Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32]I)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(OCCCI)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCOc3ccc(F)cc3)CC1)O2

Procedure:
Compound 151 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and 1-fluoro-4-(3-iodopropoxy)benzene and conditions outlined in procedure V. M.p.=164-165° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92-7.87 (m, 1H), 7.82-7.76 (m, 2H), 7.6-7.52 (m, 1H), 7.18-7.06 (m, 2H), 6.97-6.9 (m, 2H), 4.03-3.95 (m, 2H), 3.07 (s, 2H), 2.82-2.72 (m, 2H), 2.55-2.48 (m, 2H), 2.4-2.25 (m, 2H), 2.05-1.75 (m, 6H); LCMS: 454 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])=[C:12]([F:23])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C(OCC)(=O)C.O>[F:23][C:12]1[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester 8a (63 mg, 0.167 mmol) is suspended in MeOH (1.5 mL) and 20% NaOH (400 μl) is added. After 16 hours, the reaction mixture is cooled to 0° C. and 1 N HCl solution is added dropwise until pH is 2 to 3. The reaction mixture is diluted with ethyl acetate and water and the layers separated. The organic layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 58 mg (95%) of desired product: MS APCI (+) m/z 366, 364 (M+1 Br pattern) detected; MS APCI (−) m/z 364, 362 (M−1 Br pattern) detected.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:21]([O:23][CH2:24]C)=[O:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]>OS(O)(=O)=O.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:21]([O:23][CH3:24])=[O:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1ccc(-c2ccc(C(=O)OC)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure E, ethyl 5-(4-ethylphenyl)-6-phenylpyridine-2-carboxylate (Compound 23, 45 mg, 0.15 mmol) and conc. H2SO4 (3 drops) in MeOH (3 ml) were reacted to produce title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Reaction time: 5 h
Yield: 355.5 %

Procedure:
4-Bromo-2-methoxy-1-nitro-benzene (691 mg, 3.14 mmol), tributyl-vinyl-stannane (1.2 g, 3.77 mmol), triphenylphospine (49 mg, 0.19 mmol) and tetrakistriphenylphosphinpalladium(0) (73 mg, 0.06 mmol) were dissolved in toluene (25 ml) and stirred for 5 hours at reflux. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 ml) and diethyl ether (50 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to yield an oil (2.0 g). The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-25%). Fractions containing the product were combined, the solvent evaporated to give an oil (435 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.[Li]CCCC.[CH:29]1(Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CCCc2ccccn2)CC1
Reactant: BrC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(c2ccccn2)C2CCCCC2)CC1
Reaction time: 8 h

Procedure:
To a dry toluene (14 ml) solution of 1-(2-methoxyphenyl)-4-(3-pyridinylpropyl)piperazine (1.5 g, 4.82 mmol) under argon at 0° C. was added nBuLi (7.4 ml, 1.3M). After anion formation the solution was treated with cyclohexylbromide (1.18 ml, 9.64 mmol) in toluene (2.8 ml). The reaction mixture was allowed to attain room temperature and stirred overnight. The reaction mixture was treated with HCl (1N) and the organic layer discarded. The acid layer was washed with ether, taken to pH 13 with solid NaOH (cool) and extracted with chloroform.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]N(C)C=O.IC>[Cl-].[Na+].O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([CH3:32])[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1c2ccccc2CN(C(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone of Example 6 (0.97 g) was added to sodium hydride (2 equivalents, 60% in oil, washed with hexane) and N,N-dimethylformamide (25 mL). Iodomethane (0.45 g) was added and after overnight stirring, the mixture was poured into brine. The precipitate was collected, redissolved in dichloromethane and the solution filtered through a short column of Magnesol®. The column was rinsed with several volumes of dichloromethane, and the combined eluate refluxed with the gradual addition of hexane until incipient crystallization. Cooling and filtration provided the title compound (0.89 g), m.p. 198-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].Cl.[NH2:33][OH:34].CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:33][OH:34])=[NH:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N=C(NO)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}propanamide (0.300 g, 0.67 mmol), hydroxylamine hydrochloride (0.117 g, 1.69 mmol), and DIPEA (0.117 mL, 0.67 mmol) in MeOH was allowed to stir at rt overnight. The mixture was concentrated and purified by column chromatography to give A-85 (68 mg). 1H NMR (300 MHz, d6 DMSO) δ: 10.48 (br s, 1H), 10.17 (br s, 1H), 8.50 (d, 1H), 8.14-8.20 (m, 1H), 7.77-7.85 (m, 1H), 7.60-7.66 (m, 1H), 7.50-7.56 (m, 1H), 7.39-7.47 (m, 1H), 7.20-7.26 (m, 1H), 7.01-7.13 (m, 3H), 2.92-3.01 (m, 2H), and 2.65-2.72 (m, 2H). LCMS, FA: Rt=1.98 min, [MH+ 479.3].
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:6]=1[NH2:7].CCN(CC)CC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].O>ClCCl>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:6]=1[NH:7][C:25](=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 17.8 mmol) in dichloromethane (50 mL) and Et3N (10.3 mL, 71.2 mmol) was added butyryl chloride (1.9 g, 17.8 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and then poured into water. The aqueous phase was separated and the organic layer was washed with water (50 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was washed with ether to give N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (3.5 g, 67%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].[Cl-].[Ca+2].[Cl-].Cl>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 80.9 %

