Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc(C#N)c2)nc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Methyl 6-chloronicotinate (467 mg, 2.72 mmol) and (3-cyanophenyl)boronic acid (400 mg, 2.72 mmol) were added to 1,4-dioxane (25 mL). To this was added 6.80 mL of a 2 M solution of aqueous potassium carbonate and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.136 mmol). The above reagents were heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the organic layer was dried over anhydrous MgSO4, filtered and evaporated to a pale yellow solid. The solid was purified using chromatography on silica eluting with a mixture of heptane: ethyl acetate 90:10, 80:20, 70:30. The product fractions were combined and evaporated to give methyl 6-(3-cyanophenyl)nicotinate as a white solid (278 mg). LCMS (ES+) 239 (M+1) 1H NMR (400 MHz CDCl3) ppm 4.00 (s, 3H) 7.62 (t, J=8.2 Hz, 1H) 7.76 (m, 1H) 7.83 (d, J=10.6 Hz, 1H) 8.31 (m, 1H) 8.40 (m, 2H) 9.30 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[C:29](O)=[O:30]>>[CH3:19][N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29]([CH:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20]3)=[O:30])[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: Cn1cc(C(=O)c2cncc(NC(=O)C3Cc4ccccc4C3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 110) and indane-2-carboxylic acid to afford the title compound. LCMS: Rt=2.58 min; m/z 398 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cncc(Br)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.44 g (2.2 mmol) 5-bromonicotinic acid, 0.30 g (2.2 mmol) 5-fluoroindoline, 0.75 g (2.3 mmol) TBTU and 0.60 mL (4.3 mmol) TEA were combined in 3.0 mL DMF and stirred overnight at RT. Then the reaction mixture was added to water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37](Cl)=[O:38])[C:25]=2[CH2:40][CH3:41])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:38])[C:25]=2[CH2:40][CH3:41])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A mixture of 3.2 g of tert-butyl hydrazinecarboxylate and 3.9 ml of triethylamine in 100 ml of DCM is cooled to 0° C., a solution of 10.5 g of the compound obtained in stage A in 100 ml of DCM is added dropwise and the mixture is left stirring while allowing the temperature to rise to AT. The reaction mixture is washed with water, with a pH=2 buffer solution and with a saturated NaHCO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. 12.7 g of the expected compound are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=1>CN(C)C=O.O1CCCC1>[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:38][CH:39]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), sodium bicarbonate (4.2 g) and 4-(5-hydroxy-3-indolyl)-1,2,3,6-tetrahydropyridine (5.3 g) in dimethylformamide (50 cc) and tetrahydrofuran (50 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 7 hours at this temperature. After purification by crystallization from water (100 cc), then recrystallization from a boiling acetoneethanol mixture (50-50 vol) (80 cc), 2-(3-[4-(5-hydroxy 3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.1 ) is obtained, m.p. 214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12](C(OCC3C=CC=CC=3)=O)[CH:13]=2)=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:7][N:8]=1
Reactant: COc1ccc(C2=CN(C(=O)OCc3ccccc3)CC2)cn1
Solvent: CO
Product: COc1ccc(C2CCNC2)cn1
Reaction time: 8 h
Yield: 102 %

Procedure:
Benzyl 4-(6-methoxypyridin-3-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (100 mg, 0.33 mmol) was dissolved in methanol (10 mL). The solution was purged with nitrogen for 10 minutes and then treated with 5% Pd/C (10 mg). The reaction was stirred under a hydrogen atmosphere overnight. The catalyst was filtered off and the filtrate was concentrated to provide the title compound (60 mg, 95%). 1HNMR (500 MHz, CDCl3) δ 8.03 (m, 1H), 7.50 (m, 1H), 6.66 (m, 1H), 3.86 (s, 3H), 3.22 (m, 2H), 3.01 (m, 2H), 2.67 (m, 1H), 2.32 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=O)[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:16]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[S:40])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:16]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-c3cccnc3)nc2C)c2ncccc2c1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-c3cccnc3)nc2C)c2ncccc2c1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-methyl-2,3′-bipyridin-5-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (139 mg, 0.346 mmol) was suspended in dioxane (6 mL) and toluene (3 mL), placed into a preheated oil bath at 100° C. and treated with Lawesson's Reagent (84.0 mg, 0.208 mmol, 0.6 equiv) portionwise over 5 minutes. After stirring for 30 minutes, the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound as brownish-green foam.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>O1CCCC1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in oil, 1.04 g, 26 mmol) was placed in a round bottom flask and washed with hexanes and then was suspended in tetrahydrofuran and cooled to 0° C. A solution of 2-dimethylamino-ethanol (Aldrich, 1.78g, 20 mmol) in tetrahydrofuran was added and the suspension was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Then, the suspension was cooled to −20° C. and a solution of 4-fluoro nitrobenzene (Aldrich, 3.95g, 28 mmol) in tetrahydrofuran was added. The mixture was stirred for 2 hours by gradually increasing the temperature to around 5° C. The reaction was quenched by addition of 1N HCl and the mixture was washed with ether and basified with 1 N NaOH and extracted with diethyl ether. The extract was dried (Na2SO4) and concentrated to give a light yellow oil. 2.8 g, 66%. MS (ES) MH+=211.
Reaction SMILES: [CH3:1][NH:2][S:3]([NH:6][C:7]1[C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:5])=[O:4].C[O-].[Na+].Cl>CO.O>[CH3:1][N:2]1[S:3](=[O:5])(=[O:4])[NH:6][C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]1=[O:15]
Reactant: CNS(=O)(=O)Nc1ncccc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1C(=O)c2cccnc2NS1(=O)=O

