Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4]1.Cl[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[CH:14]=[C:13]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:12]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:2][CH:3]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[CH:14]=[C:13]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:12]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC1CCOCCN1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCOCCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a suspension of 5-methyl-[1,4]oxazepane hydrochloride (0.08 g, 0.50 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.09 g, 0.40 mmol) in tetrahydrofuran (2 mL) in a sealed tube was added triethylamine (0.14 mL) at room temperature. The mixture was heated to 150° C. under microwave irradiation and stirred for 30 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (chloroform/methanol=10/1 as an eluant) to yield 2-(5-methyl-[1,4]oxazepane-4-yl)-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (0.03 g, 0.09 mmol, 22%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:12]([CH3:22])=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])[C:5]([CH3:23])=[CH:4][CH:3]=1.[C:24]([Si:28]([CH3:38])([CH3:37])[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[C:12]([CH3:22])=[C:13]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])[C:5]([CH3:23])=[CH:4][CH:3]=2)[CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(Cl)ccc2C)c1C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 25.4 %

Procedure:
To a solution of methyl 3-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-2,4-dimethyl-benzoate (0.5 g, 0.0015 mol, see preparation 40), tert-butyl-dimethyl-(3-piperidylmethoxy)silane (0.41 g, 0.0018 mol, see preparation 14) and Cs2CO3 (1.95 g, 0.006 mol) in 1,4-dioxane (20 ml) is added Pd2(dba)3 (0.137 g, 0.00015 mol) followed by S-Phos (0.06 g, 0.00015 mol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 80° C. After 24 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (silica gel) using 20% EtOAc in hexane to afford the title compound as a brown semi-solid (0.2 g, 38%). Mass spectrum (m/z): 525.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=1)=O.[C:16]([NH:19][C:20]([NH2:22])=[NH:21])(=[O:18])[CH3:17]>C(#N)C>[F:13][C:12]([F:15])([F:14])[O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[NH:22][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2cccc(OC(F)(F)F)c2)c[nH]1

Procedure:
The title compound was prepared according to described procedure using 2-bromo-1-[3-(trifluoromethoxy)phenyl]ethanone (1.7 g, 6.00 mmol) and acetyl guanidine (0.91 g, 9.01 mmol)) in acetonitrile (17 ml) to obtain 460 g of the product as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H), 5.50 (s, 1H), 7.10-7.15 (m, 1H), 7.39 (t, J=7.8, 1H), 7.47-7.64 (m, 3H), 7.92 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1C=CC=CC=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[OH:34][CH2:31][C:32]#[C:33][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1)c1cccc(C#CCO)c1
Yield: 64.2 %

Procedure:
A mixture of 3-bromo-N-phenyl-benzenesulfonamide (52a) (1.0 g, 3.2 mmol), benzene (2.4 ml), tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.34 mmol), copper iodide (0.032 g, 0.16 mmol), triethylamine (2.4 ml, 17.2 mmol), and propargyl alcohol (1.0 ml, 17.2 mmol)) was refluxed under argon for 30 min. The reaction mixture was diluted with 5% HCl (50 ml) and product was extracted with ethyl acetate (50 ml). The extract was washed successively with 5% NaHCO3, water and dried (Na2SO4). The solvents were removed under reduced pressure and the product was purified on silica gel with ethyl acetate-hexane (1:1, v/v) as eluent. The title compound (0.59 g, 64%) was obtained as an oil. 1H NMR (DMSO-d6, HMDSO) δ: 4.29 (2H, d, J=6.0 Hz, CH2); 5.36 (1H, t, J=6.0 Hz, OH); 6.94–7.32 (5H, m, C6H5); 7.35–7.91 (4H, m, C6H4); 10.32 (1H, s, NH).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1.O>CS(C)=O>[C:17]1([C:8]2[N:7]=[C:6]([CH2:5][C:1]#[N:2])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1nc(-c2ccccc2)nn1-c1cccnc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)nn1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of potassium cyanide (30.7 mg, 472 μmol) and 3-(5-(bromomethyl)-3-phenyl-1H-1,2,4-triazol-1-yl)pyridine (124 mg, 393 μmol) in DMSO (3 mL) was stirred at RT for 2 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with water and brine, dried, filtrated and evaporated. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (47 mg with 80% purity, 180 μmol, 36.6%).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:2][O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: COc1ccc(COc2ccc(C(=O)OCCl)cc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C(=O)OCI)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl-4-(4-methoxybenzyloxy)benzoate (0.77 g, 2.5 mmole) in 15 ml dry acetone was added sodium iodide (1.87 g, 12.5 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield 0.86 g=86%
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([CH2:20][O:21][CH3:22])[C:11]=1[O:23][CH2:24][O:25][CH3:26])=[O:4]>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([CH2:20][O:21][CH3:22])[C:11]=1[O:23][CH2:24][O:25][CH3:26])=[O:4]
Reactant: COCOc1cc(COC)c(OCOC)c(C2=C(C(=O)OC)CCC2)c1
Solvent: CCO
Product: COCOc1cc(COC)c(OCOC)c(C2CCCC2C(=O)OC)c1
Yield: 67.9 %