Procedure:
10 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 100 ml of a 67% v/v aqueous methanol solution. 100 g of anhydrous calcium chloride were added to the solution, and then the mixture was stirred at 70° C. for 45 minutes. At the end of this time, 100 ml of ice-water, followed by 10 ml of 1N hydrochloric acid, were added to the reaction mixture. The reaction mixture was then extracted three times, each time with 100 ml of ethyl acetate. The extracts were combined, washed with an aqueous solution of sodium chloride and then extracted with two 50 ml portions of a 10% w/v aqueous solution of dipotassium phosphate. The extracts were combined, washed with a small amount of ethyl acetate and then acidified by the addition of a saturated aqueous solution of potassium hydrogen sulphate. The mixture was then extracted twice, each time with 100 ml of ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous solution of sodium chloride, dehydrated by the addition of anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure, to give 7.15 g of 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid, in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:23][C:24](OC(C)=O)=[O:25]>C1COCC1.O>[Br:1][C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[N:17]([C:24](=[O:25])[CH3:23])[N:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2Br)cc1C1CC1
Reaction time: 14 h
Yield: 67.3 %

Procedure:
To the mixture of 5-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (200 mg, 0.56 mmol, 1.0 eq) in THF (8 mL) and water (5 mL) was added a solution of Ac2O (0.18 mL, 1.68 mmol, 3.0 eq) in THF (2 mL). The reaction mixture was stirred for 14 hours and water was added. The mixture was filtered and the solid was washed with water and dried by co-evaporated with ethanol to give 1-(3-(5-bromo-2-phenylpyrimidin-4-ylamino)-5-cyclopropyl-1H-pyrazol-1-yl)ethanone (150 mg, 67%). LC-MS (m/z)=398.0, 400.0 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:8]([O:7][C:5](=[O:6])[C:4]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:10])[CH3:9]
Reactant: CCNCC
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)N(CC)CC
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 85.8 %

Procedure:
To 30.00 g (203.2 mmol) diethyloxalate (7) were added at room temperature 42.2 mL diethylamine (406.4 mmol, 2.0 eq). The colorless clear solution was heated to reflux (oil bath temperature: 90° C.) and the reaction was monitored by HPLC. After 2.5 h, the resulting yellow-orange liquid was cooled to room temperature and all volatile compounds (ethanol, diethylamine) were removed in a rotary evaporator (50° C., 10 mbar) furnishing the crude product (35.073 g, 100% by weight) as a yellow liquid. Purification was achieved using a high vacuum distillation (bp 85° C. at 0.08 mbar) furnishing the title compound (30.22 g, 174.4 mmol, 86% by weight) as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][C:21]([NH2:30])([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:29][C:21]([NH:30][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:19])([CH3:20])[CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CN1CCOCC1
Product: CC(C)(CN1CCOCC1)NC(=O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(6-bromopyridin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-methyl-1-morpholinopropan-2-amine. LCMS m/z=460.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (td, J=4.7, 3.4 Hz, 1H), 1.27 (td, J=7.8, 4.8 Hz, 1H), 1.48 (s, 6H), 2.32-2.37 (m, 1H), 2.63-2.67 (m, 1H), 2.77 (d, J=16.4 Hz, 1H), 2.90 (dd, J=16.4, 6.6 Hz, 1H), 3.14-3.94 (m, 10H), 7.70 (s, 1H), 7.86 (dd, J=8.7, 0.5 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 8.97 (s, 1H), 9.39 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[C:8](Cl)=[C:9]2[CH:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[N:11][CH:12]=1>>[Br:6][C:7]1[C:8]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[C:9]2[CH:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[N:11][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(Br)cnc21
Reactant: CNCCO
Product: CN(CCO)c1c(Br)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 145 °C

