Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.Cl([O-])=[O:14].[Na+].O.O.P(O)(O)([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]([OH:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(Br)cc(F)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Br)cc(F)c1C(=O)O
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of 4-bromo-2-fluoro-6-methoxy-benzaldehyde (3.4 g, 14.6 mmol) in tert-butanol (70 ml) and water (35 ml), sodium chlorite (2.64 g, 29.2 mmol), monosodium phosphate dihydrate (11.4 g, 72.9 mmol) and 2-methyl-2-butene (12.4 ml, 116.7 mmol) are added successively at room temperature and the mixture is stirred for 2 h. After completion of the reaction (monitored by TLC), the mixture is concentrated under reduced pressure and the residue is diluted with ice water (50 ml) and acidified to pH 5 by adding 2N hydrochloric acid. The mixture is extracted with methyl tert-butyl ether (2×100 ml). The methyl tert-butyl ether layer is extracted again with 10% aqueous sodium hydroxide (100 ml). The aqueous layer is acidified to pH 2 with 5N hydrochloric acid and extracted with dichloromethane (2×50 ml). The organic layer is washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to obtain 4-bromo-2-fluoro-6-methoxy-benzoic acid (2.5 g, 10.0 mmol, 68%).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC1CCCNC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(C(OC2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows. The mixture of 8.28 g of diphenylmethanol, 5.05 g of 3-hydroxypiperidine and 9.5 g of p-toluene sulfonic acid monohydrate is heated to 160°-165° while evacuating the evolving water rapidly. After the water emission ceases, the mixture is heated to said temperature for 3 hours. It is allowed to cool to room temperature and is partitioned between 2 N aqueous sodium hydroxide and diethyl ether. The organic solution is separated, washed with water and saturated aqueous sodium chloride, dried and evaporated. The residue is taken up in diethyl ether, the solution extracted with 0.1 N hydrochloric acid, the extract washed with diethyl ether and made basic with saturated aqueous ammonia. It is re-extracted with diethyl ether, the extract dried and evaporated, to yield the 3-diphenylmethoxypiperidine as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N:10]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: OCc1ccnc(Br)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCc1ccnc(-n2cccn2)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of (2-bromopyridin-4-yl)methanol [118289-16-0] (370 mg, 2.00 mmol), 1H-pyrazole (204 mg, 3.00 mmol), Cu powder (26 mg, 0.40 mmol) and Cs2CO3 (1.30 g, 4.00 mmol) in acetonitrile (4 mL) was heated under reflux for 16 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the organic layer was evaporated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: 50% ethyl acetate in hexane) to yield the title compound (260 mg, 74%). [LCMS RtF=0.31 min, [M+H]+=176.1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[O:15]=[C:14]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:13]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccccc2)C1
Temperature: 110 °C
Yield: 97.2 %

Procedure:
A mixture of aniline (3.26 g; 34.68 mmol) and 2-methylenesuccinic acid (5.47 g; 41.62 mmol) in water (10 mL) was heated in a sealed tube at 110° C. for 30 hours. After cooling to room temperature, 6N NaOH (13 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 6.92 g (97%) of 5-oxo-1-phenypyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([CH3:20])[C:17](I)=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[F-:22].[K+].COC(=O)[C:27](Cl)([F:29])[F:28].O>CN(C)C=O.[Cu](I)I.ClCCl>[Br:1][C:2]1[CH:19]=[C:18]([CH3:20])[C:17]([C:27]([F:29])([F:22])[F:28])=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: [F-]
Reactant: COC(=O)C(F)(F)Cl
Reactant: Cc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1I
Agent: I[Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of 2-(2-bromo-5-iodo-4-methylbenzyl) isoindoline-1,3-dione (560 mg, 1.22 mmol) in N,N-dimethylformamide (10 mL) was added copper iodide (467.6 mg, 2.45 mmol) and potassium fluoride (291.1 mg, 4.91 mmol). The solution was heated to 120° C. After 20 minutes methyl-2-chloro-2,2-difluoroacetate (709.71 mg, 4.91 mmol) was added to the orange suspension and the heating was continued for 8 hours. After about 30 minutes gas evolution was observed and the solution became yellow. After cooling the mixture was poured into water (50 mL), forming an emulsion, to which was added dichloromethane (300 mL). The mixture was stirred for 20 minutes then filtered through a pad of Celite®, rinsing through with dichloromethane. The organic layer was washed with 25 mL of 2 N HCl, dried with anhydrous sodium sulfate and concentrated under reduced pressure to a yellow solid (510 mg). This material was recrystallized from hot ethanol (30 mL) then allowed to stand at room temperature for 72 hours. The crystals were collected by filtration and rinsed with ethanol to give a white crystalline solid (314 mg). Final purification was achieved by recrystallization from hot acetonitrile to give the title compound (200 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H) 7.74(m, 2H) 7.50 (s, 1H) 7.39(s, 1H) 4.84(s, 2H) 2.32(s, 3H). GC-MS calc. 398, found 376 (M-F)
Reaction SMILES: O(C[C@H:10]([OH:12])C)[Si](C(C)(C)C)(C)C.N[C:14]1C=CN(C)N=1.[CH3:20][O:21][C:22](=[O:40])[C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[C:25]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=2)[CH:24]=1>>[CH3:20][O:21][C:22](=[O:40])[C:23]1[CH:28]=[C:27]([O:29][CH2:14][O:12][CH3:10])[CH:26]=[C:25]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=2)[CH:24]=1
Reactant: Cn1ccc(N)n1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(C(C)=O)cc2)c1
Product: COCOc1cc(Oc2ccc(C(C)=O)cc2)cc(C(=O)OC)c1

