Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([CH:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)=O.Cl.[Cl:17][C:18]1[C:19]([CH2:24][NH2:25])=[N:20][CH:21]=[CH:22][N:23]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:17][C:18]1[C:19]2[N:20]([C:9]([CH:11]3[CH2:12][C:13](=[O:15])[CH2:14]3)=[N:25][CH:24]=2)[CH:21]=[CH:22][N:23]=1
Reactant: O=C1CC(C(=O)ON2C(=O)CCC2=O)C1
Reactant: NCc1nccnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(c2ncc3c(Cl)nccn23)C1

Procedure:
Into a round bottom 1-neck flask (5 L), 3-oxo-cyclobutanecarboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (217.2 g, 0.937 mol), C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (153.3 g, 0.852 mol), and THF (760 mL) were added. A solution of 10% NaHCO3 (1.07 kg) was then added and after 20 min, the layers were allowed to separate and the aqueous layer was removed. The aqueous layer was back extracted with EtOAc (1×700 mL, 1×300 mL). The combined organics were washed with brine (350 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. This solid was resuspended in ethyl acetate (915 mL) and DMF (132 mL) and the solution was put under an atmosphere of nitrogen and cooled to 10.5° C. Phosphorus oxychloride (159 mL, 1.70 mol) was then added over 15 minutes and the reaction was allowed to stir for 45 min. The reaction solution was then poured slowly into a 22% aqueous Na2CO3 solution at 10° C. Water (1 L) was added and the layers were allowed to separate. The organic layer was removed and the aqueous was back extracted with EtOAc (1×1 L, 1×0.5 L). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo until about 0.5 L of solvent remained. Heptane was added and the slurry was concentrated in vacuo until most of the EtOAc was removed. The resultant slurry was filtered to give desired product. 1H NMR (400 Adz, CDCl3) δ 3.59-3.68 (m, 2H), 3.72-3.79 (m, 2H), 3.86-3.94 (m, 1H), 7.40 (d, 1H, J=5.2 Hz), 7.60 (d, 1H, J=5.2 Hz) and 7.85 (s, 1H).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[N-:8]=[N+:9]=[N-:10].[Na+]>CC(C)=O.O>[N:8]([C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(C)(C)N=[N+]=[N-]
Yield: 64.5 %

Procedure:
A stirred solution of 3-bromo-3-methylbutan-2-one (1 g, 6.1 mmol) in 50 mL of acetone and 5 mL of water was treated with NaN3 (0.4 g, 6.1 mmol). The reaction mixture was stirred at reflux for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and water and the organic layer was washed with brine, evaporated to dryness to give 3-azido-3-methylbutan-2-one (0.5 g, 65%) which was used in the next step without further purification. LCMS: No molecular ion observed for desired mass.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[S:9][C:5]1[N:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cn1ccnc1Sc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1ccnc1Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 5.5 %

Procedure:
2-Cyano-6-(1-methyl-1H-imidazol-2-yl)thiopyridine (1.56 g, 7.22 mmol) and methyl thiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene (100 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The reaction mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.14 g, 5%) as pale yellow crystals.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26](O)=[O:27])[N:21]=1>>[F:30][C:19]([F:18])([F:29])[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:27])[N:21]=1
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3ccc(C(F)(F)F)n3)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.86 g). This gives, after chromatographic purification, ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.1 g, 62%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([C:17](=[O:18])[NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([C:17](=[O:18])[N:16]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(Cc1ccc(Br)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Introduce 600 mg (14.7 mmol) of sodium hydride (60% suspension in mineral oil) in a 500 mL round bottom flask under nitrogen before adding successively 20 mL of anhydrous DMF and 2.5 g (9.8 mmol) of 1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester previously dissolved in 20 mL of anhydrous DMF. After agitating one hour at room temperature, 2.5 g (9.8 mmol) of 4-bromobenzylbromide diluted in 20 mL of anhydrous DMF were added and the reaction mixture was agitated an additional hour at room temperature. Then 100 mL of water were added and the solution was extracted with diethyl ether (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure to yield 4.63 g of 2-(4-bromobenzyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:28])=[CH:17][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)ccc3OCc3ccccc3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1ccc(OCc2ccccc2)c(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 15.5 %

