Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[C@H:8]([OH:12])[CH2:9][N:10]([C:17]([N:16]([CH3:20])[CH3:15])=[O:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: OC1CNCC1Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1

Procedure:
A solution of 3.5 g. of 4-(4-chlorophenoxy)-3-pyrrolidinol, 1.8 g. of dimethylcarbamyl chloride and 1.7 g. of triethylamine in 300 ml of methylene chloride was stirred for 60 hr. The solvent was removed under vacuum, 300 ml of benzene was added and the mixture was refluxed for 2 hr., then filtered. After solvent evaporation, the residue was dissolved in cyclohexane-benzene and charcoaled. The product was then crystallized, collected by filtration and recrystallized from cyclohexane-benzene; m.p. 137°-142° C. Analysis: Calculated for C13H17N2O3Cl: C, 54.84; H, 6.02; N, 9.84. Found: C, 54.64; H, 6.01; N, 9.77.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C[O-].[Na+].[C:14]([O:18][CH3:19])([CH3:17])(C)C.O>CN(C)C=O>[O:18]1[CH2:19][C@H:14]1[CH2:17][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: COC(C)(C)C
Reactant: Oc1cccc2[nH]ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reaction time: 0.08 h

Procedure:
A 3.2 g portion of 4-hydroxy-1H-indole was dissolved in 31 mL of dimethylformamide in a 50 mL flask equipped with a magnetic stirrer, nitrogen bubbler and thermometer. To it was added 1.27 g of sodium methoxide and the mixture was stirred until a blue-black solution resulted. The warm mixture was placed under vacuum for 5 minutes to remove most of the resulting methanol. To the mixture was added 6 g of oxiranylmethoxysulfonyl-3-nitrobenzene, resulting in an exotherm to about 37° C. The mixture was stirred at ambient temperature for 1 hour, and was then poured into a separatory funnel containing 55 mL of methyl t-butyl ether and 80 mL of water. The mixture was shaken well, and the layers were separated. The organic layer was removed and the aqueous layer was extracted with 2×55 mL of methyl t-butyl ether. The organic layers were combined and back-extracted with 50 mL of 5% aqueous lithium chloride. The layers were separated again, and the organic layer was dried with magnesium sulfate and filtered. The organic filtrate was concentrated under vacuum to about 15 mL of volume, and was seeded with pure desired product and stirred. The product was crystallized to a thick slurry to which 20 mL of heptane was slowly added. The mixture was stirred for one hour more and filtered, and the filter cake was rinsed with 3:1 heptane:methyl t-butyl ether, and then with heptane. The product was dried in a vacuum oven at 40° C. to obtain about 3.5 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([C:13](=[O:24])[CH2:14][N:15]3[N:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]3)[CH:10]=[C:9]2[C:25]([O:27]C)=[O:26])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([C:13](=[O:24])[CH2:14][N:15]3[N:19]=[N:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16]3)[CH:10]=[C:9]2[C:25]([OH:27])=[O:26])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)Cn2nnc(C(F)(F)F)n2)cn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cn1nnc(C(F)(F)F)n1)c1cc(C(=O)O)n(-c2ncccc2Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
130 mg (0.31 mmol) of methyl 1-(3-chloropyridin-2-yl)-4-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]acetyl}-1H-pyrrole-2-carboxylate were dissolved in 3 ml of ethanol, 19 mg (0.47 mmol) of 2N aqueous sodium hydroxide solution were added and the mixture was stirred at RT for 4 h. The solvent was distilled off under reduced pressure, the residue was taken up in water and the mixture was extracted once with methyl tert-butyl ether. The aqueous phase was then acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14](Br)=[C:13]([CH3:19])[N:12]=1.O.Cl>C(O)CO>[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[C:13]([CH3:19])[N:12]=1
Reactant: OCc1ccc(S)cc1
Reactant: Cc1nc(N)nc(O)c1Br
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Temperature: 155 °C

