Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:21]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:20][C:19]([O:30][CH3:31])=[CH:18][C:4]=1[C:5]([O:7]CC1C=CC([N+]([O-])=O)=CC=1)=[O:6].[CH3:32][O:33][C:34](=[O:53])[C@H:35]([CH2:51][SH:52])[NH:36][C:37](=[O:50])[C@@H:38]([C@H:47]([CH3:49])O)[NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>>[Si:23]([O:22][C:21]1[C:3]2[CH2:2][S:52][CH2:51][C@@H:35]([C:34]([O:33][CH3:32])=[O:53])[NH:36][C:37](=[O:50])[C@H:38]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:47]([CH3:49])[O:7][C:5](=[O:6])[C:4]=2[CH:18]=[C:19]([O:30][CH3:31])[CH:20]=1)([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H](CS)NC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)O
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c(CBr)c(C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Product: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)cc2C(=O)O[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1

Procedure:
p-Nitrobenzyl 2-bromomethyl-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate was reacted with N-[N-(tert-butoxycarbonyl)-D-threonyl]-L-cysteine methyl ester in an analogous manner to the procedure described in Example 1 (f), and the product was subjected in-an analogous manner to a sequence of procedures described in Example 13 (f) and in Example 21 to yield tert-butyl (4R, 7R, 8R)-14-(tert-butyldimethylsilyloxy)-1,3,4,5,6, 7,8,10-octahydro-12-methoxy-4-methoxycarbonyl-8-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as white crystals. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from methanol/diethylether/hexane, tert-butyl (4R, 7R, 8R)-1,3,4,5,6,7,8,10-octahydro- 14-hydroxy-12-methoxy-4-methoxycarbonyl-8-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][OH:34])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:35]1(C)C=CC(S(O)(=O)=O)=C[CH:36]=1>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][O:34][CH2:35][CH3:36])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Yield: 13.2 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (49 mg, 0.10 mmol) and para-toluenesulfonic acid (38 mg, 0.2 mmol) were dissolved in ethanol (1.0 mL) and irradiated in the microwave at 140° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford the pure product (6.4 mg, 13%). ESI-MS m/z calc. 486.2. found 487.5 (M+1)+; retention time 3.17 minutes.
Reaction SMILES: [Cl-].[NH2:2][N+:3]([NH2:7])=[C:4]([NH2:6])[NH2:5].[C:8]([C-](C#N)C#N)#[N:9]>>[N-:5]([C:8]#[N:9])[C:4]#[N:6].[NH2:2][N+:3]([NH2:7])=[C:4]([NH2:6])[NH2:5]
Reactant: N#C[C-](C#N)C#N
Agent: NC(N)=[N+](N)N
Agent: [Cl-]
Product: N#C[N-]C#N

Procedure:
0.94 g (7.49 mmol) diaminoguanidinium chloride (C13H8N5Cl) used for anion exchange to tricyanomethanide (C5H8N8): yield 92%; mp. 90° C.; decomp. (onset) 189° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:12][OH:13])[CH3:11])=[N:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:27][O:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:12][O:13][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[CH:27][O:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])[CH3:11])=[N:2]1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(=NO)c1noc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC=C(C(=O)OC)c1ccccc1CON=C(C)c1noc2ccccc12

Procedure:
A mixture of 0.8 g of 1-(1,2-benzisoxazol-3-yl)ethanone oxime, 1.3 g of methyl 2-(bromomethyl)-α-(methoxymethylene)phenylacetate and 1 g of potassium carbonate in 15 ml of acetonitrile is refluxed for 4 h. The reaction mixture is cooled and filtered and the filtrate is concentrated under vacuum. The residue is dissolved in ethyl acetate and the solution is washed twice with water and once with a saturated solution of sodium chloride and dried over sodium sulfate. After removal of the solvent under vacuum, the residue is purified by chromatography on silica gel with ethyl acetate/hexane (1:3), giving the title compound having a melting point of 97°-98° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:4]=12.Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1.C(N(CC)CC)C>CN(C=O)C.CO>[CH3:33][C@H:32]1[C:25]2[C:24]([N:9]3[C:5]4[C:4](=[C:3]([CH2:2][NH:1][C:35]5[N:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH:8]=[CH:7][CH:6]=4)[C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)=[N:29][CH:28]=[N:27][C:26]=2[CH2:30][CH2:31]1
Reactant: Clc1ncccn1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CN)cccc43)c21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNc5ncccn5)cccc43)c21
Yield: 39.4 %

