Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:14]2[S:13](=[O:16])(=[O:15])[N:12]=[C:11]([CH2:17][C:18]([OH:20])=O)[NH:10][C:9]=2[S:8][CH:7]=1.C([O:23][C:24]([C@H:26]1[C@@H:31]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C@H:30]2[CH2:41][C@@H:27]1[CH2:28][CH2:29]2)=O)C.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:32]2[C:18](=[O:20])[C:17]([C:11]3[NH:10][C:9]4[S:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[C:14]=4[S:13](=[O:15])(=[O:16])[N:12]=3)=[C:24]([OH:23])[C@H:26]3[C@@H:31]2[C@H:30]2[CH2:41][C@@H:27]3[CH2:28][CH2:29]2)=[CH:39][CH:38]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 75 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid (0.38 g, 1.20 mmol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.42 g, 1.44 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g, 1.80 mmol). The reaction was stirred at 25° C. for 15 min before triethylamine (1 mL, 7.20 mmol) was added. The reaction was then stirred at 75° C. overnight. The reaction was cooled to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (5 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-50% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.44 g, 0.80 mmol, 67%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.55-2.56 (1H, m), 2.82-2.86 (2H, m), 3.45 (3H, s), 4.21 (1H, d, J=15.6 Hz), 4.79 (2H, s), 4.82 (2H, s), 5.15 (1H, d, J=15.2 Hz), 7.00-7.07 (3H, m), 7.20 (2H, dd, J=5.6, 8.8 Hz).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:31]=1)[CH2:2][CH2:3][CH3:4].C(C1[N:38](C)C2C3C=C(OCCCCCCOCCCCC4C=CC=CC=4)C=CC=3[N+]([O-])=CC=2N=1)CCC>>[CH2:1]([C:5]1[N:6]([CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:38])[C:8]=2[N:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c[n+]([O-])c3ccc(OCCCCCCOCCCCc4ccccc4)cc3c2n1C
Reactant: CCCCc1nc2c[n+]([O-])c3ccc(OCc4ccc(OC(F)(F)F)cc4)cc3c2n1C
Product: CCCCc1nc2c(N)nc3ccc(OCc4ccc(OC(F)(F)F)cc4)cc3c2n1C

Procedure:
The general method described in Example 61 was followed using 2-butyl-1-methyl-8-{[4-(trifluoromethoxy)benzyl]oxy}-5-oxido-1H-imidazo[4,5-c]quinoline (0.380 g, 0.853 mmol) in lieu of 2-butyl-1-methyl-5-oxido-8-{[6-(4-phenylbutoxy)hexyl]oxy}-1H-imidazo[4,5-c]quinoline. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) to provide 93.9 mg of 2-butyl-1-methyl-8-{[4-(trifluoromethoxy)benzyl]oxy}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 219.4-220.2° C.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].S(=O)(=O)(O)O.[OH-].[Na+].C[O:32][CH2:33][CH2:34]O>>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]3[NH:5][C@H:4]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:3]([OH:23])[C@H:2]([O:1][CH2:34][CH2:33][OH:32])[C:11]=3[CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: COCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c3c(ccn2c1C)[C@@H](OCCO)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.00 g (6.40 mmol) (7R,8R,9R)-7,8-Dihydroxy-2,3-dimethyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in 2-methoxyethanol (100 ml) is added 1.26 g (12.8 mmol) sulfuric acid and the mixture is stirred for 3 h at 55° C. Subsequently the reaction is poured out into a of 0° C. cooled aqueous solution of sodium hydroxide (2N). The mixture is extracted with dichloromethane two times. The combined organic layer are washed with water four times, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (diethyl ether/2-propanol: 10/1) to give 0.35 g (0.99 mmol/16%) of the title compound as a colourless solid with a melting point of 107–109° C. (diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>O1CCCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:3][CH:4]=1)#[N:9]
Reactant: O=C1CCC(=O)O1
Reactant: N#Cc1cnc(N)cn1