Procedure:
Stir a solution of 2-(2,5-bis-methoxymethoxy-3-methoxymethyl-phenyl)-cyclopent-1-enecarboxylic acid methyl ester (1.76 g, 4.80 mmol) in EtOH (75 mL, pre-filtered through a plug of basic alumina) for 1 minute with activated carbon, then filter through Celite®. Add 10% Pd/C (50% wet, 0.83 g) to the filtrate and hydrogenate this mixture at 55-60 psi for at least 20 hours. Filter the reaction through Celite® and concentrate the filtrate to afford the subtitled product (1.20 g, 68%) as an oil that may be used without further purification. 1H NMR (CDCl3) δ 1.63-1.74 (m, 1H), 1.92-2.10 (m, 4H), 2.11-2.20 (m, 1H), 3.20-3.27 (m, 4H), 3.40 (s, 3H), 3.46 (s, 3H), 3.60 (s, 3H), 3.69-3.78 (m, 1H), 4.44-1.53 (m, 2H), 4.95-5.01 (m, 2H), 5.08-5.14 (m, 2H), 6.80 (d, J=3.0 Hz, 1H), 6.94 (d, J=3.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1ccccn1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCSCc1ccccn1)c1ccccc1

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]pyridine (6.0 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) is heated under reflux for one hour and concentrated to give N-benzoyl-N'-[2-(2-pyridylmethylthio)ethyl]thiourea.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: C[C@@H](O)CN
Reactant: O=CCC1Cc2cc(F)ccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1ccc(F)cc1C2
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
A solution of 2.88 g of (RS)-2-(2-oxoethyl)-5-fluoro-1-indanone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 4.51 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.75 g (79%) of (R)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12]OC(OC)N(C)C.N1CCCC1>CN(C)C=O.C(OCC)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:12][NH:9]2)=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCNC1
Product: Brc1ccc2cc[nH]c2c1
Temperature: 110 °C
Yield: 36.4 %