Procedure:
The compound of Production Example 123 was obtained as a colorless amorphous substance by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method, using (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane, 3-amino-1-methyl-1H-pyrazole and 3-(4-acetyl-phenoxy)-5-hydroxy-benzoic acid methyl ester obtained by deprotection of the methoxymethyl group of 3-(4-acetyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtained by reaction of the formyl group of 3-(4-formyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtained by the same method as in Production Example 122 with methylmagnesium bromide, followed by oxidation.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.Cl.[CH3:24][NH:25][C:26](=[O:29])[CH2:27][NH2:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:48][OH:49]>>[F:18][C:17]([F:20])([F:19])[C:48]([OH:29])=[O:49].[CH3:24][NH:25][C:26]([CH2:27][NH:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)=[O:29].[CH3:24][NH:25][C:26]([CH2:27][NH:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)=[O:29]
Reactant: CO
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CNC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CNC(=O)CNCCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Product: O=C(O)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (50 mg) in methanol (1 mL) was added glycine methyl amide hydrochloride (41 mg) and acetic acid (12 μL). The mixture was stirred for 5 minutes then sodium triacetoxy borohydride (42 mg) was added and stirring was continued at room temperature overnight. Methanol was removed in vacuo and the resulting residue dissolved in DCM (20 mL) and washed with saturated sodium bicarbonate and water (1:1, 2×20 mL). The organic layer was separated, dried over sodium sulphate and evaporated to yield crude product as an oil. Purification by preparative-HPLC afforded the TFA salt of 4-[3-(methylcarbamoylmethyl-amino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid (13 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.[IH:20]>>[I:20][C:13]1[CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:16]=[CH:15][N:14]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Fc1ccc(-c2cc(I)ncn2)cc1F

Procedure:
The compound was prepared according to Example 1 using 3,4-difluorophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[Br:20]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([Br:20])[CH2:18][CH3:19]
Reactant: BrBr
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a stirred suspension of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (30.3 g., 0.10 moles) in acetic acid (300 ml.) is added a solution of bromine (16.0 g., 0.10 moles) in acetic acid (50 ml.) over a period of 30 minutes. The reaction is catalyzed by the addition of 48% aqueous hydrobromic acid (2 drops). The clear yellow solution is stirred at room temperature for 30 minutes then poured into ice water (1 l.) containing sodium bisulfite (2 g.). The crude (1-oxo-2-bromo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (36 g., 97%) thus obtained is filtered, washed with water and dried. It melts at 189°-191° C. after recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[NH2:14][C:12]1[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CO
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1

Procedure:
A solution of 15.2 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-nitrobenzothiazole in 600 ml of methanol is hydrogenated in presence of 6.5 g of Raney Nickel at room temperature. After removing the catalyst the solution is concentrated and the solid filtered to give 6-amino-2-tert-butyl-5-(4-methylpiperidin-1-yl)benzothiazole melting at 146°-148°.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][N:11]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCN1C[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)C1
Yield: 66.3 %

