Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N.CN(C=O)C>O>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(Nc2ccc(N(C)C)cc2)c1C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 130 °C

Procedure:
A mixture of 5 g (16.8 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-dimethylamino-phenylamino)-pyrazole, 3.3 g (20.1 mmol) of 3-chloro-aniline hydrochloride and 40 ml of DMF is heated for 8 hours, with stirring, at 130° C. The reaction mixture is then cooled to RT, water is added dropwise thereto, and the reaction mixture is then filtered and the filter residue is dissolved in approx. 20 ml of DMF. After precipitation with water, followed by recrystallization from DMF/water, the resulting crystals are suspended in 10 ml of water. 6 ml of 1N hydrochloric acid are added, the mixture is heated briefly to reflux and filtered and 3 ml of 2N sodium hydroxide solution are added to the filtrate. The crystalline precipitate is filtered off, washed with water and dried under a high vacuum at 120° C., yielding the title compound having a water content of 2.32%; m.p. 250-255° C. (decomp.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:3]1.[H-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CN(C=O)C.CCOCC.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH2:1][CH2:2][CH2:3][NH2:4])[CH2:3]1
Reactant: CC1CCCN(Cc2cccc(O)c2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC1CCCN(Cc2cccc(OCCCN)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.13 g (0.025 mol) of 3-[(3-Methylpiperidin-1-yl) methyl]phenol are introduced into a suspension of 1.0 g (0.025 mol) of sodium hydride (60%) in absolute DMF and stirred overnight at room temperature. After the addition of 2.23 g (0.025 mol) of 3-chloropropionic acid nitrile, the reaction mixture is stirred for 7 hours at 60° C. and then poured into ice water and extracted with ether, and the organic phase is washed with 5% NaOH. After dehydration over Na2SO4, the ethereal phase is introduced dropwise into a suspension of 1.14 g (0.03 mol) of LiAlH4 in absolute ether and then hydrolysed with 2.2 ml of H2O. After filtration and removal of solvent by evaporation under vacuum, 2.96 g of a pale yellow oil are left behind.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccccc1N
Product: Nc1ccccc1CNc1cnccc1C(=O)O
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from 2-aminobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.97 (td, 1H, J=7.8, 1.4 Hz), 6.66 (d, 1H, J=7.9 Hz), 6.52 (td, 1H, J=7.4, 1.0 Hz), 4.35 (s, 2H). [M+H] calc'd for C13H13N3O2, 244. found 244.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>C(O)C.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Cl)c1
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)c(Cl)c1

Procedure:
2-Phenylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (34.0g) was dissolved in ethanol (300 ml) and paraformaldehyde (6.0g) in water (600 ml) added. The mixture was refluxed 4 hours, cooled and worked up as in Example 2(c) to yield 20 g m.p. 206°
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][S:15]([C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)(=[O:17])=[O:16]>>[NH2:14][S:15]([C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:32][CH:33]=3)=[N:24][C:20]=2[CH:19]=1)(=[O:16])=[O:17]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 482 was prepared from 4-morpholinoaniline and 4-(5-aminosulfonyl-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C24H23N5O4S: 478.16; found: 477.93.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([S:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([C:8]1([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(=O)CC2)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(O)CC2)CCOCC1
Temperature: 25 °C
Yield: 99 %

Procedure:
A 250 mL round-bottom flask was charged with 4-(4-oxo-piperidine-1-sulfonyl)-tetrahydro-pyran-4-carboxylic acid tert-butyl ester (10 g, 29 mmol) and methanol (100 mL). The resulting slurry was rapidly stirred with an overhead-stirring paddle, and the flask was immersed into an ice bath. Sodium borohydride (1.09 g, 29 mmol) was added in three portions over 15 min. After complete addition, the homogeneous mixture was warmed to room temperature and stirred for 30 min. The flask was again immersed into an ice water bath, and the reaction was quenched by careful addition of a saturated ammonium chloride solution (25 mL). The mixture was then warmed to room temperature, diluted with water (100 mL), and extracted with methylene chloride (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. This afforded 10 g of an off-white, crystalline solid (99% yield). 1H NMR (CDCl3) δ 1.50 (s, 9H), 1.53–1.62 (m, 2H), 1.68 (br s, 1H), 1.86–1.92 (m, 2H), 2.11 (td, J=4.7, 12.8 Hz, 2H), 2.30 (d, J=11.2 Hz, 2H), 3.17 (m, 2H), 3.29 (t, J=12.2 Hz, 2H), 3.63 (m, 2H), 385 (m, 1H), 3.94 (dd, J=4, 11.2 Hz, 2H); Electrospray mass spectrometry showed m/z=350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17]>>[O:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1ccccc1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-oxo-2-phenylethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. m/z (ES+)=314 [M+H]+; RT=3.30 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:28].[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br-:28].[CH3:15][N:8]([C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
4-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid (J. Organic Chemistry, 1985, 50, 1302-1304, 349 mg, 1.61 mol) was dissolved in N,N-dimethylformamide (3.5 mL) and treated with N,N-carbonyldiimidazole (273 mg, 1.69 mmol). The mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (929 mg, 1.40 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.91 g, 92%, 83% pure) as a white foam. Sample was used crude in next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CN(C)CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccccc1N1CCNCC1
Reaction time: 8 h

