Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[P:29]([O-:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>CN(C)C=O.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>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CCOP([O-])OCC
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccc2c(c1)/C(=C/Nc1ccc(N3CCN(C)CC3)cc1)C(=O)NC2=O
Temperature: 120 °C

Procedure:
To a solution of (4Z)-6-bromo-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (67 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) is added diethyl phosphite (22 μL) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 8 μmol, 0.05 mol %). The mixture is heated in a 120° C. oil bath for 6 hour and then purified by reverse phase high performance liquid chromatography to give diethyl [(4Z)-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl]phosphonate as its ditrifluoroacetate salt (8.8 mg, 3.1%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:20][C:19]1[CH:21]=[CH:22][C:16]([CH3:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: Cc1ccc(N=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-methylaniline (0.31 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.56 g, 2.4 mmol, yield: 90%) as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:18]C)=[C:16]([CH3:17])[C:11]=2[O:10][N:9]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([CH3:17])[C:11]=2[O:10][N:9]=1
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(O)ccc2c(-c3ccccc3F)noc12

Procedure:
3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole (16.1 g) is heated at 200° C. for two hours with 64 g of pyridine hydrochloride. The melt is poured into H2O and extracted with ethyl acetate. After washing with 5% HCl the ethyl acetate is dried and evaporated to give 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole, mp 216°-219° C.
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[CH:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:21])[CH2:18][CH2:19]O)([CH3:13])[CH3:12]>>[Br:2][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16][CH2:15][O:14][CH:11]([CH3:13])[CH3:12]
Reactant: BrP(Br)Br
Reactant: CC(CCO)CCOC(C)C
Solvent: c1ccncc1
Product: CC(CCBr)CCOC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.6 g (0.05 mol) of phosphorus tribromide and 2.47 g (0.03 mol) of pyridine are mixed and cooled to 0°-5°C. 20 g (0.125 mol) of 5-isopropoxy-3-methyl-1-pentanol are added dropwise, whilst stirring, over the course of 1 hour. The turbid mixture is then heated to 25°C and after 2 hours at 12 mm Hg, the reaction mixture is distilled into a receiver containing ice cold saturated sodium bicarbonate solution. (B.P.: 92°-103° /12 mm). The distillate is taken up in ether, successively washed with saturated sodium bicarbonate solution, water, 2N sulphuric acid, water, dried with sodium sulphate and evaporated. The residue is distilled, whereby 1-bromo-5-isopropoxy-3-methyl-pentane is obtained. B.P.: 92°-95° /12 mm Hg.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][NH:5][C:6]1[N:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11]C)=[O:9])[CH3:2].[O:19]=C(Cl)OC(Cl)(Cl)Cl>ClCCCl.O1CCOCC1>[CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][N:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8](=[O:9])[O:10][C:11]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CCC(CC)Cn1c(=O)oc(=O)c2cccnc21
Yield: 35.7 %

Procedure:
The product of Example 3A (0.664 g, 2.65 mmol) and diphosgene (1.57 g, 7.96 mmol) in 13 mL of 1,2-dichloroethane and 1.3 mL of 1,4 dioxane were reacted at 80° C. for 16 hours. The reaction was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to provide the title compound (0.235 g, 36%). 1H NMR (300 MHz, CDCl3) δ 0.95 (m, 6H), 1.40 (m, 4H), 1.52 (m, 2H), 4.21 (m, 1H), 7.25 (m, 1H), 8.41 (dd, J=7.72, 1.84 Hz, 1H), 8.70 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](B(O)O)=[CH:11][N:10]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[CH:38][C:39]2[N:40]([C:42]([C:45]3[S:46][C:47]([S:50][CH3:51])=[CH:48][CH:49]=3)=[CH:43][N:44]=2)[CH:41]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:36]3[CH:37]=[CH:38][C:39]4[N:40]([C:42]([C:45]5[S:46][C:47]([S:50][CH3:51])=[CH:48][CH:49]=5)=[CH:43][N:44]=4)[CH:41]=3)=[CH:11][N:10]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Reactant: CSc1ccc(-c2cnc3ccc(Br)cn23)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)s1
Yield: 64.3 %

Procedure:
736 mg 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25), 550 mg 6-bromo-3-[5-(methylsulfanyl)-2-thienyl]imidazo[1,2-a]-pyridine (compound in Production Example 58) and 100 mg tetrakis (triphenylphosphine)palladium were stirred at 80° C. for 3 hours in a solution mixture of 5 mL toluene, 5 mL ethanol and 2.5 mL of 2 N aqueous sodium carbonate under nitrogen atmosphere. The reaction solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 685 mg of the title compound (pale greenish yellow crystals; recrystallization solvent, ethyl acetate/methanol).
Reaction SMILES: C([NH:8][C:9]1[C:14]2=[N:15][O:16][N:17]=[C:13]2[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([C:21]([O:23]CC)=O)=[O:20])(C(OCC)=O)=O>Cl>[OH:20][C:19]1[C:21]([OH:23])=[N:8][C:9]2[C:14]3=[N:15][O:16][N:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[N:18]=1
Reactant: CCOC(=O)C(=O)Nc1ccc2nonc2c1NC(=O)C(=O)OCC
Agent: Cl
Product: Oc1nc2ccc3nonc3c2nc1O
Temperature: 0 °C
Yield: 96.6 %

