Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15](O)=[O:16])=[CH2:13]>[OH-].[Na+]>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([OH:19])=[O:18])[CH2:13]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(N2CC(C(=O)O)CC2=O)cc1
Temperature: 125 °C
Reaction time: 0.33 h
Yield: 751.6 %

Procedure:
A mixture of 4-isopropylaniline (0.76 g, 0.565 mmol) and itaconic acid (0.70 g, 0.538 mmol) was heated at 120-130° C. in a sealed tube for 2.5 hrs. The mixture was cooled and dissolved in 10% NaOH solution (15 ml) and stirred for 20 min. The aqueous layer was washed with ethyl acetate and acidified with dil. HCl. The precipitate was filtered to obtain 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid (1.0 g, 75%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][S:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2F)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30]>CS(C)=O.CCOCC>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30].[F:3][C:4]1[CH:5]=[C:6]([CH:7]2[S:8][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=3)[CH:23]=[CH:24][CH:25]=1
Reactant: CN1CCC(SCc2cccc(F)c2)(c2ccccc2F)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To 1.404 g of sodium hydride (from 2.87 g of a 50% dispersion), under nitrogen, is added 120 ml of sieve-dried dimethylsulfoxide. The mixture is stirred in an 80°-85° C. bath for 35 minutes, then cooled to room temperature. A solution of 14.0 g of the free base 4-(3-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine of Example 55a in 47 ml of DMSO is added over 60 seconds and the solution stirred for one hour. The reaction is then poured into 700 ml of ice water and extracted with three 200 ml portions of dichloromethane. The combined dichloromethane extracts are washed with three 300 ml portions of water and one 75 ml portion of saturated sodium chloride solution, and dried over magnesium sulfate to an oil. The oil is chromatographed on alumina with ether to give crystals. A portion of this, in ether is treated with ethereal maleic acid. The resulting salt is washed with ether and dried to give a powder of 3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] maleate, m.p. 137°-140° C. A twice recrystallized portion melts at 138.5°-140.5° C. [Upon continued heating, a new crystalline form develops which collapses in the 175°-180° C. range.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1.P(OCC)(OCC)[O:30]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC)(C)(C)C.Cl>C1COCC1>[CH:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26](=[O:27])[CH:25]([OH:30])[C:20]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:19][C:18]3=[O:28])[CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Buspirone (8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro(4.5)-decane-7,9-dione) (246.5 g, 639.6 mmol) was charged to a 12 L flask equipped with a mechanical stirrer and a React-IR probe under inert gas. Tetrahydrofuran (4.383 kg, 60.8 mol, 4.930 L, 20 mL/g) was charged and the mixture agitated at ambient temperature until homogeneous. Triethyl phosphite (371.9 g, 2.238 mol, 383.8 mL, 3.5 eq) was added and the mixture was cooled to −68 to −75° C. The mixture was agitated at this temperature for at least 10 minutes to allow the React-IR signal to stabilize. 1.0 M Sodium bis(trimethylsilyl)amide in THF (600.4 g, 664.1 mmol, 664.1 mL, 1.00 eq) was charged to the mixture at such a rate so as to maintain the temperature less than −60° C. Small amounts of sodium bis(trimethylsilyl)amide were charged to the mixture until the IR signal for buspirone reached a minimum indicating complete deprotonation of buspirone. Additional buspirone in THF (10-20 mL/g) was then charged to the reaction mixture in small increments until the IR signal indicated a 0.5% to 5% excess of buspirone. Air was sparged into the reaction mixture, controlling the initial rate of sparging so as to maintain the temperature of the reaction mixture less than −60° C. The sparging was continued until the reaction was complete as indicated by HPLC. Methyl tert-butyl ether (384.8 g, 4.365 mol, 520.0 mL) was added followed by 1M hydrochloric acid (1350.8 g, 1.328 mmol, 1328 mL) and the solution was warmed to ambient temperature. The pH was adjusted to between 6.5 and 6.9 using hydrochloric acid and Na3PO4. The phases were separated and the organic phase was washed twice with brine (542.3 g, 493 mL). The solvent of the rich organic layer was then replaced by isopropyl alcohol and the solution was cooled to crystallize the reaction product. There is an option to seed with 0.01 to 5% buspirone at approximately 54 to 56° C. The crystalline slurry was then filtered and the wet cake was washed with isopropyl alcohol and dried to provide 6-hydroxybuspirone (220.0 g, 82%), mp 109.5° C.