Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[C:28]1([C:34]2[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:39]([C:37]4[N:38]=[C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[S:35][CH:36]=4)=[O:40])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4csc(-c5ccccc5)n4)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 2-phenylthiazole-4-carboxylic acid (3 eq), HATU (3 eq) and DIPEA (5 eq). The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C30H30N6O2S2: 570.19. Found (M+H)+ m/z=571.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 46.7 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (170 mg, 0.37 mmol), 2-tributylstannanyl-pyridine (202 mg, 0.55 mmol) and PdCl2(PPh3)2 (51 mg, 0.073 mmol) in 8 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH, then 0-10% EtOAc/CH2Cl2) to give 80 mg of the title compound. MS: (+) m/z 464.41 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@:7]12[CH2:15][CH2:14][C:13]3[C:16]4[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=4[CH2:22][CH2:23][C:12]=3[C@@H:11]1[CH2:10][CH2:9][C:8]2=[O:26])[CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO>[CH2:3]([C@:7]12[CH2:15][CH2:14][C:13]3[C:16]4[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=4[CH2:22][CH2:23][C:12]=3[C@@H:11]1[CH2:10][CH2:9][C@@H:8]2[OH:26])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]12
Reaction time: 1 h

Procedure:
To a stirred solution of sodium borohydride (6.0 g.) in methanol (500 cc. under nitrogen) add 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (17 g.). Gently heat the reaction mixture for one minute to initiate the reaction and then allow to stand for one hour at room temperature. After adding cautiously glacial acetic acid (20 cc.), concentrate the solution in vacuo to 1/3 of its volume followed by addition of water. Extract the product with ether. Wash the ethereal solution successively with water, sodium bicarbonate, and water, and dry. Evaporate the ether to obtain 13β-isobutyl-3-methoxygona-1,3,5(10), 8-tetraen-17β-ol as a gum, (17.0 g.; 99%); ultraviolet absorption peak at 278 mμ (ε14,560).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N.O>CN(C)C=O>[O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([NH2:28])=[O:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Ammonia (1 g) in 30 mL of dimethylformamide was added and the stirring continued overnight. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate that formed was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed with 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11 g (83% yield) of 3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:32][C:33]#[N:34])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=2)=[CH:32][C:33]#[N:34])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOc1cc(C(=O)c2cc(OC)cc(OC)c2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2cc(OC)cc(OC)c2)ccc1OC
Yield: 88.4 %

Procedure:
(3,5-Dimethoxyphenyl)-(3-ethoxy-4-methoxyphenyl)methanone (0.63 g, 2.00 mmol), cyanomethylphosphonic acid diethyl ester (0.63 ml, 3.98 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 3.98 ml, 3.98 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give 3-(3,5-dimethoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile as an off-white solid (0.60 g, 89%): mp, 110-112° C.; 1HNMR (CDCl3) δ 7.04-6.82 (m, 3H, Ar), 6.55-6.43 (m, 3H, Ar), 5.65 (s, 0.50H, double bond proton of one isomer), 5.43 (s, 0.5H, double bond proton of the other isomer), 4.13-3.99 (m, 2H, CH2CH3 from the two isomers), 3.92 & 3.90 (s, 3H, single OCH3 group from the two isomers), 3.80 & 3.77 (s, 6H, 2OCH3 from the two isomers), 1.49-1.41 (two triplets, 3H, CH2CH3 from the two isomers); 13C NMR (CDCl3) δ 162.9, 162.8, 160.9, 160.8, 151.7, 151.1, 148.3, 148.0, 141.6, 139.1, 131.2, 129.3, 123.3, 122.2, 118.2, 114.2, 112.7, 111.2, 111.1, 107.8, 107.2, 102.3, 102.2, 93.8, 93.2, 64.7, 56.2, 56.1, 55.7, 14.8; Anal. Calcd. For C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.62; H, 6.25; N, 4.01.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([NH:26][CH:23]([CH3:25])[CH3:24])([NH:26][CH:23]([CH3:25])[CH3:24])=[O:9])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(NC(C)C)NC(C)C)C(=O)SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (10.5 g.; 0.027 mol.) dissolved in 100 ml. of diethyl ether was added to a solution containing isopropylamine (6.7 g.; 0.11 mol.) in 50 ml. of diethyl ether. The reaction mixture was stirred for 2 hours at 25° C., then filtered. The filtrate was washed with 5% sodium bicarbonate, then water. The ether layer was separated, dried over sodium sulfate and concentrated in vacuo. To remove remaining traces of solvent, the residue was concentrated at 25° C. and 0.05 mm. and yielded ethyl-N-[(benzylthio)carbonyl]-N-[bis(isopropylamino)phosphinylmethyl]-glycinate (7.0 g.) as crystals having a melting point of 69°-72° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[C:12]3=[N:19][CH:20]=[C:21]([C:22]#[N:23])[N:11]3[N:10]=2)=[CH:6][C:5]([C:24]#[N:25])=[CH:4][C:3]=1[N:26]1[CH2:31][CH2:30][NH:29][CH:28]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:27]1.[O:37]1[CH2:40][C:39](=O)[CH2:38]1.C(OC)(OC)OC.C([BH3-])#N.[Na+].O1CCC1=O>CO.CC(O)=O.O.C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[C:12]3=[N:19][CH:20]=[C:21]([C:22]#[N:23])[N:11]3[N:10]=2)=[CH:6][C:5]([C:24]#[N:25])=[CH:4][C:3]=1[N:26]1[CH2:31][CH2:30][N:29]([CH:39]2[CH2:40][O:37][CH2:38]2)[CH:28]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:27]1
Reactant: O=C1COC1
Reactant: CN(C)C(=O)C1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCN1
Agent: O=C1CCO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCN1C1COC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.6 %