Procedure:
A solution of (R)-tert-butyl 4-(aminomethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (15 mg, 0.033 mmol), 2-chloropyrimidine (3.8 mg, 0.033 mmol), and triethylamine (25 μL, 0.16 mmol) in DMF (0.50 mL) was heated at 100° C. for 24 hours. The material was diluted with MeOH and purified with a Gilson C18 prep HPLC system to give (R)-tert-butyl 1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((pyrimidin-2-ylamino)methyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (7.0 mg, 0.013 mmol, 40%). LCMS (APCI+) M+H+ 528 (85%); Rt=3.89 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25]>CC(N(C)C)=O>[I:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[C:4]([NH2:5])=[N:25][C:24]([NH2:26])=[N:23]3)=[CH:17][CH:16]=1
Reactant: N#Cc1c(F)cccc1OCc1ccc(I)cc1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCc3ccc(I)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2-Fluoro-6-(4-iodobenzyloxy)benzonitrile (176.6 mg, 0.5 mmol) and guanidine carbonate (110 mg; 0.66 mmol) were heated at 140° C. in dimethyl acetamide for 7 hours. The mixture was cooled to room temperature and stored in the freezer overnight. The precipitate was collected by filtration and the filtrate was diluted with dichloromethane. The filtrate was stored in the freezer for 3 hours. The resulting precipitate was collected by filtration and all the solids were combined and crystallized from 50% ethanol/water to yield 114 milligrams of 5-(4-iodobenzyloxy)quinazoline-2,4-diamine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5][C:4]=2[C:3]=1[C:17]([NH2:19])=[O:18].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[CH3:22][N:23]([CH3:25])[CH:24]=[N:19][C:17]([C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2)=[O:18]
Reactant: COC(OC)N(C)C
Reactant: COc1nc2cc(Cl)c(Cl)c(C(N)=O)c2nc1OC
Product: COc1nc2cc(Cl)c(Cl)c(C(=O)N=CN(C)C)c2nc1OC
Yield: 92 %

Procedure:
6,7-Dichloro-2,3-dimethoxyquinoxaline-5-carboxamide (Preparation 24, 1.96 g, 6.49 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated under reflux for 2 hours. After being cooled the mixture was concentrated under reduced pressure and the residue triturated with diethyl ether to afford N1,N1-dimethyl-N2-[6,7-dichloro-2,3-dimethoxyquinoxalin-5-ylcarbonyl]formamidine (2.14 g, 92%) as a pale yellow solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][O:45][C:46]1[CH:69]=[CH:68][C:49]([CH2:50][N:51]2[CH2:57][C:56]3[CH:58]=[C:59](/[CH:62]=[CH:63]/[C:64](O)=[O:65])[CH:60]=[N:61][C:55]=3[NH:54][C:53](=[O:67])[CH2:52]2)=[CH:48][CH:47]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:44][O:45][C:46]1[CH:69]=[CH:68][C:49]([CH2:50][N:51]2[CH2:57][C:56]3[CH:58]=[C:59](/[CH:62]=[CH:63]/[C:64](=[O:65])[N:11]4[CH2:12][CH:9]([O:8][CH2:7][C:3]5[S:2][CH:6]=[CH:5][CH:4]=5)[CH2:10]4)[CH:60]=[N:61][C:55]=3[NH:54][C:53](=[O:67])[CH2:52]2)=[CH:48][CH:47]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)cc1
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)N4CC(OCc5cccs5)C4)cc3C2)cc1
Reaction time: 8 h
Yield: 39.9 %

