Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH2:5])(=O)[CH3:2].[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14]=[C:15]=[S:16])[CH2:8][CH2:7]1>C(O)C>[CH3:2][C:1]1[N:14]([CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][O:6][CH2:11][CH2:10]2)[C:15]([SH:16])=[N:5][N:4]=1
Reactant: CC(=O)NN
Reactant: S=C=NCCN1CCOCC1
Solvent: CCO
Product: Cc1nnc(S)n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.2 %

Procedure:
The title compound was prepared by a modification of a procedure reported for related compounds: Henichart, J. P.; Bernier, J. L. Synthesis 1980, 4, 311. Acetic hydrazide (3.7 g, 50 mmol) in ethanol (50 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. 2-morpholinoethyl isothiocyanate (8.61 g, 500 mmol) in ethanol (50 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting resin was dissolved in minimal ethanol and ether. A white solid precipitated out, was filtered and washed with cold ether. The filtrate, containing uncyclized intermediate, was concentrated and dissolved in xylenes. The mixture was refluxed under N2 for 8 h, then allowed to sit at room temperature, under N2. for 48 h. A white solid formed, was filtered and washed with cold ether. The first and second batches of white solid were combined to yield 7.33 g (64%) of the desired product.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[C@@H](C1C=CC=CC=1)CN>C(C(C)=O)C(C)C>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 40 °C
Yield: 56.5 %

Procedure:
(±)-2-(3-Benzoylphenyl)propionic acid (20.3 g, 80 mmol) was dissolved in methyl isobutyl ketone (hereinafter abbreviated to "MIBK") (90 g) with heating. Then, (S)-(+)-3-methyl-2-phenylbutylamine (6.68 g, 41 mmol) was added dropwise with stirring at 40° C. After completing the addition, the reaction solution was stirred at 40° C. for one hour and then cooled slowly to 10° C. over 6 hours. After stirring at 10° C. for 3 hours, the precipitated crystal was filtered and the filter cake was washed with cold MIBK (50 ml) and then dried. In this manner, a diastereomer salt (11.5 g) of (S)-(+)-2-(3-benzoylphenyl)propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6](CCC2C(Cl)=CC=CC=2C(N)=S)[CH:7]=1.[SH2:22].BrC1C=CC(OC)=C(C[CH2:31][C:32]2[C:39](Cl)=[CH:38][CH:37]=[CH:36][C:33]=2[C:34]#[N:35])C=1>C(O)C.C(N(CC)CC)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:22][CH2:31][C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[C:34]2[NH:35][CH2:32][CH2:33][CH2:34][N:35]=2)[CH:7]=1
Reactant: COc1ccc(Br)cc1CCc1c(Cl)cccc1C(N)=S
Reactant: COc1ccc(Br)cc1CCc1c(Cl)cccc1C#N
Reactant: S
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Br)cc1SCc1ccccc1C1=NCCCN1
Temperature: 80 °C