Procedure:
To a solution of 4-bromo-2-nitrotoluene (7.9 g, 36.6 mmol) in dimethylformamide (73 mL) were added N,N-dimethylformamide dimethylacetal (14.5 mL, 110 mmol) and pyrrolidine (4.7 mL), and the mixture was heated at 110° C. for 90 minutes. The cooled reaction mixture was diluted with diethyl ether, and washed with water. The aqueous layer was re-extracted with diethyl ether twice, and the combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in aqueous acetic acid (245 mL, 80%), and heated to 75° C. Zinc powder (20.8 g, 318 mmol) was added to the hot solution in small portions over 2 hours. The reaction mixture was then heated at 85° C. for 3 hours and 30 minutes, cooled to room temperature and then to 0° C. The precipitate formed was removed by filtration, and the filtrate was diluted with ethyl acetate and washed with water twice. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate, then 90:10 hexanes/ethyl acetate) to give 6-bromoindole as a grey solid (2.61 g, 36%): 1H NMR (500 MHz, CDCl3) δ 8.14 (br s, 1H), 7.53 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.15 (m, 1H), 6.53-6.51 (m, 1H).
Reaction SMILES: S1C=CC(C(Cl)=O)=C1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[S:9]1[CH:13]=[CH:12][C:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])=[CH:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:17]([NH:16][C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[O:15])=[S:18])=[CH:39][CH:40]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccsc1
Agent: O=C(N=C=S)c1ccsc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccsc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-Thiophenecarbonyl isothiocyanate was prepared using commercially available 3-thiophenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([OH:26])=[O:25].C[O-].[Na+].C(=O)(O)[O-:31].[Na+].OO.Cl>C(#N)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])(=[O:31])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([OH:26])=[O:25]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)=O)cc1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: Cl
Agent: OO
Solvent: CC#N
Solvent: CO
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 30 h

Procedure:
5-methoxy-2-methyl-1-(ρ-methylsulfonylbenzylidene)-3-indenyl acetic acid is prepared by the dissolving 0.03 moles of the sulfoxide in 25 ml. methanol, and 50 ml. acetonitrile are added. The solution is stirred at 0 C., and 0.03 moles of sodium methoxide are added dropwise. Stirring is continued, and 0.06 mole sodium bicarbonate is added as well a 0.06 moles of H2O2 (30% solution in water). The temperature is then dropped to -10 C., and stirring continued for 30 hours. At this time the NaHCO3 is filtered and washed on the filter with a few ml. of cold methanol. The washings are returned to the filtrate and the NaHCO3 is discarded. The filtrate is neutralized with 0.07 moles of HCl (concentrated HCl), partially evaporated to 50% of the original volume, and returned to the freezer for crystallization. Crystals of the sulfone derivative are collected. Additional sulfone can be collected from the mother liquor in a similar manner. (R1 =hydrogen; R2 =CH3 ; R3 =5--OCH3 ; R4 =hydrogen; R5 =p--CH3SO2)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]1)[CH2:6][CH2:5]2.Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(N2CCc3cc(Br)ccc32)CC1
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A solution of compound 4 (4.0 g, 11.83 mmol) in acetone (50 mL) was treated with 10% HCl solution (50 mL) and the resulting mixture was stirred for over night (16 h). Acetone was evaporated, crude was basified with 2 N NaOH solution and product was extracted into CH2Cl2 (3×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography on silica gel (ethyl acetate:hexanes, 1:4) to obtain compound 5 (2.9 g, 83%) as a solid. 1H NMR (CDCl3) δ 7.15 (d, J=6.6 Hz, 2H), 6.32 (d, J=8.7 Hz, 1H), 3.81 (tt, J=7.2, 23.4 Hz, 1H), 3.37 (t, J=16.8 Hz, 2H), 2.95 (t, J=16.5 Hz, 2H), 2.51-2.41 (m, 4H), 2.18-2.11 (m, 2H), 1.92-1.78 (m, 2H). MS-ESI (m/z, %): 296 (96), 294 (M+, 100), 200 (30).
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[OH:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:35])=[N-].C(O)(=O)C>CCOCC.ClCCl>[C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[C:28]([C:29]#[N:30])[C:31]#[N:32])[O:27][CH3:35])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(C#N)=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(C#N)C#N
Reaction time: 6 h