Procedure:
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.073 mmol, Example 563) was taken up in MeOH (0.2 mL) and THF (0.2 mL) and oxetan-3-one (9.38 μl, 0.146 mmol) and trimethyl orthoformate (0.081 mL, 0.731 mmol) were added. The reaction was stirred at room temperature for 3 h. Next, sodium cyanoborohydride (9.19 mg, 0.146 mmol) and one drop of AcOH were added and the reaction was stirred at room temperature overnight. Only a trace of product detected by LCMS, so an additional 2 eq. each of oxetanone and NaCNBH3 were added, and the reaction was heated at 50° C. for 8 h. The reaction was cooled to room temperature and an additional 2 eq. each of oxetanone and reducing agent were added. The reaction was stirred at room temperature over the weekend. An additional 2 eq. each of oxetanone and NaCNBH3 were added, along with 1 drop of AcOH, and the reaction was heated at 50° C. for 6 h. The reaction was cooled to room temperature and water was added; a yellow solid crashed out. The solid was collected by filtration and purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carboxamide (1.9 mg).
Reaction SMILES: CN(C)C=O.[NH2:6][S:7]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8].[CH2:21](Br)[CH:22]=[CH:23][CH3:24].O>C(O)(C)C>[CH2:21]([N:16]([C:10]1[CH:11]=[CH:12][CH:17]=[CH:18][CH:19]=1)[NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:10]([S:7](=[O:9])(=[O:8])[NH2:6])[CH:11]=1)[CH:22]=[CH:23][CH3:24]
Reactant: CC=CCBr
Reactant: NNC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 0 °C

Procedure:
In a 250 ml round bottomed flask is placed 90 ml of N,N-dimethylformamide and 30 grams (0.092 mole) of 3-amino sulfonyl-4-chlorobenzhydrazide. The mixture was stirred to dissolve the solid, then 18.63 gms (0.138 mole) of crotyl bromide were added. The mixture was heated at 100° for 1.66 hours at which point TLC showed the reaction to be complete. The reaction mixture was cooled and diluted with 200 ml isopropanol. This solution was dripped into a slurry of 1.5 liters of ice and 4 liters of water. The solid which precipitated was collected, washed with water and air dried overnight, yielding the product which could be recrystallized from chloroform/carbon tetrachloride.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][NH:14][C:13]3=[O:20])=[CH:6][CH:5]=1.Cl[CH2:24][C:25]1[O:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O.ClCCl>[O:20]=[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH:11]=2)[N:16]=[CH:15][N:14]1[CH2:24][C:25]1[O:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1
Reactant: O=c1[nH]cnc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: COC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1coc(Cn2cnc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3c2=O)n1