Procedure:
Methyl 2-(((methylamino)sulfonyl)amino)-3-pyridine carboxylate (11.0 grams; 0.045 mole) was dissolved in 150 ml of methanol and sodium methoxide (7.3 grams; 0.135 mole) added thereto. The resulting reaction mixture was heated at reflux temperatures for a period of about four hours. After cooling the reaction mixture, the solvent was removed in vacuo and the residue thus obtained suspended in 30 ml of water and the resulting suspension acidified to a pH of about 1.0 with concentrated hydrochloric acid. The reaction mixture was filtered and the precipitate thus obtained was washed with several portions of water and dried in vacuo. As a result of such operations, the desired title compound was obtained as a white powder having a melting point of 290° C.-292° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.C(N(CC)CC)C>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:36])=[O:35]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC
Reactant: O=S(=O)(Cl)CCCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCCl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 1.2 g (3 mM) of 2-methoxy-3-octadecylcarbamoyloxypropylamine IV a1 in 24 ml of dichloromethane and 0.5 ml (3.6 mM) of triethylamine is added 0.75 g (3.93 mM) of 4-chlorobutanesulfonyl chloride with ice-cooling and the mixture is stirred at room temperature overnight. The product is isolated with dichloromethane extraction and dichloromethane layer is washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:2) mixture as an eluent. The product is recrystallized from dichloromethane-n-hexane to give 1.28 g (2.305 mM) of 3-(4-chlorobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane III a5 as colorless crystals in 77% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]Br>[OH-].[Na+]>[Br:12][C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1cnc2ccccc2c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc2ccccc2nc1Br
Temperature: -5 °C
Reaction time: 3 h

Procedure:
6.0 mg (41 mmol) of 3-hydroxyquinoline are dissolved in 50 ml of 10% strength sodium hydroxide solution, giving a yellowish brown color. The reaction mixture is cooled to -5° C. using an ice/common salt mixture. A mixture comprising 6.6 g (2.1 ml, 41 mmol) of bromine dissolved in 50 ml of 10% strength sodium hydroxide solution is added dropwise to this solution over a period of 1 hour. During this the temperature of the reaction solution must never exceed 0° C. After this time, the cooling is removed and the reaction solution is stirred at room temperature for another 3 hours. The reaction solution is then cooled to -10° C. The reaction solution cooled to -10° C. [sic]. The reaction solution is then brought to a pH of 3 with 2N hydrochloric acid, during which the temperature of the reaction solution must never exceed -5° to 0° C. This gives the crude product as a light yellow solid. The crude product is recrystallized from 180 ml of ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[O:19])[CH:5]=[C:6]2[C:14]=1[C:13](=[CH2:15])[C:12]1([OH:17])[O:16][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2.[H-].[Na+].[CH3:22]I>CN(C)C=O>[OH:17][C:12]12[O:16][N:7]([CH2:8][CH:9]3[CH:11]1[NH:10]3)[C:6]1[C:14](=[C:2]([O:1][CH3:22])[CH:3]=[C:4]([CH:18]=[O:19])[CH:5]=1)[C:13]2=[CH2:15]
Reactant: CI
Reactant: C=C1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1c2c(OC)cc(C=O)cc2N2CC3NC3C1(O)O2
Reaction time: 1 h

