Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1N
Temperature: 90 °C
Yield: 50.8 %

Procedure:
A solution of 1.0 g (3.6 mmol) of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester, 0.9 g (7.2 mmol) of pyridine-4-boronic acid, 0.42 g (0.36 mmol) of (tetrakistriphenyl phosphine) palladium (0) in 50 mL of DME and 8.4 mL of 2 N Na2CO3 was degassed with nitrogen for 20 min and then heated at 90° C. for 12 h. The reaction mixture was cooled to r.t., extracted with ethyl acetate (100 mL), washed with water, brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 8:2 hexane and ethyl acetate to afford 0.5 g (50%) of the 2-Amino-3-nitro-5-pyridin-4-yl-benzoic acid methyl ester as a solid. LCMS: 273 (M+1)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:44][C:45]1[CH:46]=[CH:47][C:48]([O:57][CH3:58])=[C:49]([CH:51]2[NH:55][CH2:54][C@H:53]([OH:56])[CH2:52]2)[CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[F:44][C:45]1[CH:46]=[CH:47][C:48]([O:57][CH3:58])=[C:49]([C@H:51]2[CH2:52][CH:53]([OH:56])[CH2:54][N:55]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:50]=1
Reactant: COc1ccc(F)cc1C1C[C@@H](O)CN1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3OC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
To a suspension of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.541 g, 2.61 mmol) and BOP reagent (1.57 g, 3.56 mmol) in DMF/CH2Cl2 (3 mL/3 mL) at 0° C. was added (R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.588 g, 2.37 mmol) followed by DIEA (1.66 mL, 9.50 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was diluted again with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO3 followed by brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography, eluting with CH2Cl2 to 5% MeOH in CH2Cl2 to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.735 g, 1.84 mmol, 77.3% yield). LC/MS (ES+APCI) m/z=401.1 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:9][CH2:10][CH:11]=[CH2:12])[CH:7]=[CH2:8].CCN(CC)CC>C(OC(=O)C)C>[CH2:6]([N:9]([CH2:10][CH:11]=[CH2:12])[C:3](=[O:4])[CH2:2][Br:1])[CH:7]=[CH2:8]
Reactant: C=CCNCC=C
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCN(CC=C)C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Bromoacetyl bromide (45 g, 0.22 mol) in ethylacetate (25 mL) was added dropwise to a solution of diallyl amine (9.6 g, 0.1 mol), Et3N (15 mL), in ethyl acetate (50 mL) at 0° C. The reaction was then warmed to ambient temperature, and the stirring was continued for about 3 h. The resulting mixture was washed with saturated NaHCO3 solution (3×100 mL) and dried over Na2SO4. The evaporation of the solvent gave 16.2 g of product as a light yellow oil (yield 75%). ESI-MS (m/z): 218 (M+H+). 1H NMR δD (CDCl3): 5.75 (m, 2H, CH), 5.19 (m, 4H, CH2), 3.95 (d, 4H, NCH2), 3.81 (2, 2H, BrCH2).
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O.[CH2:28]1[C:36]2C=CC3C4C(CC(=O)C=3[C:31]=2[C:30](=O)[C:29]1=O)=CC=CC=4.NCC(N)=O.C(N)C#N.NCC(O)=O>O.CO>[C:5]1(=[O:4])[C:9]2[CH:10]=[CH:11][C:12]3[C:30]4[C:16]([CH:15]=[CH:14][C:13]=3[C:8]=2[CH:7]=[CH:6]1)=[CH:31][CH:36]=[CH:28][CH:29]=4
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: O=C1Cc2ccc3c(c2C1=O)C(=O)Cc1ccccc1-3
Agent: N#CCN
Agent: NCC(=O)O
Agent: NCC(N)=O
Solvent: CO
Solvent: O
Product: O=C1C=Cc2c1ccc1c2ccc2ccccc21
Temperature: 25 °C

