ethoxide in ethanol, obtained from 1.3 g of sodium and 50 ml of absolute ethanol was treated dropwise with 5.5 g (0.05mol) of thiophenol in 15 ml of absolute ethanol. The reaction mixture was refluxed for 1 hour and then treated with 5.84 g (0.025 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether, refluxing the mixture for 2 additional hours. It was then cooled, poured into water and extracted withmethylene chloride. The organic extract was washed with water, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, to produce 4-phenylthiobut-2-yn-1-ol tetrahydropyranyl ether, as an oil. Upon hydrolysis of the ether group with pyridinium p-toluenesulfonate in ethanol, in accordance with the method of Example 16, part E, there was obtained 4-phenylthiobut-2-yn-1-ol.
Reaction SMILES: C(OC([N:8]1[CH2:31][C@H:30]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[C:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:34]=2)[CH2:29][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:11])=O)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:44][O:43][C:39]1[CH:38]=[C:37]2[C:42]([C:33]([O:32][C@H:30]3[CH2:31][NH:8][C@H:9]([C:10]([NH:12][C@H:13]([C:17]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:11])[CH2:29]3)=[CH:34][C:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:36]2)=[CH:41][CH:40]=1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)NS(=O)(=O)c1ccccc1
Yield: 100 %

Procedure:
Compound 72 was kept in DCM-TFA 2:1 (2 mL) for 2.5 hr at RT. The solution was co-evaporated with toluene to dryness. Yield 100%. M+H 603.12