Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[N-:27]=[N+:28]=[N-:29].[Na+]>>[N:27]([CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13][CH:14]=1)=[N+:28]=[N-:29]
Reactant: CCCCC(Cc1ccc(OCCCOS(C)(=O)=O)cc1)C(=O)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCCCC(Cc1ccc(OCCCN=[N+]=[N-])cc1)C(=O)OCC
Yield: 95.3 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-butyl-3-[4-(3-methanesulfonyloxypropoxy)phenyl]propionate (2.98 g) and sodium azide (1.50 g) and the reaction mixture was treated to afford the desired compound (2.45 g) as a colorless oil.
Reaction SMILES: [Cl-:1].[K+].[Pt+2:3].[Cl-:4].[Cl-].[NH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1>O>[Pt+2:3].[Cl:1][C@H:8]1[C@@H:7]([NH2:6])[CH2:11][CH2:10][N:9]1[Cl:4]
Reactant: NC1CCNC1
Reactant: [Cl-]
Agent: [Pt+2]
Agent: [K+]
Solvent: O
Product: N[C@H]1CCN(Cl)[C@H]1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 67.9 %

Procedure:
To a solution of platinum (II) potassium chloride (12.2 g) in water (800 ml) is added (3RS)-3-aminopyrrolidine (2.5 g), and the mixture is stirred at room temperature for 19 hours. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added a small amount of water, and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3RS)-3-aminopyrrolidine platinum (II) (6.9 g) as pale yellow crystal.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:16][C:15]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][C:7]=2[O:6]1>C(Cl)(Cl)(Cl)Cl>[CH2:5]1[O:16][C:15]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Br:2])=[CH:8][C:7]=2[O:6]1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2c(c1)OCO2
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)OCO2
Yield: 121.1 %

Procedure:
A solution of phosphorus tribromide (8.1 g) in carbon tetrachloride (50 ml) was added dropwise over 30 minutes to a stirred solution of 3,4-methylenedioxyphenethyl alcohol (15.0 g) (see Preparation 14) in carbon tetrachloride (200 ml) and the mixture was heated under reflux for 3 hours, washed sequentially with water (twice), 5M aqueous sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (100 g) using carbon tetrachloride as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a pale yellow oil (8.3 g, 40%), which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[CH:5][CH:4]=1.[OH:26]O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[O:26])=[CH:5][CH:4]=1
Reactant: OO
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-methoxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([CH2:12][C:13](=[N:30]C(=O)OC(C)(C)C)[NH:14][C:15](=[O:29])[CH2:16][C:17](=[N:26][O:27][CH3:28])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:7][C:6]=1[Cl:38])(=[O:3])[CH3:2].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>ClCCl>[C:1]([NH:4][C:5]1[C:6]([Cl:38])=[CH:7][C:8]([CH2:12][C:13](=[N:14][C:15](=[O:29])[CH2:16][C:17](=[N:26][O:27][CH3:28])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[NH2:30])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: CON=C(CC(=O)NC(Cc1cc(Cl)c(NC(C)=O)c(Cl)c1)=NC(=O)OC(C)(C)C)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C(CC(=O)N=C(N)Cc1cc(Cl)c(NC(C)=O)c(Cl)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 2-(4-acetamido-3,5-dichlorophenyl)-1-(3-(methoxyimino)-3-(4-methoxyphenyl)-propanamido)ethylidenecarbamate (12 mg) in dichloromethane (0.10 mL) was added TFA (0.10 mL), and the resulting mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo to give the title compound as its TFA salt (10 mg). Retention time: 1.75 min (method A). MS (ESI) (M+H)+ 482.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[CH3:14][C:15]1([CH3:36])[C:19]([CH3:21])([CH3:20])[O:18][B:17](C2C=CC(OC3C=CC=CC=3)=CC=2C)[O:16]1>>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([B:17]2[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:36])([CH3:14])[O:16]2)[CH:3]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCOc1cccc(Br)c1
Product: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Prepared from [2-(3-bromo-phenoxy)-ethyl]-dimethyl-amine according to general Method I for borylation described above for preparation of 4,4,5,5-tetramethyl-2-(2-methyl-4-phenoxy-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][S:31]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:30]=4[N:21]=[CH:22][CH:23]=[CH:24]5)(=[O:32])=[O:33])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CSc2nc3ccc(N)cc3s2)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: c1ccncc1
Product: N#Cc1ccc(CSc2nc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3s2)cc1