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[OH:28][C:24]([CH:20]1[CH2:21][CH2:22][CH2:23][O:19]1)([CH3:25])[C:26]#[C:27][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Reactant: C#CC(C)(O)C1CCCO1
Product: CC(O)(C#Cc1ccc2c(c1)-n1nc(C(N)=O)cc1CCO2)C1CCCO1

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with 2-(tetrahydrofuran-2-yl)but-3-yn-2-ol to give a mixture of titled compounds after purification by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[C:17]([OH:19])=O.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][CH2:6][C:5]3[CH:20]=[CH:21][CH:22]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:11]2=[O:13])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1cccc(COc2cccc(C(=O)O)c2C(=O)O)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(COc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Yield: 12.2 %

Procedure:
A mixture of 3-(3-methoxy-benzyloxy)-phthalic acid (1.5 g, 5.2 mmol), alpha-amino-glutarimide hydrochloride (0.89 g, 5.4 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(3-methoxy-benzyloxy)-isoindole-1,3-dione as a white solid (0.25 g, 12% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.41 min (99.1%); mp, 197-201° C.: 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.59-2.62 (m, 2H, CH2), 2.83-2.90 (m, 1H, CHH), 3.77 (s, 3H, CH3), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.35 (s, 2H, CH2), 6.89-7.85 (m, 7H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.95, 30.92, 48.75, 55.01, 69.80, 112.72, 113.27, 115.55, 116.66, 119.17, 120.21, 129.61, 133.25, 136.98, 137.74, 155.42, 159.35, 165.32, 166.77, 169.90, 172.74. Anal Calcd For C21H18N2O6+0.1H2O: C, 63.67; H, 4.63; N, 7.07. Found: C, 63.49; H, 4.40; N, 7.00.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[ClH:28]>CC(O)C>[ClH:28].[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Agent: Cl
Solvent: CC(C)O
Product: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(3S,9aR)-tert-Butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (158.8 g, 423.0 mmol) was suspended with 318 mL of 2-propanol. The resulting slurry was treated with HCl solution in 2-propanol (5.5 M, 1000 mL, 5499 mmol), and the mixture was heated to 50° C. for 2 hours. The mixture was concentrated to remove approximately 400 mL of 2-propanol, then was cooled to rt and agitated overnight. The mixture was filtered to collect the solid product and the wet cake was washed with 50 mL of 2-propanol. The filter cake was dried under vacuum for two days at 40° C. with nitrogen bleed to afford the title compound.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][CH:5]([C:13]([O:15]CC)=[O:14])[CH2:4]2.[OH-].[Na+].Cl>C(O)C>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][CH:5]([C:13]([OH:15])=[O:14])[CH2:4]2
Reactant: CCOC(=O)C1Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a solution of 5.13 g (20.7 mM) of ethyl 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylate in ethanol (20 ml) was added 12 ml (24 mM) of 2N-aqueous solution of sodium hydroxide at room temperature and the mixture was stirred for 1 hour. To this reaction mixture was added 4 ml (24 mM) of 6N-hydrochloric acid and the resulting crystals were collected by filtration. This crystal crop was rinsed with ethanol and diethyl ether to provide 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid as light-brown crystals. This carboxylic acid was not purified but used as it was in the next reaction. To 2.2 ml (30.0 mM) of thionyl chloride was added 661 mg (3.0 mM) of the above 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and the mixture was heated at 60° C. for 1 hour. Then, the excess thionyl chloride was distilled off under reduced pressure and 10 ml of toluene was added to the residue. After thorough mixing, the solvent was distilled off under reduced pressure to provide 