Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[NH:10][CH2:11][C:12]1[CH:37]=[CH:36][C:15]2[CH:16]=[C:17]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28]C(OC(C)(C)C)=O)=[O:20])[S:18][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][NH:10][C:9](=[O:38])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:37]=[CH:36][C:15]=2[CH:16]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2ccc(CNC(=O)OCc3ccccc3)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1cc2ccc(CNC(=O)OCc3ccccc3)cc2s1
Reaction time: 2 h

Procedure:
To a solution of benzyl({2-[({2-[(tert-butoxycarbonyl)amino]phenyl}amino)carbonyl]-1-benzothien-6-yl}methyl)carbamate (85 mg, 0.16 mmol) in CH2Cl2 (4 mL) was added TFA (2 mL). The reaction mixture was stirred for 2 h, the solvent was removed. The residue was triturated with CH2Cl2 and sat. NaHCO3, and the resultant solid was filtered yielding the desired product. 1H NMR (DMSO-d6, 600 MHz) δ 10.05 (br s, 1H), 8.23 (s, 1H), 7.87 (m, 2H), 7.80 (s, 1H), 7.32-7.29 (m, 4H), 7.27 (m, 1H), 7.17 (br d, J=6.8 Hz, 1H), 7.02 (dd, J=6.8, 6.8 Hz, 1H), 6.87 (br d, J=6.8 Hz, 1H), 6.75 (br s, 1H), 5.00 (s, 2H), 4.29 (d, J=6.2 Hz, 2H). MS: cal'd 432 (MH+), exp 432 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40]C)=[O:38])=[CH:35][CH:34]=1.[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]O)=[CH:50][CH:49]=1)[CH2:45][CH2:46][CH3:47]>C1COCC1>[CH2:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][O:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:54][CH:55]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCc1ccc(CO)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(COc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (656 mg, 2.50 mmol) in THF (12 mL) at 0° C. was treated with diethyl azodicarboxylate (442 mg, 2.54 mmol), stirred for 20 minutes, treated with ethyl 4-hydroxybenzoate (350 mg, 2-30 mmol) and 4-butylbenzyl alcohol (414 mg, 2.52 mmol), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N1CCN(C2C=CC=CN=2)CC1)=O>>[CH3:14][CH:12]([CH3:13])[CH2:11][C@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[C:15]([N:27]1[CH2:28][CH2:29][N:24]([C:19]2[N:18]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1)=[O:17]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ncccn2)CC1
Yield: 71 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (12.5 g) and 1-(2-pyrimidinyl)piperazine (8.21 g) were condensed in the same manner as employed in the preparation of tertbutyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl-carbonyl]-butylcarbamate to yield 13.4 g of tert-butyl (s)-3-methyl-1-[4-(2-pyrimidinyl)piperazine-1-yl carbonyl]butylcarbamate (yield: 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:12]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-:12])=[CH:7][CH:6]=[CH:5]2
Reactant: OO
Reactant: Fc1ccc2ncccc2c1
Solvent: CC(=O)O
Product: [O-][n+]1cccc2cc(F)ccc21
Temperature: 78 °C

Procedure:
The 6-fluoroquinoline from Step A (6.0 g, 40.8 mmol) in glacial acetic acid (60 mL) is treated dropwise with hydrogen peroxide (14 mL) and heated with an oil bath to 78° C. overnight. The reaction mixture is concentrated at reduced pressure and the concentrate basified with solid sodium carbonate and extracted with dichloromethane. The extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to a light yellow solid (6.0 g). The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (5–10%) in dichloromethane to provide the title compound as a white solid (0.99 g), m.p. 105–106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Cl:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
p-Chloroaniline (3.82 g) was dissolved in ethyl acetate (30 mL), and, at room temperature, chloroacetyl chloride (2.39 mL) was added to the solution, followed by stirring for 1 hour. After the reaction mixture was heated and stirred at 60° C. for 3.5 hours, crystals precipitated were collected by filtration, to thereby give the title compound (4.78 g). The filtrate was concentrated to about ¼, and crystals precipitated were collected by filtration, to thereby give the title compound (1.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CSc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 98.1 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro-benzaldehyde (2 g, 12.8 mmol) (Beta Pharma) was reacted with 4-(methylthio)phenol (1.97 g, 14 mmol) (Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-methylsulfanyl-phenoxy)-benzaldehyde as a brown oil (Yield 3.5 g, 98%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9].[NH3:12].CO.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[NH2:12][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CBr)ccc1F
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1cc(CN)ccc1F