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)CCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The 5-aminopyrazine-2-carbonitrile (commercially available, 1.0 g, 8.32 mmol) was dissolved in tetrahydrofuran then succinic anhydride (1.04 g, 10.4 mmol) was added, the mixture was stirred at room temperature for 2 h and at reflux overnight. Then 1.0 equivalent of succinic anhydride was added and the solution was refluxed for 4 days. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated, acidified and extracted with ethyl acetate (3×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (1/3) with acid acetic (1%) to give 4-[(5-cyanopyrazin-2-yl)amino]-4-oxo-butanoic acid A1 (1.30 g, 71%). M.p.=201-202° C., 1H NMR (400 MHz, DMSO-d6) δ 12.09 (bs, 1H), 11.40 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 2.73 (t, 2H), 2.55 (t, 2H) ppm. LC-MS (Method B): RT 0.96, 219 (M−H+)
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:21][N:22]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(Br)cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (28 g, 81.4 mmol) in EtOH (100 mL) was added hydrazine hydrate (98%, 13.1 g, 162.8 mmol). The reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×10 mL) to give 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (22.0 g, 74.3 mmol, 92%). 1H NMR (DMSO-d6, 400 MHz): δ 10.83 (s, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.82 (q, J=6.8 Hz, 1H), 4.62 (d, J=13.2 Hz, 2H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl-].[CH:2]([O:5][C:6]1[CH:31]=[C:30]([CH3:32])[C:9](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:8]([CH3:33])[C:7]=1[CH3:34])([CH3:4])[CH3:3].CC1C(C)=CC(C)=CC=1O>>[CH:2]([O:5][C:6]1[CH:31]=[C:30]([CH3:32])[CH:9]=[C:8]([CH3:33])[C:7]=1[CH3:34])([CH3:4])[CH3:3]
Reactant: Cc1cc(OC(C)C)c(C)c(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C)c(C)c(O)c1
Agent: [Cl-]
Product: Cc1cc(C)c(C)c(OC(C)C)c1

Procedure:
The 4-isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride employed as the starting material is prepared by the procedure described in Example 18 by alkylation of 2,3,5-trimethylphenol to give 2,3,5-trimethylphenyl isopropyl ether (boiling point 115° C./11 mmHg), by haloformylation of the ether obtained to give 4-isopropoxy-2,3,6-trimethyl-benzyl chloride (nD20 =1.5433) and by reaction of the latter compound with triphenylphosphine.
Reaction SMILES: [CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][C@@H:46]([C:48]2[CH:59]=[CH:58][C:51]3[O:52][C:53]([CH3:57])([CH3:56])[O:54][CH2:55][C:50]=3[CH:49]=2)[O:45][C:44]1=[O:60])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C@@H:46]([C:48]4[CH:59]=[CH:58][C:51]5[O:52][C:53]([CH3:56])([CH3:57])[O:54][CH2:55][C:50]=5[CH:49]=4)[O:45][C:44]3=[O:60])[CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)C5CCCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)-N-({2-(trimethylsilyl)ethoxy}-methyl)benzenesulfonamide (508 mg) in DMF (8 ml) under nitrogen at 200 was treated with sodium hydride (60% dispersion in mineral oil, 58 mg) and the mixture was stirred 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (400 mg) in DMF (2 ml) was added and the mixture was stirred at 20° for 72 h. Phosphate buffer solution (pH 6.5, 10 ml) and water (20 ml) were added and the mixture was extracted with EtOAc (30 ml). The extract was washed with water (2×30 ml), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-PE (1:1) gave the title compound (530 mg). LCMS RT=4.47 min, ES+ve 793 (MH)+.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.C(O)C(C)C>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Solvent: CC(C)CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 130 °C
Reaction time: 7 h

Procedure:
A mixture of 70 weight parts of “Fastogen Super Magenta RTS (produced by Dainippon Ink Chemical Co., Ltd.)”, (C.I. Pigment Red 122), 290 weight parts of isobutanol and 380 weight parts of water was stirred at 130° C. for 7 hours in a reaction vessel with a stirrer. Thereafter, the resulting mixture was cooled to room temperature, and the resulting precipitates were filtered off, washed with hot water, dried and pulverized. Thus, quinacridone pigment was obtained. This quinacridone pigment was designated as Quinacridone Pigment 13. The number average primary particle size, the major axis direction length, the minor axis direction length and the ratio of the major axis direction length to the minor axis direction length of Quinacridone Pigment 13 are as shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[NH2:29][C@@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])[C:31]([O:33]CC)=[O:32]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH:29][C@@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:31]([OH:33])=[O:32])=[O:25])=[CH:27][CH:28]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CCCC[C@H](N)C(=O)OCC