Procedure:
To a solution of 1-Boc-4(2-hydroxyphenyl)-piperazine (300 mg, 1.08 mmol), 2-dimethylaminoethyl chloride hydrochloride (233 mg, 1.62 mmol), K2CO3 (450 mg, 3.26 mmol), and KI (357 mg, 2.15 mmol) in DMF (10 mL) was added 18-crown-6 (1.42 g, 5.37 mmol). After stirring overnight, water was added and the solution extracted with CH2Cl2 (3×). The combined organic extracts were concentrated to an oil. The oil was loaded onto a 10 g SCX ion exchange column equilibrated with MeOH. The column was flushed with 20 mL of MeOH, 20 mL of 0.2 M NH3 in MeOH, and 20 mL of 2 M NH3 in MeOH. The fractions containing desired product were combined and concentrated to an oil. To a solution of the oil in MeOH (2 mL) was added 1M HCl (6 mL) in Et2O. After stirring overnight the solution was concentrated to an oil to obtain the final compound. MS: 250.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:8]([N:10]([CH:19]1[CH2:22][N:21]([CH:23]([C:27]([OH:29])=[O:28])[CH:24]([CH3:26])[CH3:25])[C:20]1=[O:30])C(OCC(Cl)(Cl)Cl)=O)=[O:9])[NH2:7].C(O)(=O)C>CN(C)C=O.[Zn]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:8]([NH:10][CH:19]1[CH2:22][N:21]([CH:23]([C:27]([OH:29])=[O:28])[CH:24]([CH3:26])[CH3:25])[C:20]1=[O:30])=[O:9])[NH2:7]
Reactant: CC(C)C(C(=O)O)N1CC(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)C(N)c2cccs2)C1=O
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)C(C(=O)O)N1CC(NC(=O)C(N)c2cccs2)C1=O
Reaction time: 3 h
Yield: 106.2 %

Procedure:
3-[2-(2-Thienyl)-N-(2,2,2-trichloroethoxycarbonyl)glycinamido]-1-(1-carboxy-2-methylpropyl)-2-azetidinone (1.0 g.) was dissolved in N,N-dimethylformamide (5 ml.), and acetic acid (3 ml.) was added thereto. To the solution, there was added zinc powder (1.2 g.) at 15° C. in the course of about half an hour, whereafter the mixture was stirred at 15° to 20° C. for 3 hours. The unreacted zinc powder was filtered off and washed with a small amount of N,N-dimethylformamide, and then this washings and the filtrate were combined. Diethyl ether (about 80 ml.) was added to the combined solution and the precipitating materials were collected by filtration, washed with diethyl ether and then dried to give 3-[2-(2-thienyl)glycinamido]-1-(1-carboxy-2-methylpropyl)-2-azetidinone (690 mg.).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:22][C:16]1[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(O)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 84.5 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.00 g, 0.003 mol) in tetrahydrofuran (18 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 18 mL, 0.009 mol). The mixture was stirred at 0° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.82 g, 86%) as a pale orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:16])[CH3:17])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isopropylamino-phenyl)-carbamic acid tert-butyl ester (Example J40) (300 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (169 mg, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23]C)[CH:18]=2)=[N:8][N:7]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([OH:23])[CH:18]=2)=[N:8][N:7]=1
Reactant: CCc1ccc(Nc2nnc(Cc3ccnc(OC)c3)c3ccccc23)cc1Br
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Nc2nnc(Cc3ccnc(O)c3)c3ccccc23)cc1Br

Procedure:
In analogy to Ex. 1, 500 mg (1.11 mMol) of 1-(3-bromo-4-ethyl-anilino)-4-[2-methoxy-(pyridin-4-yl)-methyl]-phthalazine in 12 ml of chloroform are reacted with 0.3 ml (2.2 mMol) Me3Sil to give the title compound: M.p. 251-252° C.; FAB-MS: (M+H)+=435/437; HPLC(Grad20-100) tRet=9.6.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12]C=C(Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.[Cl:31][C:32]([Cl:38])(Cl)[C:33](Cl)(Cl)Cl>>[ClH:31].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:33]=[C:32]([Cl:38])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(Cl)cc2OCc2ccccc2)n1
Yield: 27.2 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 0.225 g, 0.598 mmol), MeLi (0.467 mL, 0.747 mmol), butyllithium (0.299 mL, 0.747 mmol), and perchloroethane (0.991 g, 4.19 mmol) were reacted according to the method of Example 7 to provide 3-(benzyloxy)-5-chloro-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.060 g, 30.2% yield). 1H NMR (CDCl3) δ 12.43 (bs, 1H), 7.91 (d, 1H), 7.59 (m, 2H), 7.41 (m, 2H), 7.33 (m, 1H), 7.20 (d, 1H), 6.41 (s, 1H), 5.36 (s, 2H), 2.47 (s, 3H). Mass spectrum (apci) m/z=332.1 (M+H-HCl).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cnc3cc(OC)ccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1ccc(-c2cnc3cc(O)ccc3c2)cc1
Yield: 63 %