Procedure:
A mixture of 2.3 g (7.74 mmol) of 2-[(4-cyanophenyl)methylthio]-6-amino-benzothiazole and 1.85 g (8.1 mmol) of quinoline-8-sulphonic acid chloride is stirred in 30 ml of pyridine for 2 hours at ambient temperature. Then the solvent is distilled off in vacuo and the crude product is purified by flash chromatography (silica gel, methylene chloride/ethanol=99:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:18](=[O:27])[NH:19]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]3[C:16]=2/[C:17](=[CH:28]/[C:29]2[NH:30][CH:31]=[CH:32][C:33]=2[O:34][CH3:35])/[C:18](=[O:27])[NH:19]3)=[CH:7][CH:6]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2c([N+](=O)[O-])ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Yield: 71.4 %

Procedure:
Using Method S above, 4-methoxycarbonyl-phenyl boronic acid (29.6 mg, 0.164 mmol) (from Step A above) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (50 mg, 0.137 mmol) (Starting Material 6) using DPPFPdCl2 (5.6 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.14 mL, 0.28 mmol) and DME (5 mL) at reflux for 18 h to give (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (yield: 41 mg, 71%).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4]1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH:3]3[CH2:4][CH2:5]3)[CH2:8][CH2:9]2)[N:16]=1
Reactant: Clc1cccc(Cl)n1
Reactant: OC1CCN(CC2CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(OC2CCN(CC3CC3)CC2)n1
Reaction time: 0.33 h
Yield: 61 %

Procedure:
Add NaH (60% dispersion in oil, 130 mg, 3.25 mmol) to a solution of 1-cyclopropylmethyl-piperidin-4-ol (preparation 11, 458 mg, 2.95 mmol) in DMF (8 mL) and stir for 20 min. Then add 2,6-dichloropyridine to the mixture and heat at 120° C. overnight. Quench the reaction with saturated NaHCO3, extract with methylene dichloride three times. Combine the organic layers, wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 4% 2M NH3-methanol in methylene dichloride provides 480 mg (61%) of the title compound: mass spectrum (ion spray): m/z=267.2 (M+1); 1H NMR (CDCl3, ppm): 7.39 (t, 1H), 6.75 (d, 1H), 6.52 (d, 1H), 4.96 (m, 1H), 2.75 (m, 2H), 2.30 (m, 2H), 2.19 (d, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 0.76 (m, 1H), 0.43 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([OH:12])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:22][C:21]([O:27][CH3:28])=[C:20]([C:10](=[O:12])[CH2:9][C:8]([O:14][CH2:15][CH3:16])=[O:13])[CH:19]=1
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CCOC(=O)CC(=O)O
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Temperature: 45 °C
Reaction time: 20 h
Yield: 76.3 %

Procedure:
A 3000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with magnesium ethoxide (67.46 g, 589.51 mmoles) and THF (1100 mL), and the resulting mixture was stirred as ethyl hydrogen malonate (162.26 g, 1.18 moles; 145.00 mL diluted in 100 ml of THF) was added and the mixture was heated at 45° C. for 4 hours. Meanwhile, a 2000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with 5-chloro-2-methoxybenzoic acid (100 g, 536 mmoles) and THF (600 mL). To this mixture stirring at room temperature was added 1,1′-carbonyldiimidazole (95.59 g, 589.5 mmoles) in portions to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45° C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (1 L) followed by 2 N HCl (500 mL). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCl (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (1000 mL) and concentrated again to afford the title compound (104.94 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]=O>CN(C)C=O.[C].[Pd]>[CH3:14][N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)CCCN2
Reactant: C=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1CCCc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinolin-6-carboxylic acid (2 g), 32% aqueous formalin solution (2 ml) and 10% palladium-carbon (400 mg) in N,N-dimethylformamide (10 ml) was stirred under hydrogen atmosphere at room temperature for one hour. After removing the palladium-carbon by filtration, the solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 1-methyl-1,2,3,4-tetrahydroquinolin-6-carboxylic acid (1.98 g) as yellowish powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:12])=[CH2:11])=[CH:6][C:5]=1[Cl:13]>CO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:11])[CH3:12])=[CH:6][C:5]=1[Cl:13]
Reactant: C=C(C)c1ccc(C(=O)OC)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc(C(C)C)cc1Cl