Reactant: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Product: C#CCN(c1ccc(C(=O)N[C@@H](CCCCC(=O)O)C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 3, p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid was coupled to diethyl (2S)-2-aminopimelate (J. Med. Chem., 1983, 26, 1719) and the resultant product was hydrolysed to give (2S)-2-{p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzamido)pimelic acid in 25% yield, m.p. 165° C.;
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncc(Cl)c(-n2nnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
A solution of benzotriazole (2.14 g, 18.03 mmol) in DMF (10 mL) was slowly added at 0° C. to a solution of NaH (60% in mineral oil, 0.850 g, 21.3 mmol) in DMF (20 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 minutes; a solution of 2,4,5-trichloropyrimidine (3 g, 16.39 mmol) in DMF (20 mL) was then slowly added at 0° C. The reaction mixture was allowed to reach RT while stirring overnight. The solvent was evaporated under reduced pressure; the residue was taken up with EtOAc and washed 3× with water. The aqueous layers were combined and extracted 3 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude oil. This material was purified via flash chromatography (heptane/EtOAc, 8/2) to give 1.5 g (34% yield) of 1-(2,5-dichloro-pyrimidin-4-yl)-1H-benzotriazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)=[C:4]([C@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:25][C:26](=[CH2:28])[CH3:27]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22]2)=[C:4]([C@H:10]([O:16][C:26]([CH3:28])([CH3:27])[CH3:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: C=C(C)C
Reactant: CCOC(=O)[C@@H](O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A stirred ice-cold yellow mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.45 g, 6.14 mmol) and 70% HClO4 (1.054 ml, 12.27 mmol) in CH2Cl2 (100 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). After 2 h, cold bath was removed and the turbid reaction mixture stirred for 22 h at rt. LCMS at this point showed 4:1 product to sm. So, saturated with isobutylene (5 min) at rt and stirred for additional 24 h. Then, neutralized with sat. Na2CO3 (30 mL), organic layer separated and aqueous layer extracted with CH2Cl2 (25 mL). The combined organic layers dried (MgSO4), filtered, concentrated and purified by flash chromatography using 5, 10, 15, 20 and 40% EtOAc/hex to afford (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (2.3074 g, 5.07 mmol, 83% yield) as yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.19 (br. s., 1H), 4.17-4.24 (m, 1H), 4.08-4.14 (m, 1H), 4.04 (dt, J=2.5, 12.1 Hz, 1H), 3.51 (dt, J=2.5, 12.1 Hz, 1H), 2.85-2.91 (m, 1H), 2.64 (s, 3H), 2.57-2.62 (m, 1H), 2.55 (s, 3H), 1.55-1.66 (m, 2H), 1.41-1.46 (m, 1H), 1.32-1.37 (m, 1H), 1.21 (s, 9H), 1.20 (t, J=7.2 Hz, 2H), 1.08 (s, 3H), 1.03 (s, 3H). LCMS (M+H)=457.4. And (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (0.3 g, 0.751 mmol, 12.24% yield) as pale yellow paste: LCMS (M+H)=401.3.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][C:29]([CH3:35])([CH2:33][CH3:34])[C:30](Cl)=[O:31]>N1C=CC=CC=1>[CH3:28][C:29]([CH3:35])([CH2:33][CH3:34])[C:30]([N:24]1[C:23](=[O:25])[O:22][N:21]=[C:20]1[C:16]1[CH:15]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:19]=[CH:18][N:17]=1)=[O:31]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CCC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C)(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To 1 ml of pyridine were added 0.3 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.26 g of 2,2-dimethylbutanoyl chloride was added at room temperature. After stirring for 3 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.24 g of 4-(2,2-dimethylbutanoyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (11)).
