Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH2:18]([O:20][C:21]([C:23]1[C:27]2[CH:28]=[CH:29][C:30](Br)=[CH:31][C:26]=2[O:25][N:24]=1)=[O:22])[CH3:19]>O1CCOCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[CH3:1])=[CH:31][C:26]=2[O:25][N:24]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1noc2cc(Br)ccc12
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Solvent: C1COCCO1
Product: CCOC(=O)c1noc2cc(-c3ccc(O)cc3C)ccc12
Temperature: 50 °C
Yield: 92.6 %

Procedure:
A solution of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.624 g, 2.67 mmol) and 6-bromo-benzo[d]isoxazole-3-carboxylic acid ethyl ester (0.360 g, 1.33 mmol) in 1,4-dioxane (20 mL) is added to a flask. The flask is evacuated and re-filled with N2 3 times. To this solution, Pd2(dba)3 (0.010 g), tricyclohexyl phosphine (10 mg), and aqueous K3PO4 (1.5 mL, 1.30 M) are added. The resulting mixture is heated to 50° C. for 2 hours under N2. The reaction mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25% ethyl acetate in hexanes to give the title compound (0.366 g, 93%). ES/MS m/e 298.0 (M+1); 296.0 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl.S([O-])([O-])(=O)=[O:15].[Mg+2].[OH-:20].[Na+]>>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:15])=[O:20])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: [OH-]
Reactant: CCCc1ccc(CC#N)cc1
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: [Mg+2]
Agent: [Na+]
Product: CCCc1ccc(CC(=O)O)cc1
Yield: 76 %

Procedure:
2-(4-propylphenyl)acetonitrile (41.0 mg, 0.257 mmol) was dissolved in 1 mL of 30% aqueous sodium hydroxide solution and stirred under reflux condition for 4 hours. Upon completion of the reaction, the reaction solution was acidified by adding 3 mL of 10% aqueous hydrogen chloride solution and extracted with diethyl ether (3 mL×3). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 34.8 mg (0.195 mmol, 76%) of the desired compound (balance unit of tag β).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][Mg]Br>C1COCC1>[CH3:12][C:8]1([OH:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: C[Mg]Br
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a cooled (−78° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (1 equiv) in THF (0.64 M) was added a solution of methylmagnesium bromide (1.8 equiv, 3 mol/L in ether) dropwise under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 20 minutes, then warmed to −30° C. for 30 minutes and then stirred at 0° C. for 30 minutes. After the reaction was complete, the resulting mixture was quenched with saturated aqueous ammonia chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a white solid (92% yield), which was used in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-d1) δ ppm 4.00-3.91 (m, 4H), 1.95-1.80 (m, 3H), 1.77-1.67 (m, 4H), 1.59-1.58 (m, 1H), 1.27 (s, 3H), 1.17 (s, 1H).
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.NC[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[NH:22]1[CH:21]=[C:20]([CH2:19][CH2:1][N:6]2[C:7](=[O:16])[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:11])[N:24]=[CH:23]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]cn1

Procedure:
N-Carbethoxy phthalimide (2.45 g, 11 mmol) is added over 10 minutes to a vigorously stirred solution of histamine (1.13 g, 1.0 mmol) and Na2CO3 (1.19 g, 1.1 mmol) in water (22 ml). After 1 h the white suspension is removed by filtration, washed with ethanol and dried to afford the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[NH:16][C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[N:16]([CH3:36])[C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2cc(F)ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1c(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)cc1=O
Reaction time: 0.25 h