Procedure:
FIG. 2 illustrates the use of the system of FIG. 1 for the analysis of a sample which contains amines. The mobile phase contains sodium dodecyl sulfate, methanol, water and sodium phosphate to adjust the pH to 2.5, which functions as the elutriant and peri-naphthindan-2,3,4-trione hydrate which functions as the reactant component. The sample to be analyzed contains glycinamide, glycinonitrile, and glycine. The objective in this instance is to detect the glycine and glycinamide in this mixture. The mobile phase is pumped through the system at the rate of 2 ml/min. The chromatographic column is of the reverse phase type and is maintained at 25° C. The oven which contains the reaction column was maintained at 105° C., and is packed with non-porous glass beads. The above components of the mixture were separated in the separation column 9, and were reacted in the reaction column 12 with the peri-naphthindan-2,3,4-trione hydrate of the mobile phase to yield di-hydroxy peri-naphthindenone as the principal reaction product. The compound which absorbs light energy in the frequency range of 380 nm was flowed with the mobile phase to the photometric detector which was set to scan this part of the visible spectrum. With particular reference to FIG. 2, the inverted peak F represents the dead volume of the system. G and H are the glycine and glycinamide peaks with peak I showing the presence of glycinonitrile. The area under the glycine and glycinamide peaks represents the relative amount of each of these materials present in the sample.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3].OCC[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].COC(=O)O.O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36](CCO)[CH2:35][CH2:34]1>>[CH3:17][CH:16]([N:13]1[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1)[CH2:3][O:2][C:1](=[O:6])[O:4][CH2:5][CH:32]([CH3:31])[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: OCCN1CCN(CCO)CC1
Reactant: COC(=O)OC
Agent: COC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(COC(=O)OCC(C)N1CCNCC1)N1CCNCC1

Procedure:
A total of 180.0 grams (2.0 mole) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. on the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of methyl bis(2-piperazinoethyl)carbonate and bis(methyl 2-piperazinoethyl)carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in bis(methyl 2-piperazinoethyl)-carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and bis[1,4-(2-hydroxyethyl)-piperazine]carbonate (ca. 9.9 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[CH3:25]I>CN(C=O)C.C(OCC)(=O)C.[Ag]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18][O:19][CH3:25])[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CI
Reactant: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1CC=C(C(=O)OC)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 41.5 h
Yield: 59.6 %