Procedure:
9, 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzamide. As shown in Scheme 9, hydrogen sulfide gas was bubbled into a solution of 2.75 g (7.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzonitrile in 20 mL of ethanol and triethylamine (5:4 v/v) for 10 minutes. The solution was then heated to 80° C. in a sealed pressure tube for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate twice. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to give 3.0 g of crude product which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15][C:16]([F:23])([F:22])[CH:17]([OH:21])[C:18](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[F:15][C:16]([F:23])([F:22])[CH:17]([C:18]1[NH:1][C:2]2[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[C:5]([C:6]#[N:7])=[CH:8][C:9]=2[N:10]=1)[OH:21]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: N#Cc1cc(N)c(N)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Diamino-2-trifluoromethyl-benzonitrile (4.14 g; 20.6 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (4.50 g; 31.2 mmoles) were suspended in 6N HCl (7 mL; 42 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (5.19 g; 62.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude dark solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a dark brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[N:12][CH:11]=[C:10]([CH:9]=2)[C:19]([NH:30][CH2:29][C:26]2[CH:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[O:28][N:27]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)on1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN 1018782-76-7) and 5-trifluoromethyl-isoxazol-3-methanamine (example BF) as starting materials; LC-MS (UV peak area/ESI) 98%, 452.0975 (M+H)+.
Reaction SMILES: CN.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1.[C:18]([BH3-])#[N:19].[Na+].C(O)(=O)C>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([NH:19][CH3:18])[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CN1CCCC1)c1cccc(Br)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCCC1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
2.0 M methylamine solution in THF (55 mL, 110.0 mmol) was added to a solution of 1-(3-bromophenyl)-2-(1-pyrrolidinyl)ethanone (7.40 g, 27.62 mmol) in anhydrous THF (30 mL) at room temperature. The reaction mixture was stirred for 1 h and then sodium cyanoborohydride (5.21 g, 82.86 mmol) and acetic acid (3 mL) were added. The resulting reaction mixture was continually stirred at room temperature for 96 h until the starting material was consumed completely. Saturated K2CO3 solution (100 mL) was added and after stirring for 15 min, the solution was extracted with ethyl acetate (2×80 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield the title compound as a yellow oil (3.75 g, 48%), MS (ES) m/e 283[M+H]+.
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[NH3:10].S(=O)(=O)(O)O.[O:16]1[CH2:20][CH2:19]CC1>ClCCl>[O:3]([CH2:4][CH3:5])[P:1]([NH:10][P:1]([O:16][CH2:20][CH3:19])([O:3][CH2:4][CH3:5])=[O:6])(=[S:2])[O:6][CH2:7][CH3:8]
Reactant: N
Reactant: C1CCOC1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOP(=O)(NP(=S)(OCC)OCC)OCC
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Diethyl chlorothiophosphate (25.04 g, supplied by Aldrich Chemical Company Ltd.) was added dropwise with stirring to a saturated solution of ammonia in tetrahydrofuran (250 cm3). Stirring was continued for two hr. The mixture was filtered to remove precipitated ammonium chloride and then concentrated by distillation of the solvent under reduced pressure to a yellow oil (diethyl thiophosphoramide, 21.0 g, 31P NMR in CDCl3, singlet, 67.4 ppm downfield of H3PO4). Without further purification, this amide (8.5 g) was redissolved in tetrahydrofuran (250 cm3) and sodium hydride (13.2 g of a 20% suspension in toluene) was added with stirring. When hydrogen ceased to be evolved, diethyl chlorothiophosphate (9.5 g) was added dropwise during 15 min. The mixture was stirred and heated at 65° C. for 2 hr. and then cooled and filtered. The solvent was distilled under reduced pressure leaving a yellow oil which was dissolved in dichloromethane (250 cm3) and stirred with dilute sulphuric acid (1 molar to ensure that the pH of the suspension was less than pH 2). The organic phase was separated, dried with magnesium sulphate, filtered, and concentrated by distillation of solvent under reduced pressure yielding tetraethyl thioimidodiphosphate (11.2 g, 31P NMR in CDCl3, singlet, 56.4 ppm downfield of H3PO4). The purity was determined by titration of a sample dissolved in 50% tetrahydrofuran--water with 0.1M aqueous sodium hydroxide solution for the acidic (NH or SH) proton, which was 50% neutralised at pH 6.1. By this method the purity was found to be 77% of theoretical based on molecular weight 321. The compound of Formula I in which R1 =R2 =R3 =R4 =ethoxy was examined as an extractant for zinc by Tests 1 and 2, with the results listed in Tables 1 and 2, which show that it is a weak extractant for zinc with high selectivity over iron.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][C:15]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:27])=[CH:25][C:20]3=[N:19][CH:18]=2)=[O:16])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:6]=1)[CH3:4].[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.CO>[ClH:1].