Procedure:
50 mg (0.11 mmol) of 4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one were placed in 0.50 mL DMSO at RT. To this were added 88 mg (0.27 mmol) caesium carbonate and the mixture was stirred for 15 min. Then a solution of 6.5 μL (0.11 mmol) methyl iodide in DMSO was added and the mixture was stirred for 2 h at RT. More methyl iodide was added (3.3 μL, 0.055 mmol) and the mixture was stirred for a further 2 h at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([S:13]([CH3:15])=O)[O:7]2.[OH:17][C:18]1[CH:23]=[CH:22]C(S)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([S:13][C:15]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[O:7]2
Reactant: CS(=O)c1cc(=O)c2c(O)cc(O)cc2o1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(Sc2ccc(O)cc2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture consisting of 32 mg (0.134 mmol) 5,7-dihydroxy-2-methylsulfinylchromone, 20 mg (0.161 mmol) 4-hydroxybenzenethiol, 41 mg (0.295 mmol) potassium carbonate, and 2 ml acetone was stirred overnight at room temperature. The solution thus reacted was neutralized by addition of dilute hydrochloric acid. Subsequently, the product was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled out under reduced pressure. The resulting crude product was subjected to recrystallization from acetone-hexane, whereby 14.6 mg of 5,7-dihydroxy-2-(4-hydroxyphenylthio)chromone was obtained (yield: 36%).
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:17][C:16]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[N:14]([S:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][C:2]([NH2:1])=[O:36])(=[O:12])=[O:13])[CH:15]=[C:16]([CH2:26][NH:27][CH3:28])[CH:17]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(N)=O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(N)=O)c2)c1
Reaction time: 2 h

Procedure:
tert-Butyl ((1-((3-(2-amino-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 2a (100 mg, 0.19 mmol) was dissolved in 20 mL of dichloromethane. The reaction solution was cooled in an ice bath, 5 mL of trifluoroacetic acid were dropwise added, and then the reaction solution was stirred for 2 h. 50 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetamide 2 (60 mg, a yellow oil) in 75% yield.
Reaction SMILES: OC(C)(C)[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.CCCCCC>[CH3:17][C:14]1([CH3:16])[O:13][C:12](=[O:18])[NH:11][C@H:3]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10]
Reactant: Cc1ccccc1[C@H](NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@@H]1NC(=O)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl (2-hydroxy-2-methyl-1-(o-tolyl)propyl)carbamate (1 g, 3.5 mmol) in THF (20 mL) was added potassium tert-butoxide (803.37 mg, 7.1 mmol) at 0-5° C. The resulting reaction mixture was stirred for 2 hours at ambient temperature. After completion of the reaction (monitored by TLC, TLC system: 50% EtOAc in hexane), the reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with, water, washed with saturated NaCl solution, dried with Na2SO4, filtered and evaporated to afford (S)-5,5-dimethyl-4-(o-tolyl)oxazolidin-2-one, 0.7 g (95.28% Y) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.27-7.25 (m, 1H), 7.22-7.19 (m, 3H), 4.83 (s, 1H), 2.29 (s, 3H), 1.55 (s, 3H), 0.81 (s, 3H). m/z (ESI) 206.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]3[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH:31]=[CH:30]C=N5)[CH:22]=4)=[CH:19][N:20]=[C:14]3[CH:13]=2)=[CH:8][CH:7]=1.C(O[C:36](=O)[C:37]1C=CC(C2C=NN3C(C4C=CN=C(C5C=CC=CC=5)C=4)=CN=C3C=2)=C[CH:38]=1)C>>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]3[C:18]([C:21]4[CH:30]=[CH:31][N:27]=[C:23]([C:24]5[CH:38]=[CH:37][CH:36]=[CH:26][CH:25]=5)[CH:22]=4)=[CH:19][N:20]=[C:14]3[CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(NCCO)c1ccc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Reactant: CCOC(=O)c1ccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)cc1
Product: O=C(NCCO)c1ccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)cc1

