Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si:9]([O:16][CH2:17][CH:18]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20](=[O:34])[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CN(C)P(N(C)C)(N(C)C)=O.I[CH2:47][C:48]#[C:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54]>C1COCC1>[CH3:56][O:55][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][C:49]#[C:48][CH2:47][C@@H:19]1[C@@H:18]([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20]1=[O:34]
Reactant: COC(=O)CCCC#CCI
Reactant: COc1ccc(CN2CC(CO[Si](C)(C)C(C)(C)C)CC2=O)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
Lithium diisopropylamide (1.5 M in cyclohexane, 9.22 mL, 13.83 mmol) was added to a solution of 4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-one (2.63 g, 6.93 mmol) in THF (41 mL) at −78° C. under nitrogen. After 30 min at −78° C., hexamethylphosphoramide (3.61 mL, 20.7 mmol) was added dropwise. After 30 min at −78° C., methyl 7-iodohept-5-ynoate (5.52 g, 20.7 mmol) in THF (20 mL +3 mL) was added. The reaction mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×50 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (40% EtOAc/hexane) to afford 579 mg (16%) of 7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.O.Cl.CO>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC1CCc2ccc(O)cc2O1
Reaction time: 24 h
Yield: 71.2 %

Procedure:
9.8 g 7-hydroxy-2-methyl-4H-1-benzopyrane-4-on in 20 cm3 dry pyridine and 20 cm3 acetic anhydride was left to stand for 24 hours. The obtained solution was admixed with the mixture of ice, water and hydrochloric acid and the precipitate [11 g of 7-acetoxy-2-methyl-4H-1-benzopyrane-4-on, m.p. 94°-95° C. from benzene] was filtered. The acetoxy compound was hydrogenated in glacial acetic acid at 60° C. in the presence of a palladium on charcoal catalyst till it absorbed 3 molar equivalents of hydrogen, then after filtration and evaporation 11.5 g 7-acetoxy-2-methyl-3,4-dihydro-2H-1-benzopyrane-4-on (m.p. 66°-68° C. from ethanol) was obtained. This compound was hydrolyzed hot in the mixture of 100 cm3 methanol and 1.5 cm3 concentrated hydrochloric acid. The solvent was distilled off, the residue was subjected to fractionated distillation to obtain 6.5 g 7-hydroxy-2-methyl-3,4-dihydro-2H-1-benzopyrane (b.p. 85°-90° C./26 Pa); starting from this compound and following the process of example 5 (b), using a piperidine catalyst and 1-chloro-2,3-epoxypropane reagent, 1-chloro-3-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-propanol (m.p. 70°-72° C.) was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:33])[NH:11][C@@H:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:14]=1)[CH2:2]2.[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.C1([C@H](NC(O[C@@H]2C3CCN(CC3)C2)=O)C2C=C(C=CC=2)OCC2C=CC(C(O)=O)=CC=2)C=CC=CC=1>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:33])[NH:11][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:44](=[O:45])[C:43]4[CH:42]=[CH:41][C:40]([CH2:39][CH:35]5[O:36][CH2:37][CH2:38][O:34]5)=[CH:48][CH:47]=4)[CH2:25][CH2:26]3)[CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2]2
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCC2CCNCC2)c1)O[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCC2CCN(C(=O)c3ccc(CC4OCCO4)cc3)CC2)c1)O[C@H]1CN2CCC1CC2

Procedure:
The title compound was prepared as described in Example 1 Step 11 with (R)-quinuclidin-3-yl((S)-phenyl(3-(piperidin-4-ylmethoxy)phenyl)methyl)carbamate and 4-(1,3-dioxolan-2-ylmethyl)benzoic acid replacing 3-(1,3-dioxolan-2-yl)propyl piperidine-4-carboxylate hydrochloride and 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid respectively.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3cccc(F)c3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3cccc(F)c3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(3-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 72 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (131.0 mg, 55%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[CH:7]=[CH:8][C:9]([O:26][CH2:27][CH3:28])=[C:10]([C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH:11]=1>>[CH2:27]([O:26][C:9]1[CH:8]=[CH:7][C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:11][C:10]=1[C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[CH3:28]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: C=CC#N
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(/C=C/C#N)ccc3OCC)nc12

Procedure:
The title compound was prepared from acrylonitrile and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 19 and was obtained as off-white crystals (33%). Found: C,65.99; H,5.52; N,19.07. C20H21N5O2 requires C,66.10; H,5.82; N,19.27%.
Reaction SMILES: [Sn](Cl)Cl.[CH:4]([Si:7]([C:14]#[C:15][C:16]1(O)[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24][C:23]=2[C:22]([C:33]#[C:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])(O)[C:21]2[C:20]3[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=3[S:18][C:17]1=2)([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])([CH3:6])[CH3:5]>C(O)(=O)C.CC(C)=O>[CH:36]([Si:35]([C:34]#[C:33][C:22]1[C:21]2[C:20]3[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=3[S:18][C:17]=2[C:16]([C:15]#[C:14][Si:7]([CH:4]([CH3:6])[CH3:5])([CH:8]([CH3:10])[CH3:9])[CH:11]([CH3:13])[CH3:12])=[C:27]2[C:23]=1[S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=12)([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:40])[CH3:41])([CH3:37])[CH3:38]
Reactant: CC(C)[Si](C#CC1(O)c2sc3ccccc3c2C(O)(C#C[Si](C(C)C)(C(C)C)C(C)C)c2sc3ccccc3c21)(C(C)C)C(C)C
Agent: Cl[Sn]Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)[Si](C#Cc1c2sc3ccccc3c2c(C#C[Si](C(C)C)(C(C)C)C(C)C)c2sc3ccccc3c12)(C(C)C)C(C)C
Temperature: 2.5 °C

