Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])=[N:8][N:9]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:38])[F:39])[CH:30]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)n[nH]c1C1CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 54 %

Procedure:
In analogy to the procedure described in Example 160C], 5-cyclopropyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester and 3-(trifluoromethoxy)benzeneboronic acid gave the title compound as a white solid (54%). MS: 500.0 (MH+).
Reaction SMILES: Br[C:2]1[S:6][N:5]=[CH:4][CH:3]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:46])([CH3:45])[CH2:15][C:16]2[N:17]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[C:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:20]=2)=[CH:10][CH:9]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:19]1[N:20]=[C:16]([CH2:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3[S:6][N:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)([OH:46])[CH3:45])[N:17]([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:18]=1
Reactant: Brc1ccns1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(Br)cc2)n1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(-c3ccns3)cc2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Palladium tetrakis(triphenylphosphine) (39 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 5-bromoisothiazole (55 mg, 0.34 mmol), 2-(4-bromophenyl)-1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]propan-2-ol (200 mg, 0.34 mmol) and hexamethylditin (110 mg, 0.34 mmol) in 1,4-dioxane (15 mL). After stirring at 90° C. for 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-2-(4-isothiazol-5-ylphenyl)propan-2-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[NH:17][C:16]2=[O:29])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[N+:41]([C:44]1[CH:54]=[CH:53][C:47]([CH2:48][O:49][CH2:50][CH2:51]Cl)=[CH:46][CH:45]=1)([O-:43])=[O:42].P([O-])([O-])([O-])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[N:17]([CH2:51][CH2:50][O:49][CH2:48][C:47]3[CH:53]=[CH:54][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)[C:16]2=[O:29])[CH3:14])=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
1.00 g (2.25 mmole) of (3S, 4R)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-[(phenylthio)carbonyl-methyl]-2-azetidinone was dissolved in 20 ml of methylene chloride. To the solutiion were added 350 mg (2.71 mmole) of diisopropylethylamine and then 660 mg (2.71 mmole) of p-nitrobenzyloxyethyl chloride, with stirring at 0° C. After 15 minutes, a further 230 mg (1.78 mmole) of diisopropylethylamine and 433 mg (1.78 mmole) of p-nitrobenzyloxyethyl chloride were added, and the mixture was stirred at that temperature for 15 minutes. After completion of the reaction, 30 ml of a 0.1M phosphate buffer solution (pH 7.1) was added to the reaction mixture and the organic layer was separated. The aqueous lager was extracted with chloroform. The organic layer was combined with the chloroform extract and then the solvent was distilled from the mixture. The residue was dissolved in 50 ml of a 1:1 by volume mixture of benzene and ethyl acetate, washed successively with 0.02N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off, to afford 1.47 g (yield 100%) of the title product as crystals which were recrystallized from a mixture of benzene and ethyl acetate, to afford the pure product melting at 129°-130° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]([O:29][CH2:30][CH3:31])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:32][N:33]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH:22]([O:29][CH2:30][CH3:31])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:20]3)(=[O:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CNC1CCCCC1
Reactant: CCOC(CN1CCN(S(=O)(=O)c2ccc3ncnc(Cl)c3c2)CC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(CN1CCN(S(=O)(=O)c2ccc3ncnc(N(C)C4CCCCC4)c3c2)CC1)c1ccccc1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
In 50 ml of chloroform was dissolved 4.6 g of 1-(4-chloro-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine, and to the solution were added 1.7 g of N-methyl-N-cyclohexylamine and 1 g of anhydrous potassium carbonate, and the mixture was stirred at a temperature of 20° C. to 25° C. for 3 hours. The reaction solution thus obtained was washed with water, dried with anhydrous potassium carbonate and then chloroform was distilled therefrom. The residue was subjected to the same silica gel-column chromatography as in Example 1 using chloroform as the solvent for purification to give 4.2 g of 1-[4-(N-methyl-N-cyclohexylamino)-6-quinazolinesulfonyl]-4-(2-ethoxy-2-phenylethyl)piperazine [i.e., Compound (19)] in a yield of 79%.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH3:9][O:10][N:11]=[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl)[C:13]1[O:18][CH2:17][CH2:16][O:15][N:14]=1.O>CN(C)C=O>[O:15]1[CH2:16][CH2:17][O:18][C:13]([C:12](=[N:11][O:10][CH3:9])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[O:5])=[N:14]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CON=C(C1=NOCCO1)c1ccccc1CCl