Procedure:
A solution of 2-chloro-4-isopropenyl-benzoic acid methyl ester (100 mg, 0.48 mmol) in MeOH (8.0 mL) was passed through H-cube equipped with a PtO2 cartridge. The solution was concentrated down to give 2-chloro-4-isopropyl-benzoic acid methyl ester as a yellow oil. Amount obtained: 68.0 mg (67%). 1H NMR (Chloroform-d) δ: 1.26 (d, J=6.8 Hz, 6 H) 2.92 (m, J=14.0, 6.9, 6.9 Hz, 1 H) 7.17 (dd, J=8.1, 1.9 Hz, 1 H) 7.31 (d, J=2.0 Hz, 1 H) 7.79 (d, J=8.0 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[F-:28].[K+]>CS(C)=O.CCOC(C)=O>[C:8]([C:7]1[C:2]([F:28])=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: [F-]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(F)c(C#N)cn1)CCC2
Temperature: 110 °C
Reaction time: 16 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 106 mg, 0.273 mmol) and KF (159 mg, 2.73 mmol) were dissolved in DMSO (3 ml). The mixture was stirred at 110° C. for 16 h. The mixture was cooled to room temperature, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The org. layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 60:40) to give the title compound as a white solid. (UPLC-MS 3) tR 1.20 min; ESI-MS 372.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH3:21][CH:22]1[O:27][CH:26]([CH3:28])[CH2:25][NH:24][CH2:23]1.N12CCC(CC1)CN2>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:24]1[CH2:23][CH:22]([CH3:21])[O:27][CH:26]([CH3:28])[CH2:25]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: CC1CNCC(C)O1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Agent: C1CN2CCC1CN2
Solvent: CS(C)=O
Product: CC1CN(c2c(Cl)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC(C)O1
Yield: 40.5 %

Procedure:
3 g (10 mmol) of the product from Example A in 35 ml of dimethyl sulphoxide are heated at 140° with 1.2 g (10 mmol) of 2,6-dimethylmorpholine and 2.2 g (20 mmol) of diazabicyclo[2.2.2]octane for 5 hours. The mixture is concentrated under high vacuum, stirred with 30 ml of water, the pH is adjusted to 6 with 2N hydrochloric acid, and the precipitate is filtered off with suction and recrystallised from glycol monomethyl ether. 1.6 g (41% of theory) of 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(2.6-dimethyl-4-morpholinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 258°-261° (with decomposition) is obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:37]=[CH:36][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:36][CH:37]=1
Reactant: C(=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2=NCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
1.0 g of 4-[4-(2-oxazolin-2-yl) benzylidene]-1-tritylpiperidine in 20 ml of methylene chloride are treated slowly with 2 ml of trifluoroacetic acid at -10° C. After stirring for 1 hour at -10° C., the reaction mixture is poured into 150 ml of ice-water and immediately adjusted to pH 11.5 using 6N sodium hydroxide solution. After stirring for 10 minutes, it is extracted twice with 150 ml of ether, and the combined organic phases are washed, dried and evaporated down. The residue is purified by column chromatography on alumina (methylene chloride/methanol=40:1, v/v). 340 mg of the title compound of melting point 126° C. are obtained.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:22][NH2:23].[OH-].[K+]>CO>[C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13]([NH:23][OH:22])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)NO)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12.6 parts of ethyl p-(2-thenoyl)hydratropate in 35 parts of methanol is added successively and while cooling, first a solution of 6.05 parts of hydroxyl amine hydrochloride in 35 parts of methanol and then a solution of 7.3 parts of potassium hydroxide in 35 parts of methanol. Upon completion, the whole is stirred for 30 minutes. The mixture is filtered and the filtrate is stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The aqueous solution is acidified with hydrochloric acid solution and the product is extracted with ether. The extract is washed with water, dried, filtered and evaporated. The residue is taken up in water, alkalized with sodium hydroxide solution, washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid solution. The product is extracted with ether. The latter is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in a mixture of petroleumether and diisopropylether. The solid product is filtered off and crystallized from 2-propanol, yielding p-(2-thenoyl)hydratropohydroxamic acid; mp. 143.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:26]2[N:27]=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=3)[N:30]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[N+:23]([C:13]1[CH:12]=[C:11]([C:26]2[N:27]=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=3)[N:30]=2)[CH:10]=[C:9]([OH:8])[C:14]=1[OH:15])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(-c2nnn(-c3ccc(C(F)(F)F)cn3)n2)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nnn(-c3ccc(C(F)(F)F)cn3)n2)cc(O)c1O
Temperature: -78 °C