Procedure:
(3R,4R,5R)-3-Benzyloxy-5-hydroxymethyl-4-piperidinol (87 mg, 0.37 mmol), 1-iodobutane (81 mg, 0.44 mmol, 50 μl), potassium carbonate (154 mg, 1.1 mmol) and dry acetone (8 ml) were stirred for 24h at 40° C. under a nitrogen atmosphere. The solvent was evaporated in vacuo, and the residue purified on a silica gel column (Eluent: ethyl acetate/methanol/25% ammonium hydroxide (6/1/1%)). This afforded the free base of (3R,4R,5R)-3-benzyloxy-1-butyl-5-hydroxymethyl-4-piperidinol (Yield: 72 mg, 67%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(OCC)(=O)C>[C:24]([C:23]1[CH:22]=[C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cccc(N)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 35.4 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 6 ml of water and 1 ml of ethyl acetate in place of the methanol, and 118 mg of 3-aminobenzonitrile in place of the 3-(tert-butyl)aniline. 120 mg of N-(3-cyanophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: O=Cc1c(F)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1C1OCCO1
Yield: 116.6 %

Procedure:
2-Chloro-6-fluorobenzaldehyde (100 g), ethylene glycol (192 g) and p-toluenesulphonic acid (17 g) were dissolved in toluene and heated under reflux for four days using a Dean and Stark adapter to collect the water. After cooling the mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 2-(2-chloro-6-fluorophenyl)-1,3-dioxolane (149 g) as an orange oil, NMR (CDCl3) 4.05(m,2H), 4.3(m,2H), 6.35(s, 1H), 7.2(m,3H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.C(Cl)(=O)CCCCCCC/C=C\CCCCCCCC>>[CH2:13]([NH:27][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCN
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: NC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
N-Tetradecyl-N-(D-galactopyranosyl)amine was prepared from 30 g of D-galactose and 53 g of tetradecylamine as described in Example 44. The galactosylamine was reacted with oleoyl chloride according to the compound described in Example 11.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([NH2:6])=[S:5])#[N:2].O=[C:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][C:20]([OH:22])=[O:21].CN1CCOCC1.Cl[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:2][C:1]1[C:3]2[C:7]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[C:18]3[CH2:17][CH2:16][CH:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]3=[N:6][C:4]=2[S:5][C:31]=1[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)CCl
Reactant: O=C(O)CC1CCCC1=O
Reactant: N#CC(=Cc1cccs1)C(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: CCO
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CCC3CC(=O)O
Temperature: 25 °C
Yield: 30 %

Procedure:
To a mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (6.3 g, 33 mmol), 2-oxocyclopentaneacetic acid (4.6 g, 33 mmol) in 70 ml of ethanol was added N-methylmorpholine (6.6 g, 65 mmol). The resulting mixture was refluxed overnight, then 2-chloroacetamide (6.1 g, 65 mmol) and anhydrous potassium carbonate (9.0 g, 65 mmol) was added with stirring. The reaction mixture was continued to reflux overnight. The reaction mixture was cooled to room temperature and the solid was filtered and washed with ethanol. The sodium salt of product was dissolved in 100 ml of water and neutralized with 10% hydrochloric acid to pH<6. The precipitate was filtered and washed with water to give 3.7 g (31%) of pure product as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 12.24 (brs, 1H), 7.87 (d, J=5.1 Hz, 1H), 7.27-7.24 (m, 2H), 7.18 (brs, 2H), 5.93 (brs, 2H), 3.55 (m, 1H), 2.94 (dd, J=3.9, 16.2 Hz, 1H), 2.68 (m, 2H), 2.40 (m, 2H), 1.75 (m, 1H). ES MS m/z 374 (M+H)+, 372 (M−H)−.
Reaction SMILES: [Na].[C:2]([NH:4][C:5]([CH:9]1[CH2:11][CH2:10]1)=[N:6][C:7]#[N:8])#[N:3].[ClH:12].CCCCCC>CC(=O)CC>[NH2:8][C:7]1[N:3]=[C:2]([Cl:12])[N:4]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:6]=1
Reactant: Cl
Reactant: N#CN=C(NC#N)C1CC1
Agent: [Na]
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: Nc1nc(Cl)nc(C2CC2)n1
Temperature: 10 °C