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C1=NOCCO1)c1ccccc1C=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
19.5 g (0.14 mol) of N-methylmorpholine N-oxide are added to a solution of 15 g (0.056 mol) of (2-chloromethyl-phenyl)-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methanone O-methyl oxime in 150 ml of dimethylformamide and the mixture is stirred at 120° C. for 2 hours. After cooling, the mixture is poured into 1000 ml of water and extracted three times with 200 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated under reduced pressure. The residue is stirred with diisopropyl ether and the solid formed is filtered off with suction. 10.5 g (76% of theory) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (76 mg, 0.24 mmol) and TBTU (86 mg, 0.27 mmol) in DMF (1.2 mL) was added DIPEA (209 μL, 1.22 mmol). Then 4-aminotetrahydropyran (27 mg, 0.27 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (67 mg, 70%) as a white solid after recrystallisation from methanol/water. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1.C(O)(C)C>[O:3]1[CH2:4][CH2:5][N:6]([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:1]1
Reactant: C=O
Reactant: CCCC(CCC)CCCC(O)COCCNCCO
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCC(CCC)CCCC(O)COCCN1CCOC1
Temperature: 25 °C

Procedure:
To a 10 mL flask containing paraformaldehyde (52 mg, 1,73 mmol, 1 eq.) in toluene (1 mL), was added 1-[2-(2-hydroxy-ethylamino)-ethoxy]-6-propyl-nonan-2-ol (500 mg 1,73 mmol) diluted with isopropanol (1mL) before heating to reflux with a Dean-Stark trap for 17 h. The reaction was cooled to room temperature and, after evaporation, 520 mg of a mixture of products was obtained with the title compound as the major component (100% crude yield). 1H NMR (CDCl3, 400 MHz) d?(ppm); 4,33 (s, 2H); 3,78 (t, J=6,8 Hz, 2H); 3,83-3,74 (m, H); 3,70-3,57 (m, 2H); 3,55 (dd, J=2,7 Hz, J=10,0 Hz, H); 3,29 (dd, J=8,2 Hz, J=10,0 Hz, H); 3,02 (t, J=6,8 Hz, 2H); 2,81-2,74 (m, 2H); 1,50-1,12 (m, 15H); 0,87 (t, J=7,0 Hz, 6H′). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 87,0; 76,0; 70,5; 70,3; 63,3; 54,3; 52,7; 36,9; 36,0 (2C); 33,7; 33,5; 22,7; 19,8 (2C); 14,5 (2C)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:7]=1.C([Li])CCC.N1(C=O)CC[O:21][CH2:20]C1.O>CCOCC>[C:8]1([C:6]2[CH:7]=[C:2]([CH:20]=[O:21])[CH:3]=[N:4][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=CN1CCOCC1
Reactant: Brc1cncc(C2=CCCC2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1cncc(C2=CCCC2)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-cyclopenten-1-ylpyridine (9) (1 g, 4.5 mmol) in 25 ml of ether is added to a solution of n-butyllithium (1.6M in hexane, 4.2 ml, 6.7 mmol) in 25 ml of ether kept at −60° C. The reaction mixture is stirred for 2 h 30 min at −60° C. and then 1.4 ml of 4-morpholinecarboxaldehyde (13.4 mmol) are added. The reaction is stirred for 1 hour at −60° C. and then poured into water, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). The title product is obtained in the form of a beige solid (0.38 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[CH:24](=O)[CH2:25][CH3:26].C(OCC)C.Cl>C(Cl)(Cl)Cl>[CH:24](=[N:23][NH:22][C:20](=[O:21])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1)[CH2:25][CH3:26]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: CCC=O
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCC=NNC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.5 g, 0.0015 mol) was mixed with propionaldehyde (0.27 g, 0.0015×3.1 mol), and further with a mixed solution of diethyl ether and chloroform and a small amount of concentrated hydrochloric acid. The resultant solution was heated and refluxed for about 8 hours. The obtained reaction solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[C:26]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]5[CH2:3][CH2:2]5)=[O:5])[N:8]=4)[N:11]=3)[CH:17]=2)=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)cc1