Procedure:
A solution of 5-(bromomethyl)-2-fluorobenzonitrile (300 mg, 1.402 mmol) in 7M NH3/methanol (5 mL, 35.0 mmol) was stirred at room temp for 18 h. After the removing the solvent the resulting residue was stirred with Et2O/sat. Na2CO3. The aqueous layer was then separated and the organic layer dried (Na2SO4), filtered and concentrated to give a 3:1 mixture of the title compound, amine 5-(aminomethyl)-2-fluorobenzonitrile contaminated and 5,5′-azanediylbis(methylene)bis(2-fluorobenzonitrile). The mixture was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.48-7.66 (2 H, m), 7.07-7.21 (1 H, m), 3.89 (2 H, s).
Reaction SMILES: C([O:5]C(N(C1C=CC=CC=1)[C@H](CO)C)=O)(C)(C)C.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.BrN1C(=O)CCC1=O.CO>CN(C=O)C>[C:32]1([P:25](=[O:5])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@H](CO)N(C(=O)OC(C)(C)C)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of the N-tert-butoxycarbonyl phenyl alaninol (1.42 mmol) and triphenylphosphine (2 equiv) in DMF, N-bromosuccinimide (2 equiv) was slowly added. The reaction was warmed to 50° for 15 min and then cooled to 20°. Methanol (0.5 mL) was added to destroy the excess reagent. After 5 min, ether was added, and the ether layer was washed with water, saturated sodium carbonate, and saturated NaCl and then evaporated to a solid under high vacuum. The product was extracted twice into hexane, leaving a residue of triphenylphosphine oxide. After evaporation of the solvent, the residue was again triturated with hexane to afford the 1-Bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane:
Reaction SMILES: [C:1]1([C@H:7]2[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:21]I>CO.O>[CH3:21][S:18][C:9]1[NH:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.8 g of trans-4,5-diphenyl-imidazolidine-2-thione are dissolved in 20 ml of methanol, a solution of 0.3 g of sodium hydroxide in 2 ml of water and also 1.2 g of methyl iodide are added and the mixture is stirred at room temperature for 4 hours and left to stand overnight at 0°. The reaction mixture is evaporated to dryness, the residue is shaken with a mixture of 40 ml of water and 40 ml of ethyl acetate, the organic phase is separated off and the aqueous phase is washed with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated to dryness. The crystalline residue is recrystallised, first from methanol and then from a mixture of diethyl ether and petroleum ether. Trans-2-methylthio-4,5-diphenyl-imidazoline with a melting point of 135°-137° is obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)=[O:28]
Reactant: c1ccc(CSc2cnc3ccccc3n2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(Cc1ccccn1)c1cnc2ccccc2n1
Yield: 11.6 %

Procedure:
In a mixture of 20 ml of chloroform and 5 ml of methanol was dissolved 2.51 g of 2-(2-pyridylmethylthio)-quinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was portionwise added 1.95 g of m-chloroperbenzoic acid (purity: 70%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (acetone/hexane), and recrystallized from ethanol/ether to give 0.27 g of 2-(2-pyridylmethylsulfinyl)quinoxaline as a pale brown crystalline powder, m.p. 117°-122° C. (decompn.).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2C(COS(C3C=CC(C)=CC=3)(=O)=O)[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[C:29]([O-:32])(=O)[CH3:30].[Na+].[OH-].[K+]>C(O)(=O)C.CO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[C:29]([OH:32])=[CH:30][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3cc(Br)ccc32)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: OC1=Cc2ccccc2C=Cc2cc(Br)ccc21
Yield: 47.7 %