Procedure:
A mixture of 2,5 g (7,1 mmol) 4,5-diethoxalylaminobenzofurazan and 20 ml 1N hydrochloric acid was refluxed for 3 h. After cooling to 0° C., the precipitate was filtered off and washed with water to give 1,4 g (97%) 7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 12,8 (1H, broad s), 12.3 (1H, broad s), 7.70 (1H,d), 7.37 (1H,d).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([O:35][CH3:36])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)[N:19]=2)=[CH:22][C:23]=1[O:35][CH3:36]
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 7 mL) was added to a solution of tert-butyl N-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (240 mg, 0.529 mmol) in dichloromethane (4 mL) at 0° C. 15 minutes later, the ice-bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The solvents were evaporated and the residue was dissolved in dichloromethane. Sodium hydroxide (1.0N) was added to adjust the pH to about 10. The layers were separated and the aqueous layer was extracted with dichloromethane four times. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (178 mg, 95%). HPLC (Waters 486-Column: delta pak, C18, 5 um, 300 Å, 150×3.9 mm. Eluents: 5% B/A to 95% B/A in 10 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 1.0 mL/min.) Rt=6.45 min.
Reaction SMILES: C1([OH:7])C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[OH-].[Na+].ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][C:18]([OH:7])=[CH:19][C:14]=1[CH3:13]
Reactant: COc1ccccc1C
Reactant: Oc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(O)cc1C
Reaction time: 2 h
Yield: 1 %

Procedure:
The synthesis for the phenol was a two step synthesis via the Vilsmer-Haack condensation to obtain the aldehyde and then by the Baeyer-Villiger oxidation to give the phenol. Phosphorus oxychloride (5.1 mL, 0.057 mol) was added the dropwise to a solution of 2-methylanisole (5.33 mL, 0.043 mol) in dimethylformamide (6 g) under nitrogen. After addition, the mixture was heated and refluxed for 4 h, cooled then added to 100 mL of water. An excess of 10% NaOH was added and the solution was extracted with 4×100 mL of ether. The ether layers were washed with water and then brine solution, dried over magnesium sulfate and evaporated under reduced pressure. The dark oil that remained (5.0 g, 77%) was purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate). The remaining oil (1.78 g, 28%) was dissolved in dichloromethane (100 mL) and then 3.03 g, (0.018 mol) 3-chloroperbenzoic acid was added. The mixture was refluxed under nitrogen for ˜5 h, cooled, and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The dark oil that remained was dissolved in 7 mL of methanol and 5.5 mL of 10% aqueous potassium hydroxide solution was added. The solution was stirred under nitrogen for ˜2 h, water was added, and the solution was extracted with ether. The ether layers were combined and washed with saturated sodium bicarbonate solution and then with water. The ether was dried over magnesium sulfate and evaporated under reduced pressure. The oil that remained (1.21 g, 74%) was recrystallized twice with hexane to give long white needles (0.34 g, <1%). The purity was assessed by NMR and GC-MS.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:13]([C:23]([OH:25])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]2[C:34]3([CH2:40][O:41][C:30]=2[CH:29]=1)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:13]([C:23]([N:37]3[CH2:38][CH2:39][C:34]4([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=5[O:41][CH2:40]4)[CH2:35][CH2:36]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 89.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.060 g, 0.176 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.040 mg, 0.194 mmol), the title compound (0.083 g, 89%) was obtained.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2(O)[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]2=[O:48])=[C:30]([OH:50])[CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]2=[O:48])=[C:30]([OH:50])[CH:29]=1
Reactant: COC(=O)CN1C(=O)C(O)(c2ccc(Cl)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: COC(=O)CN1C(=O)C(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with methyl [3-(4-chloro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (83%) as a semi-solid; 1H NMR (300 MHz, CDCl3) δ 7.36 (t, 1H), 7.29 (bd, 1H), 7.18 (t, 1H), 6.95 (br, 1H), 6.86-6.78 (m, 3H), 5.13 (br, 1H), 4.55 (d, 1H), 4.45 (d, 1H), 3.75 (s, 3H); MS (ES+) m/z 332.5 (M+1), 334.5 (M+1).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:32]([CH3:35])(=[O:34])=[O:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:32]([CH3:35])(=[O:34])=[O:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(S(C)(=O)=O)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nc(S(C)(=O)=O)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.3 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (0.024 g, 37.5 μmol, Eq: 1.00) was dissolved in dichloromethane (0.3 ml) and trifluoroacetic acid (0.12 ml, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane/methanol/ammonium hydroxide (60:10:1) (3.5 ml). The solution was stirred at room temperature overnight then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-7% MeOH) to afford 6 mg (30%) of 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow solid. MS: (M+H)+=511; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.17 (s, 1H), 9.01-9.10 (m, 1H), 8.95 (d, J=3.0 Hz, 1H), 8.47-8.53 (m, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.43-7.53 (m, 1H), 4.51-4.80 (m, 3H), 4.27 (q, J=9.6 Hz, 1H), 4.11-4.21 (m, 1H), 3.81-3.94 (m, 1H), 3.57 (s, 3H), 1.40 (t, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:23])([CH2:17][O:18]S(C)(=O)=O)[CH2:10]OC(=O)C(C)C.[Na].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:23][CH2:10]1)[CH2:17][OH:18]
Reactant: CC(C)C(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Agent: Cl
Agent: [Na]
Solvent: CO
Product: OC[C@@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
In 14 ml of methanol was dissolved 4.06 g of (S)-2-(2,4-difluorophenyl)-1-isobutyryloxy-3-methane-sulfonyloxy-2-propanol obtained in Example 44. After a temperature of the resulting liquid was kept at 5° C., 14 ml of aqueous solution of 2N sodium m hydroxide was added dropwise thereto with cooling at 15° C. or below. After dropping, the resulting liquid was stirred at a temperature of 10° to 15° C. for 2 hours. Thereto 1N hydrochloric acid was added until the liquid was adjusted to pH 7 and methanol was removed under reduced pressure. To the residue was added ethyl acetate to extract. The resulting organic layer was washed with saturated aqueous solution with sodium chloride. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 2.04 g of oily (S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 9.24 minutes ((S)-form) and 10.7 minutes ((R)-form)).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].[F:14][C:15]([F:39])([F:38])[O:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[F:39][C:15]([F:14])([F:38])[O:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([NH:13][C@@H:9]3[CH2:8][O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10]3)=[O:34])[CH2:24][CH2:23]2)=[CH:36][CH:37]=1
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Reactant: O=C(Cl)CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Product: O=C(CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 38 %