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (231 mg, 1.12 mmol), EDCI (215 mg, 1.12 mmol), HOBt (152 mg, 1.12 mmol) and diisopropylethylamine (321 μL, 1.87 mmol) were successively added to a solution of (E)-3-(4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride (292 mg, 0.75 mmol) in dimethylformamide (20 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (30 ml) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (2×30 mL) and dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was precipitated from a mixture ethyl acetate/diethyl ether to afford the title product as an off-white solid (151 mg, 40%).
Reaction SMILES: [CH:1]1([O:4][C:5]2[C:6]([N+:14]([O-])=O)=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1>[Pd].CO>[NH2:14][C:6]1[C:5]([O:4][CH:1]2[CH2:2][CH2:3]2)=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1c(OC2CC2)cccc1C(=O)O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A 50 mL round bottom flask was charged with 3-cyclopropoxy-2-nitrobenzoic acid (205 mg, 0.919 mmol), 10% Pd/C (25 mg, 0.919 mmol) and methanol (6 mL). The flask was vacuum flushed with nitrogen (3×) followed by a vacuum flush with a hydrogen balloon (3×). The resulting suspension was stirred under a balloon of hydrogen at room temperature over night. The solution was filtered through CELITE®, washing with methanol, and the filtrate was concentrated to provide reddish oil. The crude material was azeotroped with toluene (2×), and dried under vacuum to provide crude 2-amino-3-cyclopropoxybenzoic acid (175 mg, 0.906 mmol, 99% yield) as a reddish solid. The product was used without further purification in the next reaction. HPLC: RT=2.31 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=194.12 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25]CC)=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([OH:25])=[O:24])=[CH:20][N:21]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:22]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(Cc2ccccn2)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
2-(Bromomethyl)pyridine hydrobromide (126 mg) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (100 mg) and cesium carbonate (437 mg) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was stirred at 80° C. for four hours and returned to room temperature. A 1 N aqueous sodium hydroxide solution (2 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. A 1 N aqueous hydrochloric acid solution and water were added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and then dried to give 94 mg of the title compound as a solid.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:34]=[C:33]([F:35])[C:32]([NH:36][C:37](OC)=[O:38])=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>CN(C)C=O>[Cl:15][C:16]1[CH:34]=[C:33]([F:35])[C:32]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(=O)OC)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To ethyl 3-amino-4,4,4-trifluorocrotonate are added N,N-dimethylformamide and sodium hydride and the mixture is stirred at 0° C. Thereafter, to the reaction solution is added a mixture of methyl [2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A9-22] and N,N-dimethylformamide, and the mixture is stirred at 80° C. Then reaction solution is cooled to room temperature, then, poured into a mixture of hydrochloric acid and ice water, and the deposited crystal is collected by filtration to obtain methyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate.
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[O:20][CH2:21][C:22]#[N:23]>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:15][C:14]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: N#CCOc1cc(N)ccc1Cl
Solvent: CC(=O)O
Product: N#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reaction time: 2.5 h

Procedure:
A mixture of 1.52 g. of cyclohexane-1,2-dicarboxylic anhydride, 1.83 g. of 4-chloro-3-cyanomethoxyaniline (melting point 89°-90° C.) and 8 ml. of acetic acid was refluxed with stirring for 2.5 hours. The solvent was distilled off under a reduced pressure and then, water was added to obtain a crude crystal. The product was recrystallized from methanol to obtain 2.83 g. of Compound No. 228 shown in Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7](C(NCCBr)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][N:17]1[C:22]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:20](=[O:29])[N:19]([CH3:30])[C:18]1=[O:31].C(N(CC)CC)C>C(O)(C)C>[CH3:16][N:17]1[C:22]([N:23]2[CH2:28][CH2:27][N:26]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=3)[CH2:25][CH2:24]2)=[CH:21][C:20](=[O:29])[N:19]([CH3:30])[C:18]1=[O:31].[CH3:16][N:17]1[C:22]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:20](=[O:29])[N:19]([CH3:30])[C:18]1=[O:31]
Reactant: O=C(NCCBr)c1ccc([N+](=O)[O-])cc1
Agent: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
A mixture of 1.3 g of the compound 46 obtained in the paragraph (1), 1.8 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione (compound 37), 1.3 ml of triethylamine and 10 ml of isopropanol was heated under reflux for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:67])([F:66])[O:57][C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1.CN(C)C=O>>[NH2:65][C:60]1[CH:59]=[C:58]([O:57][C:56]([F:55])([F:66])[F:67])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:37]([CH3:39])[CH3:38])[CH2:31]1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N,N′,N-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.14 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (1.3 g, 2.1 mmol) and N,N-Diisopropylethylamine (1.20 mL, 6.90 mmol) and 4-(trifluoromethoxy)benzene-1,2-diamine (0.482 g, 2.51 mmol) in N,N-Dimethylformamide (13.0 mL, 167 mmol). The reaction was stirred overnight at RT and was partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to the desired amide (1.4 g) as a solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:44]([O:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=[O:57])=[C:54]([CH3:60])[CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:56]([C:55]1[CH:58]=[CH:59][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:53][C:54]=1[CH3:60])[OH:57])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 97 %