Procedure:
A solution of 500 mg 6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one, 340 mg of methyl 2-(chloromethyl)oxazole-4-carboxylate, and 220 mg potassium carbonate in 5 mL of DMA was heated at 80° C. for 16 h. The reaction was diluted with water and dichloromethane, aqueous layer washed with dichloromethane, combined organic layers dried over sodium sulphate and concentrated. The residue was recrystallized from acetonitrile to produce methyl 2-((4-oxo-6-(4-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)methyl)oxazole-4-carboxylate Compound 177-A as a white solid (420 mg). MS m/z (ESI)=446.0 (base peak, M+H+); 891.1 (2M+H+); 913.1 (2M+Na+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[N:10]([CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:9]1)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:7][CH:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[N:10]([CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(CC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CN(CC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the [1-(2-benzyloxy-ethyl)-2-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with hydrochlorid acid (37%) in dioxane yielded quantitatively the title compound as a light yellow solid; MS (m/e): 394 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCN1CCOCC1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (20.0 g, 109 mmol, prepared using procedure in WO9849166), 4-(2-chloroethyl)morpholine hydrochloride (22.2 g, 120 mmol), K2CO3 (29.9 g, 217 mmol) and cesium carbonate (7.08 g, 21.7 mmol) in N,N-dimethylformamide (100 ml) was stirred at 55° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (350 ml) and water (500 ml). The phases were separated, and the aqueous layer extracted with further EtOAc (150 ml). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc/MeOH, 100:0-80:20, followed by EtOAc/MeOH/NH3, 80:20:1) to afford the title compound of preparation 21 (16.21 g, 54.5 mmol, 50%); mp 132-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10](CC2C=CC(OC)=CC=2OC)[CH2:9][C:8]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:7]=2[C:6]1=[O:31])=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:7]=2[C:6]=1[OH:31])=[O:4]
Reactant: COC(=O)C1C(=O)c2oc(-c3ccccc3)nc2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Reaction time: 5 h
Yield: 29.7 %

Procedure:
5-(2,4-Dimethoxy-benzyl)-7-oxo-2-phenyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (1.05 g, 2.49 mmol), was dissolved in 17 mL of anhydrous dichloromethane. To the solution was added 272 μL of thionyl chloride, and the reaction was stirred for 5 hours. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 0.20 g of the title compound as a white solid. MS: (−) m/z 269.1 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:26])=[N:23][CH:24]=2)[CH:21]=1)=O)(C)(C)C>ClCCl>[CH3:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:26])=[N:23][CH:24]=2)[CH:21]=1
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccc(N(C)C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc2cnc(C(=O)c3ccc([N+](=O)[O-])c(C(=O)OC)c3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1.3 ml of trifluoroacetic acid are added to 460 mg (1.01 mmol) of methyl 5-({6-[(tert-butoxycarbonyl)-(methyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoate in 5 ml of dichloromethane and the mixture is stirred at ambient temperature overnight. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and basified with a saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. 350 mg of a red powder are obtained. Melting point: 183° C.; 1H NMR (d6-DMSO): 2.79 (3H, d), 3.90 (3H, s), 7.11 (1H, d), 7.77 (1H, s), 7.82 (1H, d), 8.31 (1H, d), 8.66 (1H, d), 8.75 (1H, s), 9.01 (1H, s)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH:25]([C:32](=O)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[NH4+:44].C(O)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[O:24][C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:44]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Yield: 82.8 %

Procedure:
A mixture of methyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.34 g), ammonium acetate (685 mg) and acetic acid (5 ml) was refluxed for 3 hrs. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionate (1.07 g, yield 83%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:5, volume ratio).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([O:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([O:24][C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]([CH3:27])[N:4]=1)[CH3:26]
Reactant: CCOc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a solution of 4′-[(5-bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1 g) and phenylboronic acid (0.43 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.77 g, 78%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.Cl.O>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CSc1ccc(N)cc1
Reactant: Oc1nc(Cl)ncc1Br
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: CSc1ccc(Nc2ncc(Br)c(O)n2)cc1

Procedure:
9.8 g of 5-bromo-2-chloropyrimidin-4-ol is suspended in 200 ml of acetonitrile. After 7.2 g of 4-methylsulfanyl-phenylamine is added, 12 ml of a 4N solution of HCl in dioxane is added in drops while being stirred vigorously. After drop-by-drop addition of 5 ml of water, the mixture is stirred for 3 hours at 78° C. and for 2 days at room temperature. The mixture is cooled in an ice bath and suctioned off. The filter cake is washed twice with acetonitrile and dried. 15.2 g (92.7% of theory) of the product with a melting point of 238° C. (decomposition) is obtained.