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid chloride hydrochloride. To a solution of this acid chloride in 30 ml of THF was added 2.5 ml (40.0 mM) of triethylamine as well as 1286 mg (6.0 mM) of 1-(tert-butoxycarbonyl)-4-aminomethylpiperidine at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured in 50 ml of iced water and extracted with 100 ml of ethyl acetate. The organic layer was washed with 100 ml of saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/ethanol=10/1) to provide 801 mg (yield 64.1%) of the title compound as brown amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Yield: 82 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and 4-methoxybenzeneboronic acid resulting in an 82% yield of the final product, m.p. 194-196° C. The product was recrystallized using hexane/ethyl acetate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]3[N:40]=[CH:39][N:38]([C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:37]=3)=[CH:33][CH:34]=2)[C:29]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[N:28]1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:66][C:62]2[CH:63]=[CH:64][CH:65]=[C:60]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[C:32]([C:36]5[N:40]=[CH:39][N:38]([C:41]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)([C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)[C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[N:37]=5)[CH:31]=4)[N:27]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)[N:28]=3)[CH:61]=2)=[O:8])=[CH:2]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(O)c1ccoc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of furan-3-carboxylic acid (0.056 g, 0.496 mmol) in 2.5 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.105 g, 0.546 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) dissolved in 1 mL of dichloromethane, was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 697 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([Cl:42])[C:37]([OH:41])=[C:38]([Cl:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1cc(Cl)c(O)c(Cl)c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3cc(Cl)c(O)c(Cl)c3)n2)c1

Procedure:
Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2,6-dichloro-phenol by procedure F and the resulting product was deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 524. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.4 (m, 2H) 8.2 (d, 1H) 7.8 (d, 1H) 7.2 (s, 2H) 4.6 (s, 2H) 3.9 (m, 2H) 3.4 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.8 (m, 2H) 1.8 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[OH:29][C@H:24]1[C@H:25]([O:27][CH3:28])[CH2:26][N:22]([C:3]2[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C[C@H]1O
Reactant: OB(O)c1cncnc1
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C[C@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using 5-bromo-6-(trans-3-hydroxy-4-methoxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 72.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.16 min, m/z=476.0 [M+H]+, m/z=474.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.95 (d, J=11.25 Hz, 1H) 3.14 (d, J=11.98 Hz, 1H) 3.23 (s, 3H) 3.28-3.35 (m, 1H) 3.46 (dd, J=11.98, 4.40 Hz, 1H) 3.61-3.65 (m, 1H) 4.08 (br. s, 1H) 5.19 (d, J=3.67 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.85 (d, 2H) 8.12 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.89 (s, 2H) 9.21 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: C1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)CC1.C([N:31]1CCC(C)(C)C(N)C1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:5]1[CH:4]=[CH:9][N:8]=[C:7]2[NH:10][CH:11]=[C:12]([C:13]([NH2:31])=[O:15])[C:6]=12
Reactant: CC1(C)CCN(Cc2ccccc2)CC1N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL flask were combined 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.45 mmol), 1-benzyl-4,4-dimethylpiperidin-3-amine (147 mg, 0.68 mmol), and HATU (188 mg, 0.50 mmol). Then added DMF (3 mL) followed by N,N-diisopropylethylamine (0.24 mL 1.35 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×), dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (30% to 80% EtOAc/hexanes) to afford 197 mg (82%) of N-(1-benzyl-4,4-dimethylpiperidin-3-yl)-2-cyclopropyl-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:18][OH:19])[CH2:13][C:12](OC)([O:14]C)[CH2:11]2)[CH:5]=[C:4]([Cl:20])[N:3]=1.Cl.N.CO>CC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:18][OH:19])[CH2:11][C:12](=[O:14])[CH2:13]2)[CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: COC1(OC)CC(CO)(CNc2cc(Cl)nc(N)n2)C1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)=O