Procedure:
(S)-4-Benzyl-3-ethoxyacetyl-oxazolidin-2-one (12.45 g, 47 mmol) (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was dissolved in dry dichloromethane (270 ml) under an argon atmosphere and the solution was cooled to −78° C. Triethylamine (7.98 ml, 57 mmol) was added, followed by the slow addition, over approximately 20 min, of di-n-butylboron triflate (1 M solution in dichloromethane, 50 ml, 50 mmol) such that the reaction temperature was kept below −70° C. The mixture was stirred at −78° C. for 50 min, the cooling bath was replaced with an ice bath and the mixture stirred at 0° C. for additional 50 min before being recooled to −78° C. A solution of 4-benzyloxy-2-methyl-benzaldehyde (10.7 g, 47 mmol) in dry dichloromethane (130 ml) was added over ca. 45 min, such that the reaction temperature was maintained below −70° C. The resulting mixture was stirred at −78° C. for 45 min, warmed from −78° C. to 0° C. and stirred at 0° C. for a further 1.5 h. The reaction mixture was poured onto ice water/brine and extracted two times with dichloromethane. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 22.3 g (45.6 mmol, 96%) of the title compound as colorless oil. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[C:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2ccccn2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1nn2ccccc2c1C(=O)C(C)C
Yield: 31.5 %

Procedure:
A mixture of 700 mg (4.7 mmol) of 2-methoxypyrazolo[1,5-a]pyridine, 550 mg of isobutyryl chloride and 300 mg of AlCl3 was stirred in 2 ml of DCE at RT for 5 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate to yield 1 g of crude product. Purification on an Al2O3 column furnished 323 mg of 1-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one. Compound 1055.
Reaction SMILES: C([N:4]1[CH:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)C.[C:13](O)(=[O:15])[CH3:14]>[Pt]>[C:13]([O:11][CH:9]([CH:8]1[NH:4][C:5](=[O:12])[CH2:6][CH2:7]1)[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CC(=O)C1CCC(=O)N1C(C)=O
Agent: [Pt]
Product: CC(=O)OC(C)C1CCC(=O)N1
Temperature: 90 °C
Reaction time: 17.5 h

Procedure:
A mixture of 1,5-diacetylpyrrolidin-2-one (3.5 g), 5 percent platinum on alumina (1.0 g) and acetic acid (30 ml) is stirred in a 200-ml Parr® pressure vessel under a hydrogen atmosphere (570 psi) at 90° C. for 17.5 hours. Analysis of the reaction mixture after the removal of catalyst and solvent by nuclear magnetic resonance shows that it is a 1:1 mixture of the reactant and the desired product.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC(C1C=C2C(=O)N(O)C(=O)C2=CC=1)=O)CCCCCCCCCCC.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Product: CCCCCCC(C)=O
Yield: 6.3 %

Procedure:
A mixture of 24 mmol of 2-octanol, 0.1 mmol of 4-dodecyloxycarbonyl-N-hydroxyphthalimide and 0.005 mmol of cobalt(II) acetate was stirred at 70° C. in an atmosphere of oxygen gas (1 atm=0.1 MPa) for 3 hours and thereby yielded 1.52 mmol of 2-octanone.