Procedure:
To a solution of 2-bromo-5-p-toluenesulphonyloxymethyl-dibenzo[a,d]cycloheptene (8.1 g) in glacial acetic acid (75 ml) was added anhydrous sodium acetate (2.9 g). The reaction mixture was refluxed for 24 h then the solvent removed under vacuum to leave a residue which was partitioned between dichloromethane (3×100 ml) and water (100 ml). The combined organic layers were dried (Na2SO4) , filtered and concentrated in vacuo to leave a residue which was dissolved in 75% aqueous methanol (100 ml) and treated with potassium hydroxide (4 g). After 14 h the reaction mixture was concentrated in vacuo and the residue partitioned between water (50 ml) and diethyl ether (3×50 ml). The combined organic layers were dried (Na2SO4) , filtered and concentrated in vacuo. Chromatography of the residue on flash silica with 10% ethyl acetate in hexane as eluent gave the less polar isomer, 2-bromo-5-hydroxy-dibenzo[a,e]cyclooctene (2.54 g, m.p. 148°-151° C.). δ (360 MHz, CDCl3) 3.26 (1H, dd, J=13.9 and 9.9 Hz, CHAHB --CHOH), 3.46 (1H, dd, J=13.9 and 6.2 Hz, CHAHB --CHOH), 5.24 (1H, dd, J=9.9 and 6.2 Hz, CHOH), 6.76 (1H, d, J=12.1 Hz, CHC =CHD), 6.87 (1H, d, J=12.1 Hz, CHC =CHD), 7.09-7.35 (7H, m, ArH), m/e 302 and 300 (M+); and as an oil the more polar isomer 2-bromo-6-hydroxy-dibenzo[a,e]cyclooctene (1.04 g), 67 (360 MHz, CDCl3) 3.25 (1H, dd, J=13.8 and 10.0 Hz CHAHB --CHOH), 3.40 (1H, dd, J=13.8 and 6.4 Hz, CHAHB --CHOH), 5.26 (1H, dd, J =10.0 and 6.4 Hz, CHAHB --CHOH), 6.75 (1H, d, J=12.1 Hz, CHC =CHD), 6.90 (1H, d, J=12.1 Hz, CHC =CHD), 7.08-7.45 (7H, m, ArH). m/e 302 and 300 (M+).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C[O:11][C:12](=O)[CH:13](NC)[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:12](=[O:11])[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:25])[F:24])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CNC(NC(=O)c1ccccc1C(F)(F)F)C(=O)OC
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: -20 °C
Yield: 23.1 %

Procedure:
To 17.6 g of 2-bromo-3,5-dichloropyridin in 5 ml of tetrahydrofuran, 58.3 ml of a 1.3M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture, 10.0 g of N-[2-methoxy(methyl)amino-2-oxoethyl]-2-(trifluoromethyl)benzamide in 57.4 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at room temperature for another 3 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of saturated aqueous ammonium chloride and 100 ml of water and extracted with ethyl acetate (150 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 3.0 g of the desired product as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O.[OH-].[Cs+].[ClH:38]>CN(C=O)C>[ClH:38].[ClH:38].[CH:32]1([CH2:31][N:1]2[CH:5]=[C:4]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)[CH:3]=[N:2]2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2cnn(CC3CC3)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol; prepared according to Example 21, Step A) in dry DMF (0.5 mL) was added (bromomethyl)cyclopropane (7.0 mg, 0.052 mmol) and cesium hydroxide hydrate (8.7 mg, 0.052 mmol). The mixture was stirred at ambient temperature for 60 minutes. The mixture was filtered, washed with methanol and ethyl acetate, and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The product was dissolved in a mixture of dichloromethane and methanol. Hydrogen chloride (0.52 mmol; 2M solution in diethyl ether) was added and the solvent was removed under reduced pressure, followed by high vacuum to give N-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (5.6 mg). MS (APCI), positive scan, m/z=440.2 (M+H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][CH2:16][C@:15]([CH3:22])([C:18]([O:20]C)=[O:19])[C:14]3([CH3:24])[CH3:23])=[C:10]([C:25](=[O:27])[NH2:26])[CH:9]=[N:8][N:7]2[CH:28]=1>C(O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][CH2:16][C@:15]([CH3:22])([C:18]([OH:20])=[O:19])[C:14]3([CH3:24])[CH3:23])=[C:10]([C:25](=[O:27])[NH2:26])[CH:9]=[N:8][N:7]2[CH:28]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)C(=O)O
Temperature: 75 °C
Yield: 89.4 %