Procedure:
A solution of methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate (Example 7, Step 9; 32.2 mg, 0.089 mmol) in DMF (0.25 mL) was diluted with methyl iodide (0.75 mL, 11.99 mmol) and treated with silver oxide (103 mg, 0.444 mmol). The resulting suspension was protected from ambient light and stirred at rt for 41.5 h. After this time, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 10-30% ethyl acetate-hexanes, to provide methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(methoxymethyl)-6-methylcyclohex-1-enecarboxylate as a colorless gum (20 mg, 60%). Mass spectrum m/z 394.1 (M+NH4+). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.2 Hz, 1 H), 7.38 (d, J=8.4 Hz, 1 H), 7.31 (dd, J=8.4, 2.2 Hz, 1 H), 7.27 (m, 1 H), 3.64 (s, 3 H), 3.24 (s, 3 H), 3.15 (d, J=5.7 Hz, 2 H), 2.44 (m, 1 H), 2.00 (ddd, J=19.5, 10.4, 2.4 Hz, 1 H), 1.74 (m, 1 H), 1.65 (s, 3 H), 1.61 (m, 1 H), 1.56 (m, 1H).
Reaction SMILES: Br[CH:2]([C:4]1([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)OCCO1)C.[C:21](=O)([O-:23])[O-:22].[Ca+2].C(N)=O>>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:4]([CH3:2])[C:21]([OH:23])=[O:22])[CH:18]=[CH:17]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2cc(C3(C(C)Br)OCCO3)ccc2c1
Agent: [Ca+2]
Solvent: NC=O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 2(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane (0.84 g; 2.5 mmol), calcium carbonate (0.3 g; 3 mmol) and formamide (5 ml) is heated at 140° C. under stirring for 1 h. The mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (0.172 g; 0.75 mmol; yield 30%), m.p. 154°-155° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH3:16])=[CH:10][C:9]=1[CH3:33])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:34][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH3:16])=[CH:10][C:9]=1[CH3:33])([CH3:6])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
To a solution of example 102 (50 mg, 0.5 mmol) in EtOH (20 mL) was added excess of a 1N NaOH solution and the mixture was stirred at 60° C. for 2 h. The reaction was cooled, evaporated to dryness, the residue taken up with water, neutralized with 1N HCl to pH 7 and then extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The residue was then chromatographed eluting with CH2Cl2 (100%) then CH2Cl2/MeOH (98/2) and finally CH2Cl2/MeOH (95/5) to afford the title compound as an oil (10 mg, 20%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH:11]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)c1cccc(S(=O)(=O)c2ccccc2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 2-methoxyaniline as the starting materials.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[C:4]([N:6]1[CH2:20][CH2:19][C:9]2([NH:13][C:12](=[O:14])[C@H:11]([CH2:15][CH2:16][S:17][CH3:18])[NH:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O.C[Si]([Cl:28])(C)C>CC(CC)=O>[ClH:28].[CH2:21]([CH:3]([CH2:1][CH3:2])[C:4]([N:6]1[CH2:7][CH2:8][C:9]2([NH:13][C:12](=[O:14])[C@H:11]([CH2:15][CH2:16][S:17][CH3:18])[NH:10]2)[CH2:19][CH2:20]1)=[O:5])[CH3:22]
Reactant: C[Si](C)(C)Cl
Agent: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](CCSC)N2
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one (140 mg, 0.4 mmol) was dissolved in ethyl methyl ketone (1 mL), and water (4 μL) and TMSCl (59 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration and dried in vacuo. The product 8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one hydrochloride was obtained in a yield of 117 mg (75%).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=C=O)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>ClCCl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (880 mg, 3.6 mmol), benzyl chloroformate (575 uL, 4.0 mmol) and Hunig's base (935 uL, 5.4 mmol) in dichloromethane (9.0 mL) was stirred at rt for 16 h. Saturated ammonium chloride was added and the separated aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried (anh. Magnesium sulfate), filtered and evaporated to yield a residue which was purified by reverse phase preparative HPLC. LC-MS m/z 377.1 [M+H]+.
Reaction SMILES: BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:22]([C:29]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:30]=1[C:31]1[C:32]([CH2:45][O:46][CH3:47])=[C:33]([C:42]([NH2:44])=O)[N:34]=[CH:35][C:36]=1[NH:37]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.O>[O:22]([C:29]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:30]=1[C:31]1[C:32]([CH2:45][O:46][CH3:47])=[C:33]([C:42]#[N:44])[N:34]=[CH:35][C:36]=1[NH:37]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCc1c(C(N)=O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCc1c(C#N)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
1.1 g of Br2 in 10 ml of methylene chloride is put in drop by drop into a stirred solution of 1.8 g (15 mmol) of triphenylphosphine in 50 ml of methylene chloride at 0° C. Then, 2 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxamide and 1.9 ml of triethylamine are added. The reaction mixture is stirred for 1 hour at 0° C. and then vigorously stirred with 25 ml of methylene chloride and 25 ml of water for 5 minutes. After removal of the aqueous phase from the organic phase by concentration, 0.8 g of the desired product is obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](NCCO)=[O:19].[Na].CCCCCCCCCC1C=CC([OH:40])=CC=1>>[C:18]([OH:19])(=[O:40])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCO
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Na]
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
(a-4) Mixture of 8 parts of stearic acid monoethanolamide (1:1) and 2 parts of sodium salt of nonylphenol-EO(4) sulfate
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(O[CH2:16][CH:17]([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][CH:17]([F:19])[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(F)F)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (3.506 g; 16.40 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 17 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-(2,2-difluoroethoxy)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.67 min.; no ionisation.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:6]1[CH2:7][CH2:8]2)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[C:38]([O:37][C:35]([N:34]1[CH:9]2[CH2:8][CH2:7][CH:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH:10]2[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C1C(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C2CCC1N2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)O)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1