Procedure:
To a solution of 6,9-dihydroxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (30 mg) in dimethylformamide (1.0 ml) was added a suspension of sodium hydride (60% in oil, 4.6 mg) in dimethylformamide (0.5 ml) in an ice-water bath. To this mixture was added a solution of methyl iodide (7.2 μl) in dimethylformamide (0.1 ml) in an ice-water bath. After stirring for 1 hour in an ice-water bath, the reaction mixture was evaporated to dryness in vacuo, and the residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (8:1, v/v) to afford 9-hydroxy-6-methoxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (19 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(OCC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 1 g (4.73 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate is added dropwise to a suspension of 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide, stirred at 0° C. under argon. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled and 1.24 g (4.8 mmol) of 3-bromomethylpyridine hydrobromide are added portionwise. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled again to 0° C. and a further 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide is added. After 30 minutes at 0° C., 1.24 g (4.8 mmol) of 3-bromomethylpyridine hydrobromide are added portionwise. The reaction mixture is stirred for 58 hours at 20° C. The mixture is then poured into a solution of 100 ml of ice-water and 100 ml of ethyl ether. The organic phase is separated out and the aqueous phase is re-extracted with 100 ml of ethyl ether. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.5 g of expected product is obtained in the form of a solid, which is used without further purification in the subsequent synthesis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=4)=[CH:15][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[S:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[C:25]1[CH:33]=O>CC(O)C.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]5[NH:22][C:33]([C:25]6[S:24][C:28]7=[N:29][CH:30]=[CH:31][CH:32]=[C:27]7[CH:26]=6)=[N:23][C:18]=5[CH:17]=4)=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1cc2cccnc2s1
Reactant: Nc1ccc(-c2ccc3[nH]c(-c4ccncc4)nc3c2)cc1N
Solvent: CC(C)O
Solvent: O
Product: c1cnc2sc(-c3nc4cc(-c5ccc6[nH]c(-c7ccncc7)nc6c5)ccc4[nH]3)cc2c1
Temperature: 170 °C
Yield: 41.2 %

Procedure:
A mixture of 4-(2-(Pyridin-4-yl)-1H-benzo[d]imidazol-5-yl)benzene-1,2-diamine (intermediate A) (50 mg, 0.17 mmol), thieno[2,3-b]pyridine-2-carbaldehyde (33 mg, 0.20 mmol) and Na2S2O5 (38 mg. 0.20 mmol) in IPA-H2O (3:1, 8 mL) was heated under microwave radiation for 170° C. for 10 min. The mixture was absorbed onto silica and purified by column chromatography eluting with (95:5 EtOAc-MeOH to 85:15 EtOAc-MeOH) afforded the title compound as a yellow solid (30 mg, 0.07 mmol, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([O:19]C)=[O:18])=[C:4]([F:21])[CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=[O:18])=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(Cl)cc1F
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1C

Procedure:
The title compound was synthesized using the procedure stated in Example 1, Step 2 except that the product from Step 1 was used and THF was not used to yield product as an off white solid. MS (ES+) m/e 298 [M+H]+
Reaction SMILES: ClC1C=C(Cl)C=CC=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1B(O)O>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2,4-dimethoxyphenylboronic acid and making non-critical variations provided the title compound as an off-white foam. IR (diffuse reflectance) 2966, 2934, 1610, 1567, 1483, 1391, 1303, 1280, 1253, 1208, 1159, 1128, 1046, 1034, 741 cm−1; OAMS supporting ions at: ESI+ 420.1; MS (EI) m/z 419 (M+); HRMS (FAB) calcd for C25H29N3O3+H1 420.2287, found 420.2278.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[O:14])[CH:3]=1
Reactant: CCOC(=O)COc1ccc(CNC(=O)c2cc(N)c(C#N)c(OCC)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1nc(C(=O)NCc2ccc(OCC(=O)O)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of Example 188A (102 mg, 0.26 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL) was added 2N NaOH (300 μL, 0.6 mmol). The reaction mixture was stirred at ambient temperature for 2 hr, and then acidified with 600 μL 1N HCl. It was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to provide the titled compound as white solid (95 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:7][CH:6]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(OCCO)cc1
Yield: 69.3 %

Procedure:
A solution of 113 (1.7 g, 5.1 mmol) in a mixture of methanol/ethyl acetate (80 and 10 mL correspondingly) was placed in a 0.5 L Parr flask and palladium on carbon (1.1 g, 5% wet. Pd/C) was added. The reaction mixture was shaken at 50 psi of hydrogen pressure at room temperature overnight. After this time, the mixture was filtered through a silica gel pad and the solvent was removed at reduced pressure to give crude 114 (1.2 g) as a brown oil. The crude 114 was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S([O-])([O-])(=O)=O.[Mg+2]>CN(C=O)C>[C:20]1([CH2:19][CH2:18][CH2:17][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CN
Reactant: BrCCCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.4 %

Procedure:
Under argon condition, glycine methyl ester (330 mg, 2.63 mmol) was dissolved in 3 mL of dry DMF and then DIPEA (573 μL, 3.29 mmol) and 1-bromo-3-phenylpropane (100 μL, 0.658 mmol) were added. The reaction mixture was then stirred for one day at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water, and the reaction mixture was extracted with diethyl ether (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 19.6 mg (0.0946 mmol, 14%) of the desired compound.