[ClH:1].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][C:15]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH3:42])[CH2:32][CH2:33]4)=[O:27])=[CH:25][C:20]3=[N:19][CH:18]=2)=[O:16])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:6]=1)[CH3:4]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCNCC5)ccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (Example 12; 5 mg, 0.0084 mmol) in dichloromethane/methanol (1:1; 1 mL) was added an excess of sodium triacetoxyborohydride and formaldehyde solution. The mixture was stirred at ambient temperature for 2 hours. Further excess sodium triacetoxyborohydride and formaldehyde solution were added and the mixture was stirred an additional 0.5 hours. The mixture was concentrated under a stream of nitrogen and the residue was purified using preparative thin layer chromatography on silica, eluting with 15% methanol and 0.5% ammonium hydroxide in dichloromethane to provide the desired product (free base form). This material was dissolved in methanol and filtered. To the filtrate was added hydrogen chloride (1 mL; 2M in ether) and the solvent was evaporated to a residual film under a stream of nitrogen. The material was dried under high vacuum to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(4-methylpiperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (3.3 mg). MS (APCI), positive scan, m/z=537.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=O)[CH:4]=[CH:5][N:6]=1.[ClH:22].Cl.[NH2:24][CH2:25][CH2:26][O:27][NH2:28].N1C=CC=CC=1.C(O)C>[OH-].[Na+].C(OCC)(=O)C>[ClH:22].[ClH:22].[NH2:24][CH2:25][CH2:26][O:27][N:28]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1nccn1CCCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nccn1CCCC(=NOCCN)c1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone (2.65 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.60 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was diluted with 10% sodium hydroxide solution and ethyl acetate. The layers were separated. The aqueous phase was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 1.4 g (37%) of product, mp 181°-184° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7]P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Br:31]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:24])/[CH:7]=[CH:32]\[C:28]1[S:29][C:30]([Br:31])=[C:26]([Br:25])[CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=Cc1cc(Br)c(Br)s1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C\c1cc(Br)c(Br)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(Diphenoxy-phosphoryl)-acetic acid tert-butyl ester (8.49 g, 24.4 mmol) was dissolved in THF (519 ml) and cooled to −78° C. followed by the addition of triton B (13.3 ml, 40% by wt. in MeOH). After 15 minutes a solution of 4,5-Dibromo-thiophene-2-carbaldehyde (7.0 g, 25.9 mmol) in THF (20 ml) was added and the reaction was stirred for 1 hour. Next, the reaction mixture was quenched with sat. NH4Cl (250 ml), diluted with H2O (500 ml), and extracted with EtOAc (2×300 ml). The organic layers were washed with water (2×200 ml), brine (100 ml), and dried (MgSO4). The crude was passed through a plug of silica gel with EtOAc providing the desired product 9.2 g (96%) as a 4:1 mixture of cis:trans. MS calculated for C10H12BrNS−H 367, observed M-tBu 309, 311, 313.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.[C:20]([NH2:24])(=[O:23])[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:24][C:20](=[O:23])[CH2:21][CH2:22][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(N)=O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C1CCC2=C(CCN(Cc3ccccc3)C2)N1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
To a solution of 1-benzyl-4-piperidone (213 g, 1.13 mol) in toluene (700 ml) was added pyrrolidine (190 ml, 2.25 mol), the reaction mixture was fitted with a Dean-Stark head and heated to 150° C. for 18 h. The reaction mixture was cooled and evaporated under reduced pressure, p-toluenesulphonic acid (4.0 g, 0.022 mol) was then added to the residue followed by acrylamide (160 g, 2.25 mol). The reaction mixture was heated with rapid stirring to 90° C. for 1.5 h and then for a further 2 h at 120° C. The cooled mixture was then filtered and the solid obtained washed with acetone followed by ether. The mother liquors were combined, evaporated under reduced pressure and the residue partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure to afford a further batch of solid. The solids were combined and heated to reflux with 4-toluenesulphonic acid (10 g, 0.056 mol) in dioxane (400 ml) for 18 h. On cooling, a colourless crystalline product was formed which was filtered and washed with EtOAc to afford the subtitle compound as colourless crystals (176 g, 65%). Rf 0.1 (EtOAc). 1H NMR (CDCl3) δ: 2.20 (4H, d), 2.50 (2H, t), 2.70 (2H, s), 3.00 (2H,s), 3.65 (2H, s), 7.20-7.45 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH2:18][CH3:19])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([CH3:11])=[N:6][C:7]=1[NH:8][CH2:9][CH3:10].[C:20](O)(=O)[CH3:21]>>[CH3:10][C:9]1[N:8]([CH2:20][CH3:21])[C:7]2=[N:6][C:5]([CH3:11])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:17][CH2:18][CH3:19])=[C:2]2[N:1]=1
Reactant: CC(=O)O
Reactant: CCNc1nc(C)c(C(=O)OCC)c(OCC)c1N
Product: CCOC(=O)c1c(C)nc2c(nc(C)n2CC)c1OCC