Procedure:
33 g of the sodium salt of N,N'-dicyano-cyclopropanecarbamidine (crude product) is suspended in 100 ml butanone. A solution of 20 g HCl in 400 ml butanone is dropped under stirring into this solution at 10° C. After the addition has been completed it is stirred for 1 h at ambient temperature. The reaction mixture is concentrated by evaporation and 200 ml of saturated aqueous NaHCO3 -solution and 300 ml diethylether are added. The organic phase is separated, washed, dried and concentrated by evaporation. One isolates 21 g of crude product which is treated with hexane to leave the pure title product.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:19][C:20]([I:24])=[C:21]([I:23])[I:22])(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[I:24][C:20](=[C:21]([I:23])[I:22])[CH2:19][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1nccn1CC(I)=C(I)I
Temperature: 60 °C

Procedure:
To a solution of 57 mg (0.5 mmoles) of 2-nitroimidazole and 300 mg (0.5 mmoles) of 3-p-toluenesulfonyloxy-1,1,2-triiodo-1-propene in 30 ml of dry DMF was added 0.07 ml (0.05 mmoles) of triethylamine and the resulting mixture was heated at 60° C. for one hour. After cooling, the reaction mixture was poured into 10 ml of ice-water, the brown crystalline substance thus separated was recovered by filtration, washed with water and then dried. Yield 246 mg (92%), mp 156°-158° C. (with decomposition).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1
Reactant: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
3-[4-(Azidomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (225 mg, 0.66 mmol) was dissolved in anhydrous THF (5.6 mL) and water (5.6 mL). The reaction was cooled to 0° C. followed by addition of triphenylphosphine (192 mg, 0.73 mmol). The reaction was allowed to warm to rt and was stirred overnight. The reaction was stripped to dryness, azeotroped with toluene and redissolved in MeOH. The crude residue was purified by preparative LCMS to yield the desired product (200 mg, 96%). MF═C11H7ClFN5O3; LCMS calculated for C11H8ClFN5O3(M+H)+: m/z=312.030.
Reaction SMILES: [C:1]([C:9]1[N:10]([N:14]2C(=O)C3=CC=CC=C3C2=O)[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN>C(O)C.O>[NH2:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: O
Solvent: CCO
Product: Nn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a suspension of 2-benzoyl-1-phthalimidopyrrole (35 g, 0.11 mole) in 350 ml ethanol was slowly added 45 ml methylamine (40% solution in water). After stirring two hours at ambient temperature, the mixture was diluted with 40 ml water and extracted with ether. The ether extract was washed with water and saturated NaCl solution, dried over anhydrous MgSO4, filtered and evaporated to 28 g oil which upon trituration with hexanes gave 21 g (99%) solid, m.p. 65°-69°. 3.5 g of this material was purified by HPLC (silica gel, 4% ethyl acetate/dichloromethane) to give 2.8 g solid, which was recrystallized from hexanes to give 2.4 g solid, m.p. 65°-67°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CC([O-])(C)C.[K+].[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20].S(=O)(=O)(O)O>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:17]([O:18][CH2:19][CH3:20])=[O:21])=[O:3])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
200 g (1.29 mol) of 4-chloroacetophenone (dissolved in 500 ml of diethyl carbonate) were added dropwise at 60° C. to a mixture of 296.4 g (2.59 mol) of potassium tert-butylate and 2.25 1 of diethyl carbonate. Thesuspension, which could be stirred with difficulty, was stirred at 60° C. for 3 h and then introduced into 2.7 1 of 10% strength sulfuric acid. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and concentration in vacuo gave the crude product, which was purified further by distillation (b.p. 130° C., 0.4 mbar). Yield: 268 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([O:11][CH3:12])=[N:4][CH:3]=1.[CH3:13][NH2:14].[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]4[N:14]([CH3:13])[C:8](=[O:10])[C:7]5[CH:6]=[C:5]([O:11][CH3:12])[N:4]=[CH:3][C:2]=5[N:1]=4)=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)O)c(N)cn1
Reactant: CN
Reactant: O=Cc1ccc(OC2CCN(C3CCCC3)CC2)cc1
Product: COc1cc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCCC5)CC4)cc3)nc2cn1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-methoxyisonicotinic acid, methylamine and 4-[(1-cyclopentyl-4-piperidinyl)oxy]benzaldehyde.