Procedure:
A stirred mixture of (4-mercaptophenyl)methanol (6.72 g), 2-amino-5-bromo-6-methylpyrimidin-4-ol (10.76 g) and K2 CO3 (7.29 g) in ethylene glycol (120 ml) was heated at 155° C. for 9 h. After cooling the mixture was poured into water (500 ml) and neutralised with conc. HCl. The precipitate was filtered, washed with water then 50% EtOH/ether and dried to give the subtitle compound as a solid, 6.7 g. 1H NMR DMSO-d6: δ11.07 (brs, 1H); 7.18 (d, 2H); 6.99 (d, 2H); 6.87 (brs, 2H); 5.09 (s, 1H); 4.41 (s, 2H); 2.24 (s, 3H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[NH:14][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: Nc1nccs1
Product: Cn1cc(C(=O)Nc2nccs2)c2ccccc21

Procedure:
1-Methyl-1H-indole-3-carboxylic acid and 2-aminothiazole was coupled and purified according to the conditions described in General Procedure (B), Step C).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17]C)=O.[CH3:19][N:20]=[C:21]=[S:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2[NH:1][C:21](=[S:22])[N:20]([CH3:19])[C:15](=[O:17])[C:3]=2[CH2:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN=C=S
Reactant: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(=S)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Temperature: 20 °C

Procedure:
788 g of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate from a) were dissolved in 2.5 l of toluene, and 447 g of methyl isothiocyanate and 625 ml of triethylamine were added, with stirring. After stirring for 24 h at an internal temperature of 100° C., the mixture was allowed to cool to 20° C. and the precipitate was filtered off with suction and washed with toluene. After drying, this gave 420 g of crude 6 benzyl-3-methyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[4,3-d]pyrimidin-4-one, which was reacted further in c).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cc2cc(OCC(=O)O)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 5-carboxymethoxy-1H-indole-2-carboxylic acid ethyl ester (1.5 g, 5.7 mmol) and 1-1′-carbonyldiimidazole (1.11 g, 6.85 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 30 mins. To the mixture was then added morpholine (1 mL) and the stirring was continued for overnight. The reaction was concentrated and the residue was dissolved in dichloromethane (200 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate and brine, dried and concentrated to give 1.6 g (85%) of 5-(2-morpholin-4-yl-2-oxo-ethoxy)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([Cl:29])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CC(=O)OCC>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([Cl:29])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1c(N2CCC(N)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of {1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (150 mg, 0.33 mmol) in EA (5 mL) was added a 5N HCl solution in EA (5 mL). The reaction mixture was stirred at RT for 2 h, and the solvent was concentrated in vacuo to give 120 mg of the title product as HCl salt (94%). 1H NMR (400 MHz, CD3OD): δ 1.67-1.72 (m, 2H), 2.02-2.06 (m, 2H), 3.13-3.16 (m, 2H), 3.34-3.38 (m, 1H), 3.42 (s, 3H), 3.98-4.02 (m, 2H), 7.82-7.90 (m, 3H). [M+H] Calc'd for C18H17FN6O, 353. Found, 353. 1H NMR (400 MHz, METHANOL-d4): δ ppm 1.73-1.91 (m, 2H), 2.18 (d, J=12.13 Hz, 2H), 3.06 (t, J=12.76 Hz, 2H), 3.33-3.40 (m, 1H), 3.57 (s, 3H), 3.83 (d, J=13.14 Hz, 2H), 7.75-7.93 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[N+:9]([O-])=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH:12]=3)[CH:7]=1.[CH:26]([N:29](CC)C(C)C)(C)C.C[Si](C#N)(C)C>C(#N)C.C(OCC)(=O)C>[C:26]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:25])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2)#[N:29]
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c[n+]1[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C#N)n1
Temperature: 100 °C
Yield: 28.9 %