Product: Nc1nc(Cl)cc(NCC2(CO)CC(=O)C2)n1
Yield: 70.1 %

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-3,3-dimethoxy-1-cyclobutyl)methyl]amino]pyrimidine (0.61 g, 2.0 mmol) were added acetone (50 ml) and 20% hydrochloric acid (0.5 ml), and the mixture was refluxed for 30 minutes. The mixture was neutralized with 10% ammonia-methanol under ice-cooling. The solvent was distilled away under reduced pressure and the residue was recrystallized from acetone to give colorless prism crystals (0.36 g, 70.1%), m.p. 171-173° C. (acetone).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O-]CC.[Na+].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>O1CCOCC1>[C:1]([NH:6][C:12](=[O:13])[O:14][CH2:15][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=C(C)C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 27 °C
Reaction time: 0.33 h
Yield: 7.6 %

Procedure:
In 52 g of dioxane, 12.5 g of methacrylamide and 1.0 g of sodium ethoxide (NaOEt) were dissolved and the solution was stirred for 20 minutes at the temperature of 27° C. Then, 4.0 g of ethyl chloroformate acid was dissolved in 2 g of dioxane and the solution was added in two portions into the above reaction solution. After leaving it for one day, the solution was neutralized with conc. hydrochloric acid and was extracted with chloroform. The extract was evaporated in vacuo. The crude product was subjected to column chromatography, thereby obtaining 0.44 g of ethyl N-methacryloylcarbamate. Melting point of the compound was 73°-74° C.
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:8])=[O:7])([CH3:5])[CH3:4].F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>O1CCCC1>[CH:3]([S:6]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COc1ccc(CNS(=O)(=O)C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cc(F)ccc2[N+](=O)[O-])S(=O)(=O)C(C)C)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
Suspend sodium hydride (60% in mineral oil, 0.85 g, 21.2 mmol) in tetrahydrofuran (100 mL). Add 1 N-[isopropylsulfonyl]-4-methoxy-benzylamine (4.73 g, 19.45 mmol) in tetrahydrofuran (400 mL) and heat to 70° C. Stir 10 minutes, then add 2,4-difluoronitrobenzene (3.2 mL, 29.2 mmol) in one portion and stir 18 hours at 70° C. Cool to ambient temperature and remove solvents under reduced pressure. Dissolve in ethyl acetate and wash twice with 1 N HCl aq., three times with saturated sodium hydrogen carbonate, saturated sodium carbonate, 1 N HCl aq., dry magnesium sulfate, filter and remove solvents under reduced pressure. Purify on silica gel with dichloromethane/hexane mixtures to give 5.395 g (72%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[Cl:9][C:10]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:10]=2[Cl:9])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)c1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
After 2.35 g (0.021 mol) of 1-ethyl-5-hydroxypyrazole was dissolved in 20 ml of tert.-amyl alcohole, the mixture was succesively added with 4.69 g (0.02 mol) of 2-chloro-4-methanesulfonyl benzoic acid, 5.33 g (0.021 mol) of N,N'-dicyclohexyl carbodiimide and 1.52 g (0.011 mol) of anhydrous potassium carbonate, and heated at 50°-60° C. for 5 hours, followed by additional stirring for 1 hour at 90° C. Then, the reaction was ceased. After cooling, solvent was distilled off from the reaction solution, and the residue was added with 50 ml of 5% aqueous solution of potassium hydroxide to dissolve the soluble matter. After insoluble matter was filtered off, the aqueous layer was washed with chloroform and separated. This operation was twice carried out. The obtained aqueous layer was adjusted to pH <1 by adding concentrated hydrochloric acid, and the precipitated solid product was dissolved in chloroform and extracted. After the chloroform layer was dried over sodium sulfate anhydrate, the solvent was distilled off to give a crude product of the objective product. Then, the crude product was recrystallized from 95% ethanol to obtain 5.38 g of 1-ethyl-4-(2-chloro-4-methanesulfonylbenzoyl)-5-hydroxypyrazole.