Procedure:
This example is prepared by an analogous method to N-(2-Hydroxy-ethyl)-4-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-b]-pyridazin-7-yl]-benzamide (Ex. 49) by replacing 4-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 34) with 4-[3-(2-Phenylpyridin -4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 48).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.[I-:15].[K+].II.[NH:19]1[CH2:24][CH2:23][CH2:22][N:21]=[C:20]1[SH:25]>CO.O>[IH:15].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[C:6]2[S:25][C:20]1[NH:21][CH2:22][CH2:23][CH2:24][N:19]=1
Reactant: SC1=NCCCN1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: [I-]
Agent: II
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c(C(=O)O)c(SC3=NCCCN3)c2c1
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5.7 g of 5-methoxy-indole-2-carboxylic acid in 70 ml of hot methanol is added portionwise to a solution of 15 g potassium iodide and 7.6 g of iodine in 45 ml of water. This is further treated with a solution of 3.48 g of 1,4,5,6-tetrahydro-2-pyrimidinethiol in 70 ml of hot methanol, stirred at room temperature for 2 hours and filtered. The filtrate is worked up in the manner described under Example 1 to yield 5-methoxy-3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole-2-carboxylic acid hydriodide which melts at 239°-240° after recrystallization from a mixture of methanol, ethyl acetate and ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[NH2:23][C@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.C(N(CC)C(C)C)(C)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][C@@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[NH:23][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1
Reactant: COC(=O)C[C@H](N)c1ccccc1Cl
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1Cl
Yield: 77.9 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 130 mg of methyl (S)-3-amino-3-(2-chlorophenyl)propionate were dissolved in 5 ml of dichloromethane and 0.52 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 20 ml of dichloromethane and washed repeatedly with 20 ml of 25% aqueous ammonia solution, until the organic phase was colorless. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (191 mg) with a molecular weight of 402.9 g/mol (C17H23ClN2O5S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6](=[O:23])[NH:5][C:4](=[O:24])[CH:3]=1.[Na].[F:26][C:27]([F:31])([F:30])[CH2:28][OH:29]>>[O:23]=[C:6]1[NH:5][C:4](=[O:24])[CH:3]=[C:2]([O:29][CH2:28][C:27]([F:31])([F:30])[F:26])[N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(Cl)cc(=O)[nH]c2=O)cc1
Agent: [Na]
Product: N#Cc1ccccc1-c1ccc(Cn2c(OCC(F)(F)F)cc(=O)[nH]c2=O)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a mixture of 4′-[(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2.7 g) and 2,2,2-trifluoroethanol (70 mL) was added a solution of sodium (0.28 g) in 2,2,2-trifluoroethanol (10 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with chloroform and 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.3 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:21][CH3:22])=[N:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][N:26]=[C:27]=S.C[N:32](C)C=O>>[NH2:8][C:6]1[N:7]=[C:2]([NH:1][C:27]([NH2:32])=[N:26][CH2:25][C:24]([F:30])([F:29])[F:23])[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:21][CH3:22])=[N:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:5]=1
Reactant: FC(F)(F)CN=C=S
Reactant: CN(C)C=O
Reactant: CNC(=NS(C)(=O)=O)NCCCCCc1nc(N)nc(N)n1
Product: CNC(=NS(C)(=O)=O)NCCCCCc1nc(N)nc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,4-diamino-6-[5-(2-methanesulphonyl-3-methylguanidino)pentyl]-1,3,5-triazine (0.4 g.), 2,2,2-trifluoroethylisothiocyanate (0.4 g.) and dimethylformamide (0.5 ml.) was heated at 120° for 1 hour and then at 60° for 18 hours. The mixture was evaporated to dryness, the residue partitioned between water and ethyl acetate, and the ethyl phase was separated, dried, and evaporated to dryness. The residue was dissolved in saturated ethanolic ammonia (10 ml.) and the solution treated with yellow mercuric oxide (0.5 g.). The mixture was stirred at room temperature for 18 hours, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 2-amino-4-[2-(2,2,2-trifluoroethyl)guanidino]-6-[5-(2-methanesulphonyl-3-methylguanidino)pentyl]-1,3,5-triazine (0.07 g.) characterised as the bishydrogen maleate, m.p. 131°-133° after recrystallisation from acetone.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:3]1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[N:14]1([CH2:13][CH2:12][O:11][C:8]2[CH:9]=[C:10]3[C:5]([C:4]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:3]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[C:2]3=[O:1])=[CH:6][CH:7]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(OCCN3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
To a solution of tert-butyl 4-(2-(1-oxo-3-phenyl-2-(pyridin-3-yl)-1H-inden-6-yloxy)ethyl)piperazine-1-carboxylate (0.38 mmol, 200 mg) obtained in Step 2 of Example 44 in CH2Cl2 (0.3M) was added TFA (20 eq). The resulting mixture was stirred at room temperature for 40 min and diluted with CH2Cl2. The solution was basicified to pH 9 by the addition of 3N NaOH. The mixture was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (acetone/hexanes=1:1) to obtain the title compound (75%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.C(O)(=O)CC.N(OS(=O)(=O)O)=O.[CH:22]([O:24][C:25](=[O:38])[CH2:26][CH2:27][N:28]([CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)=[CH2:23].S(=O)(=O)(O)[NH2:40]>CO.C(O)(=O)C>[CH:22]([O:24][C:25](=[O:38])[CH2:26][CH2:27][N:28]([CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([N:40]=[N:1][C:2]2[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=2)=[C:31]([CH3:35])[CH:30]=1)=[CH2:23]
Reactant: C=COC(=O)CCN(CC)c1cccc(C)c1
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: NS(=O)(=O)O
Agent: O=NOS(=O)(=O)O
Solvent: CO
Solvent: CCC(=O)O
Solvent: CC(=O)O
Product: C=COC(=O)CCN(CC)c1ccc(N=Nc2ncc([N+](=O)[O-])s2)c(C)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
4.4 parts of 2-amino-5-nitrothiazole, 20 parts of propionic acid and 30 parts of acetic acid were charged and cooled to 5° C. 11.4 parts of 40% (w/w) nitrosyl sulfuric acid were added, whilst the temperature was held below 10° C. The diazotization mixture was stirred for a further 2 hrs at 5-10° C. To a separate vessel were charged 7.0 parts of 3-(ethyl-[3-methylphenyl]-amino)-propionic acid vinyl ester, 100 parts of methanol, 1 part sulfamic acid and 100 parts of ice. With stirring, the diazotization mixture was slowly added followed by a further 300 parts of ice. The reaction mixture was stirred over night and the product was isolated by filtration, washed subsequently with water, methanol and again water, then dried to yield 9.5 parts of 3-{ethyl-[3-methyl-4-(5-nitro-thiazol-2-ylazo)-phenyl]-amino}-propionic acid vinyl ester. λmax=602 nm (DMF).
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.[CH3:21][C:22]1([CH3:45])[CH:31]([CH2:32][CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:23]1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:33][CH2:32][CH:31]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:23][C:22]2([CH3:21])[CH3:45])[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CCC2Cc3ccccc3OC2(C)C)C1
Reaction time: 15 h