Yield: 49.7 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), 4-tert-butylaniline (57 mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (68 mg, 0.36 mmol), 4-(dimethylamino)pyridine (43 mg, 0.36 mmol) and pyridine (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (70 mg, 50%) was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:40]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([NH2:40])=[O:38])[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}biphenyl-3-carboxylic acid (74 mg) and N-methylmorpholine (0.0197 ml) in THF (4 ml) was added isobutyl chloroformate (0.0232 ml) at 0° C. After stirring for 15 minutes, 28% ammonia solution (0.1 ml) was added thereto. The mixture was stirred at the same temperature for 15 minutes, then stirred at room temperature for 15 minutes. The reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2-MeOH 25:1) to give 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}-biphenyl-3-carboxamide (51.8 mg) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([OH:32])=O)=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:33]([O:40][CH2:41][CH2:42][N:43]([CH:44]([CH3:46])[CH3:45])[C:30]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]=1)=[O:32])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 63.1 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (9-04) (2.74 g, 63.03%) was synthesized as a dark liquid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (7-02) (3 g, 6.72 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl amine (8-b) (1.6 g, 7.399 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1)[CH3:2].[CH3:15]CN(C(C)C)C(C)C>C(#N)C.CO>[CH2:1]([N:3]1[C:7](=[O:8])[C:6]([O:9][CH3:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1CN(CC)C(=O)C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)C1=C(OC)C(=O)N(CC)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.2 %

Procedure:
To a solution of ethyl 1-ethyl-4,5-dioxopyrrolidine-3-carboxylate (200 mg, 1.0 mmol) and DIPEA (0.18 mL, 1.0 mmol) in ACN (1.8 mL) and MeOH (0.2 mL) was added TMS-CH2N2 (2.0 M in Et2O; 0.5 mL, 1.0 mmol). The reaction mixture was stirred at rt for 3.5 h, then evaporated in vacuo. The product was purified by silica gel chromatography (40 g silica gel; linear gradient of 0-50% MeOH:EtOAc (10:1) in hexanes over 15 min) to obtain Intermediate 9A (203 mg, 95% yield). HPLC/MS (Method D) RT=0.73 min, [M+H]+ 214.2.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].Cl[C:10]1[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[NH:38][N:39]=[CH:40][CH:41]=3)=[CH:33][CH:32]=2)=[CH:12][C:13]2[N:17]=[C:16](S(C)(=O)=O)[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[CH:30]=1>C1COCC1.C(#N)C>[N:39]1[NH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([C:11]3[CH:10]=[CH:30][C:14]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:16]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:17][C:13]=4[CH:12]=3)=[CH:32][CH:33]=2)=[CH:41][CH:40]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)c(Cl)cc21
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (18.0 mg, 60% suspension in mineral oil, 0.45 mmol). A solution of hydroxyacetic acid methyl ester (81.0 mg, 0.90 mmol) in THF (1.5 mL) was added dropwise to the vial. Immediately after the addition was complete, a solution of 6-chloro-2-methanesulfonyl-5-[4-(2H-pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (compound 45-1, 75.0 mg, 0.150 mmol) in THF (1 mL) was added. The resulting suspension was stirred at rt for 5 min, then diluted with ACN (2 mL) and quenched by slow addition of water (2 mL). The resulting solution was stirred at rt for 5 min, and then additional 15 min at 65° C. The solution was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water and evaporated to dryness in vacuo to give the title compound as yellowish oil. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C24H27ClN4O4Si 498.2, observed m/e 499.0 (M+H)+ (Rt 3.01, 3.15 min). The compound was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:40]3[CH:39]=[CH:38][CH:37]=[CH:29][N:36]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccccn3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(2-bromoethyl)pyridine hydrobromide and isolated as colorless gum. MS (m/e): 388.3 (MH+).
Reaction SMILES: CC(C)([O-])C.[Li+].[OH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>CN(C=O)C>[CH2:21]([O:17][C:12]1[CH:11]=[CH:10][C:9]([C:18](=[O:20])[CH3:19])=[C:8]([OH:7])[C:13]=1[N+:14]([O-:16])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Lithium tert-butoxide (4.06 g) was added to a stirred solution of 1-(2,4-dihydroxy-3-nitrophenyl)ethanone (example 11, step a) (10 g) in DMF (100 mL), under nitrogen, whilst maintaining the internal temperature below 30° C. After stirring for a further 10 minutes at ambient temperature, benzyl bromide (6.03 mL) was added and the mixture stirred for a further 20 h. Further benzyl bromide (3 mL) was added and the mixture stirred for 24 h. The reaction was quenched with water (300 mL), 1M aqueous sodium hydroxide (50 mL) was added and the mixture was washed with diethyl ether (2×300 mL), filtering through Celite to aid separation. The basic solution was cooled in ice/water, acidified with ice cold 2M hydrochloric acid (200 mL) and the resulting precipitate filtered off, washed with water and dried to afford a light brown solid. The solid was slurried with ethanol (100 mL) for 1 h and the solid filtered off, washed with cold ethanol (20 mL), and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid. Yield 6.8 g.