Procedure:
A suspension of the malononitrile of Example 2 (13 g, 31 mmole) in ether/dichloromethane (900 mL/100 mL), cooled in an ice bath, was treated with a freshly prepared ethereal solution of diazomethane (from 50 mmole of DiazaldR (Aldrich Chemical Company)). The solution was stirred for 6 hours and then neutralized with acetic acid (10 mL). The solution was evaporated to dryness and the residue chromatographed on silica gel using dichloromethane/acetone (4/1) as the eluent. Fractions containing product were pooled and evaporated to a syrup. The syrup was triturated with dichloromethane to induce crystallization. The crystals were filtered an dried to give 8.3 g (61%) of chromatographically pure product, useful as an intermediate compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=CC2[C:4](=CC(S(O)(=O)=O)=CC=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.N1[CH2:35][CH2:34][O:33][CH2:32]C1>>[NH2:1][C:2]1[CH:11]=[C:35]([S:17]([OH:20])(=[O:19])=[O:18])[C:34]([O:33][CH3:32])=[CH:4][C:3]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Reactant: C1COCCN1
Agent: Fc1nnnc(F)c1F
Product: COc1cc(S(=O)(=O)O)c(N)cc1S(=O)(=O)O

Procedure:
31.9 g of 2-amino-5-hydroxy-naphthalene-1,7-disulphonic acid are subjected to a condensation reaction with trifluorotriazine and then with morpholine as described in Example 1. A diazo compound obtained by the customary route by direct diazotisation of 28.3 g of 1-amino-4-methoxy-benzene-2,5-disulphonic acid is added to the resulting suspension of the monofluorotriazinyl compound at 5°-10°, the pH simultaneously being kept at 7.0-7.5 by sprinkling in sodium bicarbonate. When the coupling has ended, the dyestuff of the formula ##STR19## is salted out, filtered off with suction, dried and ground. The red dyestuff powder dissolves readily in water and dyes cotton a brilliant reddish-tinged orange (colour code number 5).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:11]([C:23]#[N:24])=[C:10]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1.Cl.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>C(O)C>[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[CH:20][CH:21]=2)[C:11]([C:23]#[N:24])=[C:10]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1
Reactant: N#Cc1c(N)nc(SCc2ccccc2)c(C#N)c1-c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccc3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.31 g (56.2 mmol) of potassium tert-butoxide are added to a solution of 8.39 g (23.4 mmol) of 2-amino-6-(benzylthio)-4-(4-hydroxyphenyl)pyridine-3,5-dicarbonitrile [preparation according to WO 01/25210, Example A 383, from 2-amino-4-(4-hydroxyphenyl)-6-mercaptopyridine-3,5-dicarbonitrile and benzyl bromide] in 105.5 ml of ethanol. The mixture is stirred at RT for 1 h, and 4.05 g (28.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride are then added. The mixture is then stirred at +78° C. for 3 h. After cooling, the reaction mixture is filtered and the filtrate is concentrated using a rotary evaporator. The residue is purified directly by preparative HPLC (column: Merck 210 g RP silica gel Gromsil 1200DS-4 HR 10 μm, 50 mm×200 mm; mobile phase A=water+0.1% formic acid, mobile phase B=acetonitrile; gradient: 0 min 10% B→5 min 10% B→6 min 90% B→22 min 90% B→22 min 10% B→28 min 10% B; flow rate: 110 ml/min; wavelength: 220 nm).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:40][CH:39]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: COc1ccc([C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)cc1
Agent: Cl
Product: COc1ccc([C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3cncn3)C2)cc1
Yield: 30 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-(4-methoxyphenyl)pyrrolidine-2-carboxamide, gave Compound 62, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methoxyphenyl)pyrrolidine-2-carboxamide (7 mg, 30%). 1H-NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.00 (s, 1H), 7.40-7.20 (m, 6H), 6.90-6.80 (m, 7H), 5.00 (dd, 2H), 4.20 (m, 2H), 3.80 (m, 1H), 3.7 (s, 3H), 3.20 (m, 1H), 3.20-3.00 (m, 2H). MS (EI) for C28H26FN5O4 found 516 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Br)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3cccc(Br)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 98A in analogy to the synthesis of the compound of Example 23. 122 mg (52% of theory) of the title compound are obtained.