Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][CH2:12][C:13]1[N:17]([CH3:18])[C:16]([SH:19])=[N:15][N:14]=1.[CH3:20]I>O.ClCCl>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[NH:11][CH2:12][C:13]1[N:17]([CH3:18])[C:16]([S:19][CH3:20])=[N:15][N:14]=1
Reactant: Cc1cccc(C)c1NCc1nnc(S)n1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CSc1nnc(CNc2c(C)cccc2C)n1C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.7 g (0.0419 mol) sodium hydroxide in 125 ml water was added in one portion, 10.4 g (0.0419 mol), 3-(2,6-dimethylphenylaminomethyl)-4-methyl-5-mercapto-1,2,4-triazole. After a homogeneous solution was obtained, 6.2 g (0.044 mol) methyl iodide was added dropwise. The reaction mixture was then diluted with 50 ml dichloromethane and vigorously stirred for 0.5 hour. The reaction mixture was diluted with another 100 ml dichloromethane and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a solid residue. The solid was triturated with ethyl ether to give the product as a colorless solid. The product is tabulated in Table I as Compound No. 14-A.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1([CH3:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4](=[O:5])[CH2:3]1
Reactant: CC(C)=CC(=O)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)c2ccccc21
Yield: 73 %

Procedure:
A solution of 25.0 g (0.25 moles) of 3,3-dimethyl acrylic acid in 250 ml of benzene was cooled to 0° C. in an ice bath. To this solution, 99 g (0.75 moles) of anhydrous aluminum chloride was slowly added using a spatula over a period of 20 minutes with stirring, after which the ice bath was removed and the reaction mixture was gradually heated to reflux. The reaction mixture was refluxed for ˜7-8 h, then excess benzene was distilled off and the mixture was quenched with ice-cold dilute hydrochloric acid (HCl). The mixture was then diluted with ethylacetate (100 ml), the organic layer was separated and the aqueous layer was again washed with ethyl acetate (50 ml). The combined organic layer was washed with water (3×100 ml) until the pH was neutral, and then dried over anhydrous sodium sulfate and concentrated under vacuum. 43.0 g of reddish brown liquid was obtained, which was distilled under vacuum to give 29 g of the desired product, 3,3-dimethyl-indan-1-one (distilled at 82-84° C. at ˜10 mm). Yield=73%, purity=99%. 1H NMR (DMSO-d6, 300 MHz): δ 7.3-7.8 (m, 4H, Ar—H), δ 2.5 (s, 2H, O═C—CH2), δ 1.3 (s, 6H, —CH3). LC/MS: 161 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].[OH-].[K+].[CH3:20]OS(OC)(=O)=O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1Cl
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(c1ccccc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Compound 1 (1.25 g, 5 mmol) was stirred at room temperature in acetone (16 mL). To this, KOH (1.23 g, 22 mmol) was added. The mixture stirred at reflux for 1 h. To this, Me2SO4 (2.18 mL, 23 mmol) was added dropwise over 10 min. The mixture stirred at reflux for 1 h. The reaction was allowed to cool to room temperature. 10M NaOH was added and the reaction was stirred at room temperature. The mixture was quenched with 10 mL H2O and extracted 3 times with 10 mL dichloromethane. Organic layers were combined and dried over Na2SO4. Solvent was removed under vacuum and the mixture was placed in an 80° C. oil bath under vacuum to remove excess Me2SO4. No further purification was needed to give the product as a black oil (1.31 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ 7.68 (1H, dd, J=8.1, 1.5 Hz), 7.54 (1H, ddd, J=8.7, 7.3, 1.7 Hz), 7.42 (1H, dd, J=7.8, 1.5 Hz), 7.19 (1H, dd, J=7.7, 1.7 Hz), 7.14-7.11 (2H, m), 7.06 (1H, dd, J=7.7, 1.9 Hz), 7.0 (1H, ddd, J=8.2, 7.3, 1.1 Hz); 13C (75 MHz, CDCl3) δ 145.0 (q), 143.0 (q), 133.2 (t), 131.3 (t), 130.9 (q), 128.7 (q), 127.9 (t), 126.7 (t), 126.2 (t), 125.9 (t), 120.8 (t), 120.6 (t), 41.1.