Procedure:
A solution of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo [2.2.1] heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester (0.15 g, 2.58 mmol) and lithium hydroxide (0.062 g, 2.57 mmol) in THF:methanol:water (2.5: 1.5:1.5 mL) was stirred at 25° C. for 19 h. The solution was then concentrated in vacuo to give 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1] heptane-2,7-dicarboxylic acid 7-tert-butyl ester as a crude solid (0.150 g, 100%). MS: 568 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N+:5]([O-])[C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.[H][H]>[Ni].C(O)C>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COc1nc2ccc(Cl)cc2[n+]([O-])n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1nnc2cc(Cl)ccc2n1

Procedure:
21.2 g (0.1 mole) of 3-methoxy-7-chloro-benzo-1,2,4-triazine 1-oxide and 5 g of Raney nickel in 150 ml of ethanol were initially introduced into a stirred VA autoclave. A pressure of 15 atmospheres of hydrogen was applied at 30° C. The mixture was stirred at 30° to 50° C for 5 hours and during this time further hydrogen was fed in under pressure until the pressure remained constant. The autoclave was let down, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from wash benzine. 15.2 g. that is to say 78% of theory, of 3-methoxy-7-chlorobenzo-1,2,4-triazine with a melting point of 122° C were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].O.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Retinoyl fluoride can be mixed with commercially available glucuronic acid. The reaction is carried out in acetone/water to facilitate the solubility of the water-insoluble retinoyl fluoride and the water-soluble glucuronic acid. The reaction takes place in slightly alkaline pH and hence sodium bicarbonate is used in the reaction mixture. Stirring the mixture at room temperature for 20-24 hours followed by acidification of the solution and extraction with ethyl acetate yields retinoyl glucuronide as the major product. Pure all-trans retinoyl β-glucuronide can be obtained by a combination of column and high-performance liquid chromatography (HPLC).
Reaction SMILES: [CH2:1]([C:6]1([CH3:18])[CH:11]([CH2:12][CH3:13])[NH:10]C(CC)[NH:8][CH:7]1[CH2:16][CH3:17])[NH:2][CH2:3][CH2:4][CH3:5].Cl>O>[NH2:8][CH:7]([CH2:16][CH3:17])[C:6]([CH:11]([NH2:10])[CH2:12][CH3:13])([CH3:18])[CH2:1][NH:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCNCC1(C)C(CC)NC(CC)NC1CC
Agent: Cl
Solvent: O
Product: CCCNCC(C)(C(N)CC)C(N)CC
Yield: 84.3 %

Procedure:
A mixture of 21.1 grams of 5-(2-azapentyl)-5-methyl-2,4,6-triethylhexahydropyrimidine, prepared as described in example 1, 25 grams of conc. HCl and 25 grams of water was refluxed for 2 hours. The organic layer which separated was removed and discarded and the aqueous solution after extraction with ether was basified with a sodium hydroxide solution. The organic layer which separated was removed and the aqueous phase extracted with ether. The ethereal solution was combined with the organic layer and after drying evaporated under diminished pressure to yield 15.0 grams of 7-amino-6-(1-aminopropyl)-6-methyl-4-azanonane; b.p. 72°-76° C./0.05 torr; Infrared spectrum, 2.97 and 3.05μ (N-H) and 6.15μ (NH2); 'H nuclear magnetic resonance spectrum, solvent CDCl3, internal reference tetramethylsilane, δ in ppm: 3.07-2.30, 6H; 2.00-1.14, 6H; 1.14-0.67, 12H. 13C nuclear magnetic resonance spectrum, solvent CDCl3, internal reference tetramethylsilane, δ in ppm: ##STR7## 11.9(1); 23.2(2); 52.9 and 52.8(3); 54.7 and 54.3(5); 42.9 and 43.1(6); 58.8, 56.7 and 57.5(7,11); 24.9, 24.7 and 25.7(8,12); 12.2(9,13); 19.2 and 17.0(10).