Procedure:
To a slurry of 3-(5-fluoro-2-methylphenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (50 mg, 0.1 mmol) in acetonitrile (0.4 mL) was added N,N-diisopropylethylamine (0.05 mL, 0.3 mmol), followed by trimethylsilyl cyanide (0.06 mL, 0.44 mmol). The mixture was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as a white solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 9.52 (s, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 7.48-7.35 (m, 2H), 7.26 (td, J=8.5, 2.8 Hz, 1H), 2.37 (s, 3H), 2.13 (m, 1H), 0.99-0.83 (m, 4H). LCMS (Method E): RT=5.495 min, M+H+=347.1.
Reaction SMILES: Cl.[O:2]=[C:3]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])(C)C)[CH2:8][CH2:7][C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[NH:4]1.N[C@@H]1C[CH2:28][C:27]2C=C[CH:32]=[CH:33][C:26]=2NC1=O.C(=O)([O-])[O-].[Na+].[Na+].ClC(OCC1C=CC=CC=1)=O>O.C(OCC)(=O)C.C(#N)C.CO>[O:2]=[C:3]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][CH2:13][C:16]2[CH:32]=[CH:33][CH:26]=[CH:27][CH:28]=2)[CH2:8][CH2:7][C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[NH:4]1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 105 %