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:31]([C:32](=[O:33])[NH:34][CH3:35])=[CH:36][CH:37]=[CH:38][C:39]=4[F:40])[C:26]([Cl:41])=[CH:25][N:24]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (35 mg, 21%). LCMS (m/e) 572 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.48-9.34 (m, 2H), 8.62-8.51 (m, 1H), 8.20 (s, 1H), 7.54-7.37 (m, 3H), 7.36-7.24 (m, 1H), 7.10 (d, 1H, J=9.1 Hz), 6.94 (d, 1H, J=8.7 Hz), 4.14-3.86 (m, 4H), 3.70-3.43 (m, 2H), 2.74 (d, 3H, J=4.4 Hz), 2.21-2.00 (m, 8H), 1.97-1.82 (m, 2H), 1.63-1.48 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH2:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH:29][C:11]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]4[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=4)[O:10][N:9]=3)=[O:13])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2cc(F)ccc12)c1cc(Cc2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A mixture of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-fluoro-1H-indol-3-yl)ethanamine (0.051 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.040 g (41%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]([CH:16]=[O:17])=[C:14]2[C:5]([C:6](=O)[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2].[OH-].[NH4+].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2=[N:4][N:3]([CH2:1][CH3:2])[C:15]([CH:16]=[O:17])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCn1nc2c(=O)[nH]c3ccccc3c2c1C=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1nc2c(Cl)nc3ccccc3c2c1C=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
2-Ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde (1 g) was combined with phosphorus oxychloride (10 mL) and heated at 100° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, poured into a mixture of ammonium hydroxide and ice, and then stirred for 20 minutes. A solid was isolated by filtration and air dried to provide 4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde as a white powder. MS (APCI) m/z 260 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]([O:31][C:32]([C:34]1[N:39]2[C:40](=[O:43])[C@@H:41]([NH2:42])[C@H:38]2[S:37][CH2:36][C:35]=1[CH2:44][O:45][C:46](=[O:48])[CH3:47])=[O:33])([CH3:30])([CH3:29])[CH3:28].P([O-])([O-])(O)=O.[K+].[K+]>C(Cl)Cl.CN1CCOCC1>[C:27]([O:31][C:32]([C:34]1[N:39]2[C:40](=[O:43])[C@@H:41]([NH:42][C:16](=[O:18])[CH2:15][C:13]3[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=3)[C@H:38]2[S:37][CH2:36][C:35]=1[CH2:44][O:45][C:46](=[O:48])[CH3:47])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Agent: CC(C)COC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The starting material can be prepared as follows: 8.15 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 500 ml of methylene chloride containing 3.06 ml of N-methylmorpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 4.13 ml of chloroformic acid isobutyl ester are added dropwise whilst keeping the temperature at between -15° C. and -20° C. After 30 minutes, a solution of 9.85 g of 3-acetoxymethyl-7β-amino-3-cephem-4-carboxylic acid tert.-butyl ester in 50 ml of methylene chloride is added, after which the solution is stirred for a further 15 hours whilst slowly raising the temperature to 20° C. to 25° C. The mixture is poured out into ice-cold water, neutralised with dipotassium hydrogen phosphate and extracted repeatedly with methylene chloride. The organic extracts are washed with an aqueous saturated sodium chloride solution and dried over magnesium sulphate, after which the solvent is removed under reduced pressure. The residue is recrystallised from diethyl ether and gives 3-acetoxymethyl-7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester, melting point 76°-78° C., thin layer chromatogram (silica gel): Rf=0.44 (system: chloroform/ethyl acetate/acetic acid, 80:19:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(C)(=O)=O)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added MsCl (55.8 μL, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 45 min then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 hexanes:EtOAc) to yield a colorless oil (245.6 mg, 71% yield). 1H NMR (CDCl3, 300 MHz): δ 9.35 (brs, 2H), 7.56 (d, J=3.0 Hz, 1H), 7.26 (m, 1H). 6.84 (d, J=9.0 Hz, 1H), 5.09 (brs, 2H), 4.53 (t, J=6.0 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.29 (m, 2H), 1.52 (s, 9H), 1.43 (s, 9H); 13C(CDCl3, 150 MHz): δ 160.7, 154.9, 154.1, 133.3, 133.1, 128.0, 132.2, 113.2, 110.7, 128.3, 84.7, 80.5, 66.9, 64.6, 46.7, 29.9, 28.5, 28.2.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([NH:5][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