Procedure:
Similar to the manipulation of example 22, with (S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (110 mg, 0.6 mmol) and 3-(2-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethoxy) propionyl chloride (296 mg, 0.72 mmol) as crude materials, title compound as 124 mg yellow powder was generated and yield was 38%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[S:4][CH:3]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:15](=[O:16])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:9])[S:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Br)cs1

Procedure:
Compound a was prepared by coupling commercially available 3-bromothiophene-5-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) using the method described in Example 128 to afford a tan solid. HPLC Ret time=3.01 min. LCMS [M+H]+ 379.0.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[Ca+2:10].[OH-].C([O-])(=O)/C=C/C([O-])=O>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[Ca+2:10].[Ca:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: [Ca]

Procedure:
A calcium fumarate salt was prepared by mixing essentially 1 mole of fumaric acid with 1 mole of calcium hydroxide in the presence of 10 moles of water. 255 g (2.22 moles) of fumaric acid and 163 g of calcium hydroxide (2.22 moles) were dispensed separately in 200 ml of water (total water =400 g or 22.2 moles). The mole ratio of fumaric acid to Ca(OH)2 to water was 1:1:10. The calcium hydroxide slurry was added slowly to the fumaric acid suspension with continuous stirring while controlling the reaction temperature to below 160° F. At about 40% base addition, the fumarate solution became thicker and thicker, behaving like a frosting. Further additions of calcium base resulted in a cement-like mass due to the high concentration of salt-to-water (1:10 mole/mole). At this point the solid mass was discarded as it is of no practical use for the product specifications of this invention.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]#[C:25][C:26]3[S:30][CH:29]=[N:28][CH:27]=3)=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:36][CH3:37].C([O-])(=O)C.[Na+].[NH4+].[OH-].C(OCC)C>C(OC(=O)C)(=O)C.O>[Br:1][C:2]1[C:3]([O:36][CH3:37])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:15]4[C:16](=[O:17])[N:18]([C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]=4[C:25]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)=[C:9]3[C:10]=2[CH:11]=1
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of 240 mg of 8d and 250 mg of sodium acetate in 5 ml of acetic anhydride was heated at 100° C. for 30 min. The reaction mixture was cooled, diluted with 10 ml of water and stirred for 1 hr at ambient temperature to hydrolyze excess anhydride. The mixture was then made alkaline with cold conc. aq. NH4OH and the product was extracted with ethyl acetate. The product thus isolated was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent. The purified product isolated was treated with diethyl ether and gave 150 mg of crystalline material 8e. Rf (toluene/acetone 7/3) 0.50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[Cl:24])(=[O:33])=[O:32])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 108 mg, 0.34 mmol) and 2-chlorobenzenesulfonyl chloride (145 mg, 0.69 mmol) in THF (6 mL) was added excess N,N-diisopropylethylamine (179 μL, 1.0 mmol) at 0° C. under a nitrogen atmosphere. The resulting light brown solution was allowed to warm slowly to room temperature over 2 hours, was and then stirred for 15 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water and brine solution and the organic compound was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration and concentration gave a crude brown oil which was purified by flash chromatography (40 g ISCO column, eluting with 0-60% ethyl acetate/hexanes) to give {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (110 mg, 65%) as an off-white solid. MS cald. for C25H26ClFNO4S [(M+H)+] 490, obsd. 490.0.