Procedure:
Combine methanol (5000 mL) and 5N aqueous hydrogen chloride solution (1393 mL, 5.57 mol) and heat to 35° C. for 15 minutes. Add tert-butyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (Armstrong III, Joseph D, et al, Tetrahedron Let. 35(20) pp. 3239-3242 (1994) (770 g, mmol and commercially available) portionwise over 1 hour. Concentrate the mixture under reduced pressure to a white solid. Combine this solid with additional (3R)-3-amino-1,3,4,5-tetrahydro-1-benzazepin-2-one (different lot, same method; 660 g, 3.78 mol) and dissolve in water (2.5 L). To the resulting solution add sodium carbonate (3.17 kg, 3.18 mol) and acetonitrile (7.5 L). Add benzyl chloroformate (7.14 mol, 1.21 Kg) dropwise over 2 hours. After 2 hours at ambient temperature, add ethyl acetate (8 L) and filter. Wash the wet cake with water (4.0 L), acetonitrile (2.0 L), and ethyl acetate (3.0 L). Dry the solid under reduced pressure for 48 hours to give the title compound (2.14 kg, 105%): MS (m/z): 310.8 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[Li+].[Cl-].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:9]([C:4]1[CH:3]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:7]=[CH:6][C:5]=1[F:8])[CH3:10]
Reactant: CCc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C#C[Si](C)(C)C)ccc1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-bromo-2-ethyl-1-fluoro-benzene (2.4 g, 11.82 mmol) in N,N-dimethylformamide (100 mL), trimethylsilyl acetylene (2.0 mL, 14.19 mmol), PdCl2(PPh3)2 (500 mg, 0.72 mmol), LiCl (1 g, 23.64 mmol), CuI (25 mg, 0.1 mmol) and triethylamine (3 mL) were added and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (hexanes) to give a brown oil. 1.58 g, 61%.
Reaction SMILES: Cl.O.[Cl-].[NH4+].[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([NH:13]O)[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[C:8]([C:23](=[O:25])[CH3:24])[CH:7]=1>C(O)C.[Fe]>[NH2:13][C:10]1[C:9]([C:15]2[CH:16]=[C:17]([F:22])[CH:18]=[C:19]([F:21])[CH:20]=2)=[C:8]([C:23](=[O:25])[CH3:24])[CH:7]=[C:6]([Cl:5])[C:11]=1[CH3:12]
Reactant: CC(=O)c1cc(Cl)c(C)c(NO)c1-c1cc(F)cc(F)c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cc(F)cc(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
Into a flask was placed a suspension of iron (1.50 g, 26.9 mmol) (<10 μm) in ethanol (22 mL) δ 0 M hydrogen chloride in water (0.374 mL, 2.24 mmol) was added and the suspension was stirred for 2 h at 60° C. A solution of 5.0 M ammonium chloride in water (3.86 mL, 19.3 mmol) was added followed by a solution of 1-[4-chloro-3′,5′-difluoro-6-(hydroxyamino)-5-methylbiphenyl-2-yl]ethanone (1.4 g, 4.5 mmol) in ethanol (5.2 mL). The resulting suspension was stirred at 60° C. for 1 hour. The mixture was cooled, filtered and evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and saturated sodium bicarbonate solution and stirred for a few minutes. The layers were separated and the ethyl acetate layer was washed with brine, dried over MgSO4 and evaporated in vacuo to give the desired product (0.95 g, 72%). LCMS calculated for C15H13ClF2NO (M+H)+: m/z=296.1. found: 296.0.
Reaction SMILES: [NH:1]1[C:5]([C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)=[CH:10][CH:9]=2)[CH3:7])=[N:4][CH:3]=[N:2]1.CC[O:26]C(C)=O>C1C=C(Cl)C=C(C(OO)=O)C=1>[F:22][C:20]([F:23])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C@H:6]([C:5]3[N:1]([OH:26])[N:2]=[CH:3][N:4]=3)[CH3:7])=[CH:9][CH:10]=2)[S:16][CH:17]=1
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ncn[nH]1
Reactant: CCOC(C)=O
Agent: O=C(OO)c1cccc(Cl)c1
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ncnn1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of intermediate 15b (0.21 g, 0.62 mmol) in EtOAc (5 ml), m-CPBA was added (0.17 g, 0.97 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water (2×10 ml) and anhydrous Na2SO4 and evaporated under vacuum to give a crude that, after purification by flash chromatography, afforded the pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-1,2,4-triazol-1-ol (15) as a white solid (67%). [α]D=−35 (c=0.82; CH3OH); 1H-NMR (CD3OD): δ 9.40 (bs, 1H, NH); 7.55 (d, 1H, J=2.5 Hz); 7.40 (d, 2H, J=7 Hz); 7.35 (d, 2H, J=7 Hz); 7.15 (s, 1H), 6.25 (d, 1H, J=2.4 Hz); 3.80 (q, 1H, J=7 Hz); 1.60 (d, 3H, J=7 Hz).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:12]2[O:11][C:10]([CH3:13])=[CH:9][C:8](=[O:14])[C:7]=2[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:22]CC1>C(#N)C>[CH:2]([C:3]1[C:12]2[O:11][C:10]([CH3:13])=[CH:9][C:8](=[O:14])[C:7]=2[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1)=[O:22]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(=O)c2c(C#N)ccc(C(Br)Br)c2o1
Solvent: CC#N
Product: Cc1cc(=O)c2c(C#N)ccc(C=O)c2o1

Procedure:
260 mg (0.72 mmol) of 8-(dibromomethyl)-2-methyl-4-oxo-4H-chromene-5-carbonitrile are heated with 187 mg (1.6 mmol) of N-methylmorpholine N-oxide with the addition of molecular sieves in 15 ml of acetonitrile under reflux overnight. After filtration through kieselguhr, the solvent is removed in vacuo, and the residue is purified by preparative HPLC. 23 mg (15% of theory) of the title compound are obtained.
Reaction SMILES: C(=O)(O)[O-].[K+].[CH:6](=O)[CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH:17]=[O:18].COP([CH2:26][C:27](=O)[CH2:28]P(OC)(OC)=O)(OC)=O.[Cl-].[Na+]>C(O)(C)(C)C.O>[C:17]1(=[O:18])[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH2:28][CH:27]=[CH:26]1
Reactant: O=CCCC=CCCC=CCCC=O
Reactant: COP(=O)(CC(=O)CP(=O)(OC)OC)OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1C=CCCC=CCCC=CCCC=C1