Procedure:
A solution of 2-(5-(3,4-bis(benzyloxy)-5-nitrophenyl)-2H-tetrazol-2-yl)-5-(trifluoromethyl)pyridine (0.274 g, 0.5 mmol) in dichloromethane (15 mL) was cooled to −78° C. with stirring under argon and treated with boron tribromide (1.00 g, 4.00 mmol) dropwise. The resulting deep purple suspension was then allowed to stir at room temperature for one hour before cooling again to −78° C. The mixture was quenched by the careful addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give 3-nitro-5-(2-(5-(trifluoromethyl)pyridin-2-yl)-2H-tetrazol-5-yl)benzene-1,2-diol as a yellow solid, 0.165 g, (90%).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=2)[O:21][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:19][C:18]3([CH3:33])[CH3:32])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+].O>CO.O1CCCC1.C(#N)C>[CH2:30]([C:20]1([CH2:28][CH3:29])[CH2:19][C:18]([CH3:32])([CH3:33])[C:17]2[C:22](=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=[C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:34])=[O:2])=[CH:8][CH:9]=3)[CH:16]=2)[O:21]1)[CH3:31]
Reactant: CCC1(CC)CC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)OC)cc3)cc(C(C)C)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CCC1(CC)CC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)cc(C(C)C)c2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.2 %

Procedure:
A solution of 2-[4-(2,2-diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionic acid methyl ester (Intermediate 30, 0.070 g, 0.15 mmol) in methanol (3 mL) and tetrahydrofuran (0.5 mL) was treated with a 5M solution of potassium hydroxide (2 mL, 10 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 days. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford a residue that on preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a yellow solid (0.035 g, 51%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([CH3:25])[NH2:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH3:25])[NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:13][CH:14]=1
Reactant: CN(C)N
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NN(C)C)cn1
Yield: 33.6 %

Procedure:
To a stirred solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) in DMF (5 mL) at room temperature under argon was added N,N-dimethylhydrazine (23 mg, 0.38 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (122 mg, 0.38 mmol) and N,N-diisopropylethylamine (223 mg, 1.7 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (38 mg, 33%) as a colourless gum. MS: m/e=333.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:36]=[CH:35][S:34][CH:33]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:21]3[N:17]4[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]5[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]5)[C:16]4=[N:23][CH:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccsc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccsc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of [4-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (70 mg, 0.135 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature for 15 h. The reaction mixture was then concentrated under reduced pressure to give N-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 83 mg). 1HNMR (300 MHz, CD3OD): δ 8.06 (s, 1H), 7.94 (d, 1H, J=5.4 Hz), 7.87 (t, 1H, J=8.7 Hz), 7.39-7.34 (m, 2H), 7.16-7.03 (m, 4H), 4.62 (s, 2H), 3.98 (brs, 1H), 3.14 (brs, 1H), 2.14-2.09 (brs, 4H), 1.70-1.60 (m, 4H). LC-MS: [M+H]+ 420.