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][OH:18])[CH:11]=1)=[O:9]>C(Cl)Cl>[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:3]([CH3:5])([CH3:4])[O:18][CH2:17][C:12]=2[CH:11]=1)=[O:9]
Reactant: C=C(C)OC
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Solvent: ClCCl
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
2-Methoxypropene (10 g) was added over 15 min to a stirred solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (5 g) and toluene-4-sulfphonic acid (0.5 g) in CH2Cl2 (100 ml) at 23° C. The mixture was stirred for 3 h, filtered through a wad of triemethylamine-deactivated silica and evaporated to give an oil. Purification by [FCTS] (300 g) [E] afforded the title compound as an oil (4.8 g) which solidified on cooling. A small sample was crystallized from light petroleum (b.p. 60°-80°) to give white crystals m.p. 47°-48°.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>C1COCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: Cn1ccnc1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
n-Butyllithium (1.6M in hexane, 20.76 mL, 33.22 mmol) was added dropwise to 1-methyl-1H-imidazole (CAS no. 616-47-7) (3 g, 36.54 mmol), in THF (10 mL) cooled to −70° C. over a period of 10 minutes under nitrogen. The resulting solution was stirred at −70° C. for 10 minutes. di-tert-Butyl diazene-1,2-dicarboxylate (CAS no. 870-50-8) (7.65 g, 33.22 mmol) in THF (6 ml) added dropwise over 10 minutes, not allowing the solution to rise above −65° C. After the addition was complete the solution was allowed to warm to ambient temperature overnight. Water (20 mL) added at RT. The THF was removed under vacuum. Extracted with EtOAc (2×40 mL). The organic extracts were combined, washed with brine (15 mL), dried over MgSO4 and reduced to give crude product. The crude product was purified by flash silica chromatography eluting with 20 to 100% EtOAc in isohexane to afford the product (6.17 g, 59.5%). m/z (ESI+) (M+H)+=313; HPLC tR=1.36 min.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]3=[CH:20][N:19]=2)=[O:17])=[CH:12][C:11]=1[O:28][CH3:29].C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:1])[C:21]3=[CH:20][N:19]=2)=[O:17])=[CH:12][C:11]=1[O:28][CH3:29]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(=O)c2ncc3c(O)cccn23)ccc1N
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2ncc3c(OC)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.79 g (2.43 mmol) of cesium carbonate and then 0.05 ml (0.84 mmol) of methyl iodide are added to 0.22 g (0.76 mmol) of (4-amino-3-methoxyphenyl)(8-hydroxyimidazo[1,5-a]pyridin-3-yl)methanone obtained in example 147 in 5 ml of DMF. The reaction medium is stirred at ambient temperature for 4 hours. After addition of a saturated sodium hydrogencarbonate solution, the reaction medium is extracted with ethyl acetate. The organic phase obtained is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.2 g of an orange-yellow solid is collected. Melting point: 229° C.; 1H NMR (CDCl3): 3.86 (3H, s), 4.01 (3H, s), 5.80 (2H, m), 6.69 (1H, m), 6.69-6.72 (1H, m), 7.03-7.09 (1H, t), 7.78 (1H, s), 7.92 (1H, s), 8.24 (1H, m), 9.25-9.28 (1H, m)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.C(N(CC)CC)C>CO>[C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 72.9 %

Procedure:
NH2—(CH2)7—COOH (5.00 g, 31.4 mmol), (BOC)2O (7.52 g, 34.5 mmol) and triethylamine (3.48 g, 34.5 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours. After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate. Then, the resultant solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate. After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH—(CH2)7—COOH (5.93 g, 22.9 mmol, yield: 73%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[CH:38][C:37]([C:40](C)(C)[O:41][SiH2]C(C)(C)C)=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C(C)(C)O[SiH2]C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Tetrabutylammonium fluoride (15.3 g, 48.6 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-(ter-butyl-dimethyl-silanyloxymethyl)-pyrimidin (10.0 g, 24.3 mmol) in THF (100 mL) and stirred at room temperature overnight. Water was added and the product extracted with chloroform. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (MeOH/CH2Cl2, 2.5:77.5) gave 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-pyrimidin (4.20 g, 53%).