Procedure:
The crude methyl 2-((S)-6-((4-(benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 36b (1 g, 1.69 mmol) was dissolved in 50 mL of a mixed solvent of methanol and tetrahydrofuran (V/V=1:4), followed by addition of 1M aqueous lithium hydroxide solution (20 mL, 20 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 150 mL of water and 30 mL of ethyl acetate, 1M hydrochloric acid was added dropwise to adjust the pH to 2˜3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 2-((S)-6-((4-(benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 36c (152 mg) as a brown oil, which was directly used in the next step without further purification.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@H:3]([C:7]([NH:9][C:10]1([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]1)=[O:8])[NH:2]2.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[C@@H:3]([C:7]([NH:9][C:10]3([C:13]4[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=4)[CH2:11][CH2:12]3)=[O:8])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@@H]4C[C@@H]4N3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@@H]4C[C@@H]4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D148) (100.8 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-((1S,3R,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (diastereoisomer trans) (D105) (71.9 mg) and 4-(trifluoromethyl)-benzylbromide (0.047 ml). (Na2CO3: 3 eq; Reaction time: 18 hrs; 68° C.)
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Br:18])[CH:13]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[Br:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:19])=[O:2])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1NCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester is dissolved in 290 ml of ethanol and mixed with 31.2 ml of 2 M sodium hydroxide solution. After having been stirred overnight at room temperature, the ethanol is drawn off, and the aqueous phase is shaken out with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid. The precipitate that is formed is suctioned off and dried. 5.93 g (62%) of 2-[(2-bromo-pyridin-4-ytmethyl)-amino]-benzoic acid accumulates in the form of a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[NH:21][CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=5[Cl:32])[N:24]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=1[CH3:43]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[N:21]([C:34]5[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=5[CH3:43])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=5[Cl:32])[N:24]=4)=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)n2)c(Cl)c1
Product: Cc1cc([N+](=O)[O-])ccc1-n1cc(-c2ccc(Cl)cc2Cl)nc1Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1

Procedure:
2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (250 mg, 0.54 mmol) was treated according to general procedure B using 2-fluoro-5-nitrotoluene to provide 2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(2-methyl-4-nitro-phenyl)-1H-imidazole, which was collected without purification. Treatment of the nitro compound as described in general procedure C provided 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-3-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH:27]([CH3:30])[CH2:28][OH:29]>CO>[OH:29][CH2:28][CH:27]([O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22])[CH3:30]
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: CC(CO)ON
Agent: Cl
Solvent: CO
Product: C/C(=N\OC(C)CO)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 44.3 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (40 mg, 0.132 mmol) and 2-(aminooxy)propan-1-ol (intermediate Q) (33.6 mg, 0.264 mmol) in 15 mL of MeOH was stirred at it overnight. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 22 mg (44%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-d4 δ ppm 8.82 (s, 1H), 8.33 (d, 1H), 8.12 (d, 1H), 7.98 (t, 3H), 7.84 (d, 1H), 7.55 (m, 1H), 4.84 (s, 2H), 4.50 (m, 1H), 3.72 (d, 2H), 2.32 (s, 3H), 1.33 (d, 3H). LC-MS (method B): [MH]+=377.0, tR=1.867 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25](O)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:25]([CH:24]1[CH2:28][CH2:29][CH2:30][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:26])[CH2:7][CH2:6]2
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCCN(C(=O)OC(C)(C)C)C1)CC2
Yield: 71.2 %

Procedure:
A conventional amidation reaction was carried out using a dichloromethane solution (40 ml) of 2.53 g of (±)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 3.0 g of N-(tert-butyloxycarbonyl)nipecotic acid, 3.0 g of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.89 g of 1-hydroxybenztriazole to give 3.77 g of (±)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Deprotection of 3.77 g of (±)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline was further carried out using 10 ml of an ethyl acetate solution containing 4N hydrochloric acid to give 2.30 g of (±)-6,7-dimethoxy-2-[(3-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([OH:19])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[C:17]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:19])[CH3:25]
Reactant: O=C(O)c1cc(-c2ccccc2)c2ccccc2n1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc(-c2ccccc2)c2ccccc2n1