Procedure:
First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g (87.5 mmol) of N-ethyl-N,N-diisopropyl-amine are added to a solution of 9 g (25 mmol) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman in 100 ml of N,N-dimethylformamide. The solution is stirred for 15 hours at 60° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution (30%) while cooling and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 5.52 g (67% of the theoretical yield) of 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester in the form of a light-yellow oil. 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallises from methanol/diethyl ether and melts at 196°-197°.
Reaction SMILES: C[CH2:2][O-:3].[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].C(OCC)=O>C(O)C>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]([CH:2]=[O:3])[C:14]#[N:15]
Reactant: N#CCc1cccc(Cl)c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Product: N#CC(C=O)c1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 45 %

Procedure:
To a solution of NaOEt (from 3.63 gms Na) in ethanol (500 ml) was added 2,3-dichlorophenylacetonitrile (Example 14.3) in ethanol (150 ml). Ethyl formate (16.67 gms) was then added and the mixture stirred at 80° C. for 45 minutes, before adding a further quantity of ethyl formate (2.78 gms). After stirring at 80° C. for a further 1.5 hours, the precipitate was filtered off and dried in vacuo. The solid was dissolved in water, filtered, acidified with concentrated hydrochloric acid and the precipitate filtered off and dried in vacuo, 14.35 gms, 45% yield.