Procedure:
Crude 5-amino-4-ethoxy-6-ethylamino-2-methylpyridine-3-carboxylic acid, ethyl ester is refluxed in acetic acid overnight. The solvent is distilled off and the residue, 2,5-dimethyl-7-ethoxy-3-ethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is recrystallized from petroleum ether, m.p. 62°-65°.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:21])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[OH:21]
Reactant: CCOC(=O)CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1c(C)c(O)c(CCCCCCO)c(C)c1O

Procedure:
A solution of 2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of ethylester) (0.1 part) in diethyl ether (10 volume parts) was treated with lithium aluminum hydride in the same manner as Example 53 to give 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-hydroquinone (formula III-2 wherein R=H3C, n=4, in the free form). The product was treated with ferric chloride in the same manner as Example 53 and then crystallized from diethyl ether. The procedure provided 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (formula IV-2, wherein R=H3C, n=4 in the free form) as yellow needles melting at 43°-45° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([NH:26][NH2:27])=[O:25].C(N(CC)CC)C>O1CCCC1>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]1[O:25][C:1](=[O:2])[NH:27][N:26]=1
Reactant: Cc1cccc(Nc2ccccc2C(=O)NN)c1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ccccc2-c2n[nH]c(=O)o2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1,1'-Carbonyldiimidazole (912.3 mg, 5.63 mmoles) is added to a 0° C. solution of 2-[(2,3-dimethylphenyl)amino]benzoic acid hydrazide (1.041 g, 4.08 mmoles) and triethylamine (608 μl, 4.36 mmoles) in 20 ml of tetrahydrofuran. The reaction is stirred at room temperature for one hour. The volatiles are removed in vacuo, and the residue is dissolved in 1:1 ethyl acetate/ether. The organic solution is washed consecutively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant white solid is purified by flash chromatography with 1:1 hexane/ethyl acetate as eluant to give 968.8 mg (85%) of 5-[2-[(2,3-dimethylphenyl)amino]phenyl]-1,3,4-oxadiazol-2(3H)-one, mp 239°-241° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[CH2:12][C:13](=O)[CH2:14]CC(O)=O>C(O)CC.Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:12][CH2:13][CH3:14])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CCCO
Product: CCCOC(=O)CCC(=O)CN
Temperature: 75 °C
Reaction time: 20 h

Procedure:
0.5 g 5-aminolevulinic acid hydrochloride was dissolved in 100 ml dry n-propanol containing 1-2 drops of cone hydrochloride in a 250 ml glass reactor equipped with a stirrer, reflux condenser and a thermometer. The Reaction mixture was stirred at 70-80° C. for approx. 20 hours. After all the 5-aminolevulinic acid was converted to its n-propylester (followed by 1H-NMR), the excess propanol was removed, and the product dried under high vacuum (<1 mBar) at 40-50° C. The reaction gave 0.49 g propyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.
Reaction SMILES: C=CC=C.O.C(=O)=[O:7].[CH2:9](O)[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>CN(C)C=O>[CH2:9]=[CH:10][CH:11]([OH:7])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: O=C=O
Reactant: C=CCCCC=CCO
Agent: C=CC=C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCC(O)C=C
Yield: 10.1 %

Procedure:
The thus deposited and separated palladium complex was placed again in the autoclave, to which 0.5 mol of 1,3-butadiene, 1 mol of water, 0.6 mol of carbon dioxide, and 63 ml of dimethyl formamide were fed afresh. Then, the reaction was conducted under the same conditions as mentioned above, with the consequence that 0.158 mol of 2,7-octadien-1-ol, and 0.016 mol of 1,7-octadien 3-ol were produced.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[NH+]([CH2:9][C:10]([CH2:15]N(C)C)=[CH:11][NH+](C)C)C.[OH-:19].[Na+].O>C(#N)C>[CH3:3][C:2]1[N:5]=[CH:11][C:10]([CH:15]=[O:19])=[CH:9][N:4]=1
Reactant: [OH-]
Reactant: CN(C)CC(=C[NH+](C)C)C[NH+](C)C
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred slurry of acetamidine hydrochloride (19.4 g, 0.20 mol) and vinamidinium salt (48.91 g, 0.183 mol) in acetonitrile (240 mL) was added a solution of 40% wt. NaOH in water (27.4 g, 0.274 mol) over a 30 minutes period. After the addition was complete, the resulting reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and diluted with water (250 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C.O>[N:12]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(N2CCNCC2)ncn1
Yield: 56.6 %

Procedure:
A solution of 4-chloro-6-(trifluoromethyl)pyrimidine (1.0 g, 5.48 mmol), piperazine (2.36 g, 27.4 mmol), and triethylamine (2.29 mL, 16.4 mmol) in DMF (20 mL) was stirred at 100° C. for 5 h. The reaction solution was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10% MeOH/5% Et3N/EtOAc) to yield the desired product (720 mg, 56.6%). LCMS calculated for C9H2F3N4: (M+H) 233.1; found 233.1.