Procedure:
The compound is prepared by reaction of 7-methoxy-3-(4-methoxyphenyl)quinoline (96 mg, 0.37 mmol, 1 eq) with aluminum trichloride (392 mg, 2.95 mmol, 6 eq) according to method F. Purification by column chromatography with dichloromethane/methanol 96/4 as the eluent yields the desired product in a yield of 63%, 55 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]Br>CN(C)C=O>[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)=CCBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous N,N-dimethylformamide (DMF) were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask and the solution was kept stirring at 0° C. for 30 minutes. 3,3-dimethylallyl bromide (192 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired product was isolated via column chromatography using a solvent system of 100% Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The purified product was characterized by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CDCl3): δ 1.76-1.87 (6H), 4.54 (d, 2H, J=6 Hz), 5.50 (m, 1H), 6.43 (m, 1H), 6.92-7.67 (4H); 13C-NMR (75 MHz, CDCl3): δ 18.68, 26.27, 65.86, 111.35, 117.42, 118.26, 119.44, 119.54, 120.53, 139.38, 143.69, 148.80, 155.71, 161.47. FIRMS (ES) Calcd. for C14H15O3: 231.1021. found: 231.1024.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH:36]=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cccc2ccccc12
Product: Clc1cccc2c(-c3cccc(NCc4cccc5ccccc45)c3)c(Cc3ccccc3)nnc12

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and naphthalene-1-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 486.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:12])=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Yield: 103.6 %

Procedure:
4-Chloro-3-nitropyridin-2-amine (0.10 g, 0.58 mmol) was dissolved in dry acetonitrile (20 mL). To the stirred solution was then added N-chlorosuccinimide (0.094 g, 0.70 mmol), and the reaction mixture was heated at 80° C. for 1 h. Volatiles were removed in vacuo and the residue purified by silica column chromatography (elution with dichloromethane) to provide the title compound as a pale brown powder (0.125 g, 85%). 1H-NMR (500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.36 (s, 1H, 6-H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[CH:11]1[CH2:19][CH2:18][CH2:17][C:13]([C:14]([OH:16])=O)=[CH:12]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10](=[O:20])[CH:11]2[CH2:19][CH2:18][CH2:17][C:13](=[CH:12]2)[C:14]1=[O:16]
Reactant: O=C(O)C1=CC(C(=O)Nc2ccc(Br)cc2F)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C1C2=CC(CCC2)C(=O)N1c1ccc(Br)cc1F
Reaction time: 2 h

Procedure:
N-(2-fluoro-4-bromophenyl)-3,4,5,6-tetrahydroisophthalamic acid (84.4 g) and dicyclohexylcarbodiimide (51.0 g) were added to toluene (600 ml) and the mixture was stirred at 0°-10° C. for 2 hours. The precipitate was removed and the filtrate was concentrated to dryness under reduced pressure. The oil was washed with n-hexane by decanting. The crystals were recovered by filtration and washed with a small quantity of cold n-hexane. Yield 36.4 g.; m.p. 45°-46° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][N:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:18]2)[CH:6]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([N:19]3[CH2:20][CH2:21][CH:17]([CH2:16][CH2:15][NH:14][CH2:13][CH2:12][O:11][C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=4)[CH2:18]3)[S:23][C:24]=2[CH:30]=1
Reactant: COC(=O)Cc1cccc(OCCNCCC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cccc(OCCNCCC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A mixture of [3-[2-[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]ethylamino]ethoxy]phenyl]acetic acid methyl ester (101 mg), 2N aqueous sodium hydroxide (0.535 mL), tetrahydrofuran (1 mL) and methanol (0.5 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was washed with ethyl acetate/n-hexane to give the title compound (13 mg). Yield: 14%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1>CO.[OH-].[OH-].[Pd+2]>[O:1]=[C:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccnc(O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(C(=O)O)CCN1
Yield: 92.3 %

Procedure:
A solution of 2-hydroxypyridine-4-carboxylic acid (40.0 g) and 10% palladium hydroxide/carbon (8.0 g) in methanol (500 mL) was stirred at 30° C. for 24 hr under a hydrogen atmosphere (50 psi). The reaction mixture was filtered, the catalyst was removed, and the filtrate was concentrated under reduced pressure to give the title compound (38.0 g).