Procedure:
The process is carried out as for Example 1, starting from 2 g of 4-phenyl quinoline 2-carboxylic acid, 6 ml of thionyl chloride and 8.3 ml of diethylamine. After treatment, 2.3 g of N,N-diethyl 4-phenyl quinoline 2-carboxamide are isolated in the form of an orange oil. After crystallization from a 50/50 hexane-ether mixture, the product has a melting point lower than 50° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].[H-].[Na+].CCO>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 174.1 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (1.0 g) and 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.3 g) in DMF (10 mL) was added 60% NaH (0.23 g) at room temperature, and the mixture was stirred at 180° C. under microwave irradiation for 30 min. To the mixture was added EtOH (10 mL). The formed crystals were collected by filtration and washed with EtOH. This microwave reaction was repeated two additional times with the same amount of starting material. The combined crystals were recrystallized from EtOH containing 5% distilled water (270 mL) and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.3 g) as white crystals (Form A).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[F:23])=[O:4].O1CCCC1>C(O)C.[C].[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[C:10]2[CH:9]=[CH:8][C:7]([F:23])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:24])[CH:11]=2)=[N:14][CH:15]=1
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 128.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N-{2-fluoro-5-[methyl(5-nitropyridin-2-yl)amino]phenyl}acetamide (18.0 g, 50.2 mmol) in ethanol (100 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (1.8 g), and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 14 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give the title compound (21.2 g, 68%) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:26][O-:27].[Na+].ClCCl>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([O:27][CH3:26])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A heterogeneous mixture containing 3-(4-(1H-imidazol-1-yl)benzyl)-2,4-dichloro-6-iodoquinoline (1.2 g, 2.5 mmol, Intermediate 17: step b) and sodium methoxide (1.6 g, 30 mmol) in toluene (25 mL) was heated to 110° C. After 2 hours, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added and the mixture was filtered through Celite®, rinsing the filter cake with dichloromethane. The filtrate was concentrated to provide the title compound as an off-white solid. This material was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC=CC=1.C(OCC)C>[CH2:30]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc(Cn2ccc3ccccc32)cc1
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of indole (1) (0.03 mole, 3.51 g), potassium hydroxide (0.03 mole, 1.97 g)) powdered in a mortar and 18-crown-6 ether (0.001 mole, 250 mg) in benzene (20 cm3) is heated under reflux with vigorous stirring for two hours. A solution of benzyl chloride (26) (0.04 mole, 5.06 g) in benzene (10 cm3) is added to the above mixture and reflux is maintained for an additional four hours. The reaction is monitored by TLC. The reaction mixture is filtered on Celite. Evaporation of the solvent gives an orange liquid which is purified by dry column chromatography eluted using a mixture of dichloromethane in 50% petroleum ether. Evaporation of the solvent gives a colourless thick liquid which is solidified in the presence of diethyl ether to give a white solid of 1-benzylindole (3b) (1.2 g, 0.007 mole, 25%), m.p. 48-51° C., shown to be pure by 1H nmr.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[C:10]([Cl:13])[CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:7]=2[CH:6]=[N:5]1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:25]1[CH2:29]CC[CH2:26]1>C(#N)C>[Cl:13][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:29][CH2:25][CH2:26][CH2:2]3)[C:12]=2[CH:11]=1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1cc(Cl)cc2c1cnn2C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc2c1cnn2C1CCCC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
To a stirred solution of methyl 1-acetyl-6-chloro-1H-indazole-4-carboxylate (1 equiv.) in acetonitrile (3 mL per 1 mmol), cesium carbonate (1.5 equiv.) was added followed by bromocyclopentane (2 equiv.). The reaction mixture was stirred at 90° C. for 3-4 h. On completion of reaction, acetonitrile was removed under reduced pressure and water was added. Extraction was carried out using ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure and residue was purified by silica gel column chromatography to obtain methyl 6-chloro-1-cyclopentyl-1H-indazole-4-carboxylate (yield 30-35%). The structure was confirmed as the desired regioisomer by NOE.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[Cl:31])(=[O:23])=[O:22].Cl[C:33]1C=CC(Cl)=C[C:34]=1S(Cl)(=O)=O>>[CH2:33]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])(=[O:22])=[O:23])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:34]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)ccc3Cl)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)ccc3Cl)c2)cc1

Procedure:
4-[4-Chloro-3-(2,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=497.0 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 2,5-dichloro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(2,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>C[O-].[Na+].CO>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCCOC(=O)c1ncc2cc(OC3CCCCC3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(OC3CCCCC3)ccc2c1O)C(=O)O
Yield: 62.3 %

Procedure:
A mixture of 7-cyclohexyloxyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg) and L-alanine (207 mg) in 0.5 M sodium methoxide in methanol (3.7 ml) was heated in a microwave reactor (sealed tube) at 120° C. for 40 min. Reaction mixture was concentrated, dissolved in water (30 ml), and acidified by 2 N HCl to pH=4. It was extracted with ethyl acetate. Organic layer was washed with water, brine, dried over magnesium sulfate, and filtered. Filtrate was concentrated and purified by silica gel chromatography to give the title compound (52 mg). MS-(+)-ion M+1=359.18.