Procedure:
A 4.5 M aqueous solution of potassium hydroxide (210 μl, 0.945 mmol) was added dropwise to a solution of (1S,3R)-methyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylate (200 mg, 0.472 mmol) in ethanol (3.2 ml). The reaction was heated at 75° C. for 24 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure to yield an oil. The oil was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1.0 N HCl and was extracted with ethyl acetate (3×). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding the title compound (182 mg, 0.422 mmol, 89% yield) as a pale yellow solid. LC/MS found [M+H]+=410.7.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][CH2:36][O:37][C:32]=2[C:31]([C:38](O)=[O:39])=[CH:30][C:29]=1[Cl:41].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1.C(#N)C>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][CH2:36][O:37][C:32]=2[C:31]([C:38]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:6][CH2:7]2)=[O:39])=[CH:30][C:29]=1[Cl:41]
Reactant: COc1cc(C(=O)CCCN2CCC(O)CC2)cc(OC)c1OC
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCCO2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1cc(C(=O)CCCN2CCC(OC(=O)c3cc(Cl)c(N)c4c3OCCC4)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
4-(4-hydroxy-1-piperidinyl)-1-(3,4,5-trimethoxyphenyl)-1-butanone (3.3 g) was added to a solution of sodium hydride (0.4 g) in tetrahydrofuran (100 ml) (solution I) under a N2 flow. A mixture of 5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (2.14 g) and 1,1'-carbonylbis-1H-imidazole (2 g) in acetonitril (100 ml) was stirred for 2 hours at room temperature and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (100 ml) (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated. The residue was diluted with water and extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /hexane/(CH3OH/NH3) 50/42/3). The desired fractions were collected and the solvent was evaporated. The residue (2.3 g) was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2 /CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried, yielding 0.93 g of 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl 5-amino-6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylate (17%); mp. 112.7° C. (compound 8).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[OH-].[Na+].COC1C=CC(O)=CC=1>>[C:8]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: NCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C(=O)NCCCC(=O)O

Procedure:
The general procedure above is utilized with 51.5 g (0.5 mol) of 4-aminobutyric acid, 52.39 (0.5 mol) of methacryloyl chloride, 40 g (1 mol) of sodium hydroxide. p-methoxyphenol is used as an inihibitor. Crystallization from ethyl acetate yielded very low melting crystalline material, melting point (30°-35° C.). Purity by bromination 100.14%. NMR (CDCl3), 10.85 gamma (br s, 1H, COOH), 7.1 gamma (br s, 1H, NH), 6.0 gamma (br s, 1H, =CH2), 5.65 gamma (br s, 1H, =CH2), 3.6 gamma (q, 2H, NCH2), 2.6 gamma (t, 2H, CH2CO), 2.2 gamma (br s, 5H, CH3 and CH2CH2CH2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)[Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc2[nH]c(CO)nc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reaction time: 28 h
Yield: 67.2 %

Procedure:
To a solution of methyl 2-hydroxymethyl-1 H-benzimidazole-4-carboxylate (1.0 g) in N,N-dimethylformamide (10 ml) were added tert-butylchlorodiphenylsilane (1.87 g) and imidazole (495 mg) at ambient temperature and the mixture was stirred at the same temperature for 28 hours. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1) to give methyl 2-tert-butyldiphenylsiloxymethyl-1 H-benzimidazole-4-carboxylate (1.45 g) as an oil.