Procedure:
A 500 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and gas inlet tube was charged with 4 g of potassium bicarbonate and 125 ml of aqueous 90% t-butanol. The stirred mixture was heated at vigorous reflux under a steady flow of argon, while a solution of 3.10 g (16 mMole) of dodeca-4,8-diene-1,12dial and 4.40 g (16 mMole) of 1,3-bis(dimethylphosphono)propan-2-one in 25 ml of 90% aqueous t-butanol was added at a constant rate over a period of 4 h. The reaction mixture was poured into water containing some sodium chloride, to avoid emulsions, extracted with ether, washed with brine, dried over sodium sulphate and evaporated. Distillation of the remaining oil gave 2.15 g (62%) of the desired tetraenone, b.p. 101°-105°/0.05 Torr. A sample was purified by chromatography on silica gel and showed m.p. 30°-37°;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: CC(C)C(=O)Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C(C)C)nn1
Yield: 72 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using isobutyryl chloride instead of methoxyacetyl chloride, to the title compound (180 mg, 72%) which was obtained as a white solid. MS: m/e=353.2 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)CN
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)CNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
A mixture of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), neopentylamine (530 mg, 6.0 mmol) and triethylamine (1 mL) in acetonitrile (20 mL) was stirred at room temp for 4 h. After the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to afford the product (1.11 g, 87%). C11H13ClFN3 MS m/e=242 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2>>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:5][C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([O:10][CH3:11])=[C:8]([CH3:12])[CH:7]=1
Reactant: COc1c(C)cc(C=O)cc1C
Reactant: O=C1Cc2cc(F)ccc2N1
Product: COc1c(C)cc(C=C2C(=O)Nc3ccc(F)cc32)cc1C

Procedure:
3,5-Dimethyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.3 g of 5-fluoro-3-(4-methoxy-3,5-dimethylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH3:18])[C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][CH:3]1[CH2:19][CH3:20].[Br:21]Br>Br.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH3:18])[C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][C:3]1([Br:21])[CH2:19][CH3:20]
Reactant: BrBr
Reactant: CCC1Cc2c(C)c(OCC(=O)O)c(C)c(C)c2C1=O
Agent: Br
Solvent: CC(=O)O
Product: CCC1(Br)Cc2c(C)c(OCC(=O)O)c(C)c(C)c2C1=O

Procedure:
(1-Oxo-2-bromo-2-ethyl-4,6,7-trimethyl-5-indanyloxy)-acetic acid is prepared by following substantially the same procedure as described in Example 1, Step B, using the following reagents: (1-oxo-2-ethyl-4,6,7-trimethyl-5-indanyloxy)-acetic acid (11.79 g., 0.0427 mole), bromine (7.51 g., 0.0470 mole), acetic acid (118 ml.) and 48% hydrobromic acid (2 drops). The crude yield is 14.76 g. (97%). Recrystallization from butyl chloride give (1-oxo-2-bromo-2-ethyl-4,6,7-trimethyl-5-indanyloxy)acetic acid as white prisms, m.p. 144°-145° C.
Reaction SMILES: N[C:2]1[C:3]([NH2:12])=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C2C(=CC(S(O)(=O)=O)=CC=2O)C=C(S(O)(=O)=O)C=1.NC1C=CC=CC=1N>>[NH2:12][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([OH:11])(=[O:9])=[O:10]
Reactant: Nc1cccc(S(=O)(=O)O)c1N
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: Nc1ccccc1N
Product: Nc1ccccc1S(=O)(=O)O

Procedure:
It is therefore possible, for example, to first acylate a diaminobenzenesulphonic acid with cyanuric chloride, to diazotise the resultant intermediate and to couple it in acid solution to the 1-amino-8-hydroxynaphthalene-3,6-disulphonic acid, to condense the resultant monoazo compound in twice the molar amount with a diaminobenzene and to couple two moles of a diazotised aminobenzenesulphonic acid to the disazo compound which has been formed.