Procedure:
2-(Methylamino)ethanol (1.5 ml) was added to 5-bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine obtained by the method described in WO 2008/150914 (700 mg), and the mixture was heated under reflux at 145° C. for 18 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (472 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[S:22][C:23]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=2[N:25]=1.C(NC(C)C)(C)C>CN(C1C=CN=CC=1)C.CS(C)=O>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[S:22][C:23]5[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1283 g, 0.455 mmol), 2-chloro-6-fluorobenzo[d]thiazole (0.094 g, 0.501 mmol, Step 1), DMAP (0.056 g, 0.455 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylamine (0.238 ml, 1.366 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (1.518 ml) and heated to 90° C. for 20 h. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 12 min. Fractions containing product peak were concentrated in vacuo. The product was taken up in DCM and loaded onto a Silicyle Si-carbonate cartridge to remove any salts to give the title compound (61.2 mg, 0.154 mmol, 33.9% yield). LCMS showed product peak at 1.732 min (m+1=397.0).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=[CH:3]1.[CH:27]([N:30](CC)C(C)C)(C)[CH3:28].C(N)C.O1CCCC1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CO>[CH2:27]([NH:30][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:8]3[NH:9][C:10](=[O:11])[C:5]4[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=4[N:7]=3)[CH2:13][CH2:14]2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ccc2c(=O)[nH]c(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)c1ccc(N2CCN(c3nc4c(ccn4C)c(=O)[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
A solution of 4-(4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)piperazin-1-yl)benzoic acid (50.4 mg, 143 μmol) in methylene chloride (1.22 mL) was treated with N,N-diisopropylethylamine (74.1 mg, 100 μL, 570 μmol), a 2M solution of ethylamine in tetrahydrofuran (86 μL, 172 μmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (49.8 mg, 260 μA mol) and 1-hydroxybenzotriazole (28.9 mg, 214 μmol). The resulting white suspension was stirred at room temperature overnight. At this time, the reaction was diluted with methylene chloride (25 mL) and methanol (5 mL), and was washed with a 1N aqueous hydrochloric acid solution (25 mL), a saturated aqueous sodium bicarbonate solution (25 mL), water (25 mL), and a saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo onto Celite®. The product remained in the aqueous layer, so it was extracted with a solution of 10% methanol/methylene chloride (6×25 mL). The combined organics were concentrated in vacuo onto Celite®. Flash chromatography (10 g silica gel column, 1-10% methanol/methylene chloride) afforded N-ethyl-4-[4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-piperazin-1-yl]-benzamide (5.1 mg, 9.4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.35 Hz, 3H) 3.32 (s, 4H) 3.57 (s, 3H) 3.70 (br. s., 4H) 6.25 (d, J=3.20 Hz, 1H) 6.78 (d, J=3.39 Hz, 1H) 7.00 (d, J=8.67 Hz, 2H) 7.74 (d, J=9.23 Hz, 2H) 8.19 (s, 1H) 10.88 (s, 1H). LC-MS calcd. for C20H25N6O2 [(M+H)+] 381, obsd. 381.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:29]=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:29]=[O:30])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCO)c(OC)cc23)c1
Solvent: c1ccncc1
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 6-(3-hydroxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (40 mg, 0.10 mmol) in pyridine (8 mL) was added acetic anhydride (0.4 mL). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (60 mg, 99% yield). The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:33]([O:37][C:38](=[O:47])[NH:39][C@@H:40]1[CH2:45][C@H:44]([CH3:46])[CH2:43][NH:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:47])[NH:39][C@@H:40]1[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:22]3[CH:23]=[C:13]4[NH:12][CH:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]4[N:21]=3)[CH:25]=2)[CH2:41]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Reactant: C[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5C[C@@H](C)C[C@@H](NC(=O)OC(C)(C)C)C5)c4)cc3N2)cc1OC
Yield: 60.7 %

Procedure:
Example ER-896389 was prepared in two steps from compound 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (25 mg, 0.056 mmol) and commercially available tert-butyl((3R,5S)-5-methylpiperidin-3-yl)carbamate (48 mg, 0.224 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl((3R,5S)-1-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)-5-methylpiperidin-3-yl)carbamate (22 mg, 0.034 mmol, 61% yield). Then, this intermediate (20 mg, 0.031 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896389 (17.5 mg, 97% yield).
Reaction SMILES: C([O:4][CH:5]1[CH:10]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:9]2[S:23][C:24]([C:26](=[O:28])[CH3:27])=[CH:25][C:8]=2[O:7][C:6]1([CH3:30])[CH3:29])(=O)C.[OH-].[Na+].O.[K+].[Br-]>CO>[C:26]([C:24]1[S:23][C:9]2[CH:10]([NH:11][C:12](=[O:22])[C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[CH:5]([OH:4])[C:6]([CH3:30])([CH3:29])[O:7][C:8]=2[CH:25]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC1C(NC(=O)c2ccc([N+](=O)[O-])cc2)c2sc(C(C)=O)cc2OC1(C)C
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc2c(s1)C(NC(=O)c1ccc([N+](=O)[O-])cc1)C(O)C(C)(C)O2
Reaction time: 2 h

Procedure:
6-Acetoxy-2-acetyl-5,6-dihydro-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thienopyran (0.60 g, 1.39 mmol) was treated with aqueous sodium hydroxide (1N, 1.5 mL, 1.5 mmol) in methanol (10 mL) at rt and stirred for 2 h. The resultant solution was poured into water and extracted with 5% isopropanol in dichloromethane. The organic phase was washed with water (3×) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resultant solid triturated in diethyl ether to give the product, 0.36 g (66%), as a pale yellow solid: mp 223°-225° C.; IR (KBr): 1647, 1601, 1530 and 1458 cm-1 ; MS: m/z 391 (MH+); 1H NMR (DMSO-d6): δ1.23(s, 3H), 1.42(s, 3H), 2.45(s, 3H), 3.84(m, 1H, simplifies to d, J=8.9 Hz with D2O), 5.01(m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.86(d, J=5.9 Hz, 1H, exchanges with D2O), 7.47(s, 1H), 8.14(d, J=8.8 Hz, 2H), 8.36(d, J=8.8 Hz, 2H) and 9.27(d, 1H, exchanges with D2O).