A solution of t-butylamine (0.2962 g, 4.05 mmol) and triethylamine (0.70 ml, 5.02 mmol) in dichloromethane (2 ml) was cooled to 0° C. in an ice-bath. To the above solution was added a solution of 2,4-difluorobenzoyl chloride (0.3652 g, 2.07 mmol) in dichloromethane (3 ml) dropwise and stirred for 2.5 hours. The mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous NaHCO3 and dried over MgSO4. The solvent was evaporated to give the title compound (0.4086 g; 93%).
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:24]1[CH2:27][N:26]([CH:28]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25]1)(=O)=O>CN(C)C=O>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:26]2[CH2:27][CH:24]([NH:10][C:3]3[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:1](=[O:11])(=[O:12])[N:2]=3)[CH2:25]2)=[CH:37][CH:38]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: NC1=NS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(NC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c2ccccc21
Temperature: 100 °C
Reaction time: 9 h
Yield: 11.2 %

Procedure:
182 mg of 1,2-benzisothiazol-3-amine 1,1-dioxide and 326 mg of cesium carbonate are added to 386 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-yl methylsulfonate in solution in 10 cm3 of dimethylformamide. The reaction medium is then stirred at 100° C. for 9 hours and then concentrated under reduced pressure (2.7 kPa). The residue is washed four times with 5 cm3 of boiling distilled water, disintegrated by stirring in 5 cm3 of distilled water at room temperature and then recovered by filtration and purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (98/2 by volume)]. 53 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1,1-dioxo-1H-1λ6-benzo[d]isothiazol-3-yl)amine are obtained in the form of a pasty product [[1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 3.17 (mt: 2H); 3.61 (broad t, J=7.5 Hz: 2H); 4.37 (s: 1H); 4.75 (mt: 1H); from 6.30 to 6.40 (unresolved complex: 1H); from 7.20 to 7.35 (mt: 8H); 7.62 (broad d, J=7.5 Hz: 1H); 7.69 (broad t, J=7.5 Hz: 1H); 7.76 (broad t, J=7.5 Hz: 1H); 7.93 (broad d, J=7.5 Hz: 1H)].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(O)C.S(Cl)(Cl)=O>[Br:1][C:2]1[S:6][C:5]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(=O)C(=Cc1ccc(Br)s1)C(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution containing 5.73 g 5-bromothiophene-2-carboxaldehyde and 5.0 g 2,4-pentanedione in 25 ml of 2-propanol, 2.9 ml thionylchloride was gradually added. The mixture was stirred for 2 h at 20° C. 120 ml of conc. Na2SO4 -solution was then added and the mixture was extracted with ether. The solvent was evaporated in vacuo and the crystalline residue was washed with cold ether. Yield 3.9 g, mp 70°-74° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:10]3[CH:19]=[C:18]4[O:20][CH2:21][O:22][C:17]4=[CH:16][C:11]=3[S:12][C:13]=2[CH:14]=[O:15])=[CH:6][CH:5]=1>CO>[CH2:21]1[O:22][C:17]2[C:18](=[CH:19][C:10]3[C:9]([O:8][C:7]4[CH:23]=[CH:24][C:4]([Cl:3])=[CH:5][CH:6]=4)=[C:13]([CH2:14][OH:15])[S:12][C:11]=3[CH:16]=2)[O:20]1
Reactant: O=Cc1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3
Reaction time: 2 h

Procedure:
26 mmol of NaBH4 are added at ambient temperature to a solution of 24 mmol of the compound obtained in Step E of Example 1 in 100 ml of methanol. After reacting for 2 hours, one equivalent of NaBH4 is added to the reaction mixture. After reacting for 12 hours, the solution is concentrated and then diluted with ethyl acetate, washed with 1N HCl solution, then with water and then with saturated NaCl solution, subsequently dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethyl acetate: 95/5) allows the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:41]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][N:15]2[CH3:41])=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 1.9 mmol) in dimethylformamide (10 ml) is placed in a 25 ml three-necked flask placed under argon, then sodium hydride (0.063 g; 2.101 mmol) is added and the mixture is left to agitate for 15 minutes. When there is no longer any gas being given off, methyl iodide (0.131 ml, 2.101 mmol) is added dropwise and the mixture is left to react at 21° C. for 2 hours. The reaction medium is run into 100 ml of distilled water, and then extracted with 2 times 100 ml of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. The evaporation compound is triturated in diisopropyl ether. The pulverulent solid compound thus obtained is filtered off and rinsed. 2-(6-Benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.888 g; 86%) is isolated in the form of a beige-colored solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21](O)=[O:22])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][N:26]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:22][N:31]=[C:29]([C:28]4[CH:33]=[CH:34][C:25]([NH2:24])=[N:26][CH:27]=4)[N:30]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccc(N)nc4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (diethyl ether) as a white solid (32 mg, 15%). MS (EI) 436.1 [(M)+]; mp 257° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:9](=[O:12])[CH:10]=[CH:11][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=Cc1ccc(N)nc1
Temperature: 110 °C

Procedure:
A mixture of 2-amino-5-bromo-pyridine (9-1) (10 g, 58 mmol), tert-butyl acrylate (50 mL, 344 mmol), triethylamine (50 mL, 359 mmol), tri-o-tolylphosphine (3.0 g, 9.8 mmol) and Pd(OAc)2 (1.0 g, 4.5 mmol) in 150 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110° C. for 20 hr. The mixture was then cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:1) to afford the desired product 9-2 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17][N:18](C)C)[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:15][C:14]1[N:18]=[CH:17][N:16]=[C:12]2[NH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]=12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C=Nc1[nH]nc(Nc2cccc(Cl)c2)c1C#N
Product: Clc1cccc(Nc2n[nH]c3ncnc(NCc4ccccc4)c23)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a mixture of 1 g (3.46 mmol) of 3-(3-chloro-phenylamino)-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole and 10 ml of benzylamine is stirred for 3 hours at 120° C. and then concentrated by evaporation under a HV. The crystalline residue is digested in 10 ml of acetonitrile, cooled to 0° C. and filtered and the filter residue is recrystallized from 35 ml of acetonitrile, yielding the title compound; m.p. 216-218° C.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([O:14]C)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1.O>ClCCl>[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([OH:14])[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c(C=O)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)c(C=O)c1O
Yield: 95.1 %

Procedure:
1M boron trichloride in dichloromethane (25 ml; 25 mmol) was added to a solution of 6-fluoro-2,3-dimethoxy-benzaldehyde [Cantrell, Amanda S.; Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; et al.; J.Med.Chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23 mmol) in dichloromethane (30 ml) keeping the reaction temperature at −70 C. The reaction mixture stirred at room temperature overnight and hydrolyzed with water. The organic phase was separated, washed with water and evaporated in vacuo. The residue was chromatographed (silica gel, EA:Hex, 5:1) to give 3.72 g (94%) of 6-fluoro-2-hydroxy-3-methoxy-benzaldehyde as yellow crystals.