Procedure:
A solution of tin(II)chloride dehydrate (2.59 g, 11.5 mmol) in 50% acetic acid (40 ml) is added within ten minutes to a solution of 6,12-bis-[(triisopropylsilanyl)-ethynyl]-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 3) in acetone (35 ml). There is a slight temperature increase (2-3° C.), and formation of a yellow suspension takes place. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with 50% acetic acid (30 ml), water (twice with 40 ml), and acetone (2*40 ml). The residue is then dried to give crude product which is recrystallised from toluene (15 ml). The product is filtered off, washed with toluene (10 ml), and hexane (10 ml). After drying, the title product is obtained as pale yellow crystals. Mp. (DSC) 155° C. (broad probably phase transition), 208° C. (sharp, probably melting point). 1H-NMR (CDCl3, 300 MHz) δ 1.31-1.336 (m (higher order), 21H, CH(CH3)2); 7.48 (m, 1H, H-2), 7.53 (m, 1H, H-3), 7.92 (d, 1H, H-4); 9.37 (d, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 11.92 (CH); 19.22 (CH3); 103.42, 106.36 (C≡C); 112.56 (C-6); 122.78 (C-4); 124.33 (C-2); 125.16 (C-1); 127.46 (C-3); 132.78 (C-6a); 135.49 (C-6b); 140.47 (C-4-a); 143.30 (C-5a).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:4]=1.CN.F[P-](F)(F)(F)(F)F.[N:44]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:48]2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:44][CH3:48])=[O:27])=[N:23][CH:24]=4)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:4]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C(=O)O)nc3)CC4)nc(N)n2)CC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)c1ccc(N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic acid HCl salt (16.4 mg, 0.0296 mmol), methylamine (0.018 ml, 0.036 mmol) (2.0 M solution in THF), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.4 mg, 0.0326 mmol) and 4-methylmorpholine (16.3 uL, 0.148 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at r.t. overnight. The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=459.4.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].C[CH2:17][O:18]CC>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH2:17][OH:18])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOCC
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Product: CCOC(OCC)c1ccc(CCO)cc1
Yield: 97 %

Procedure:
To a solution of 4-(diethoxymethyl)benzaldehyde (5.0 g, 24 mmol) in ether (65 ml), cooled to -10° C., was added dropwise a 1.5M toluene-THF methylmagnesium bromide solution (64 ml, 96 mmol) at such a rate that the temperature remains below 0° C. After the addition the reaction was quenched with saturated ammonium chloride (80 ml) and the solution was diluted with water (50 ml) and extracted with ether (2×75 ml). The combined extracts were washed with water (50 ml) and brine (50 ml), dried over sodium sulfate and concentrated in vacuo, leaving present title product (5.2 g, 97%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=C3C[N+:8]([O-])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[C:25]([O:28][C:29](=[O:31])[CH3:30])(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([OH:28])(=[O:27])[CH3:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:30]3[CH:29]([OH:31])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Solvent: CC(=O)O
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2O

Procedure:
A stirred mixture of 1.0 g. of 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide (III), 5 ml. of acetic anhydride and 3 ml. of acetic acid is warmed on the steam bath, under nitrogen, for 30 minutes and concentrated in vacuo. The residue is suspended in water, neutralized with sodium carbonate and extracted with methylene chloride. The extract is dried, concentrated and chromatographed on silica gel eluting with ethyl acetate to yield 8-chloro-6-(2-chlorophenyl)-4-hydroxy-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCOC.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][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([C:11]5[CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=5)[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(I)c4)C(=O)O3)ccc2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCOC
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(-c5cccc(O)c5)c4)C(=O)O3)ccc2O1
Yield: 91.8 %

Procedure:
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{[(3-iodophenyl)methyl]oxy}ethoxy]hexyl}-1,3-oxazolidin-2-one (300 mg), 3-hydroxphenylboronic add (102 mg), tripotassium phosphate (417 mg) and dichlorobis(triphenylphosphine)palladium(II) (100 mg) in dimethoxymethane (10 ml) under nitrogen was heated under reflux for 4 h. The mixture was cooled to 20° and diluted with water (50 ml). The mixture was extracted with EtOAc (2×25 ml) and the combined extracts washed with water (50 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with diethyl ether gave the title compound (130 mg). LCMS RT=3.74 min, ES +ve 593 (MNH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[C:8](Br)=[N:7][CH:6]=1)=[O:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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]>[CH3:10][N:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][N:7]=[C:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cnc(Br)n1C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cnc(-c2ccccc2)n1C
Temperature: 100 °C
Yield: 81.1 %

Procedure:
Methyl-2-bromo-1-methyl-1H-imidazole-5-carboxylate (1 g, 4.56 mmol) and phenylboronic acid (0.67 g, 5.48 mmol) were dissolved in toluene-EtOH (80 mL, 5:3 v/v) and the solution was purged with argon for 10 min. K2CO3 (10 mL, 2M solution) and catalytic PdCl2(dppf) (82 mg, 0.12 mmol) were added and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and washed with EtOAc. The aqueous layer was acidified to pH ˜6 using 1.5N HCl and the crude product was extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 35-45% EtOAc in petroleum ether) to get methyl 1-methyl-2-phenyl-1H-imidazole-5-carboxylate (800 mg, yield 81%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.63-7.61 (m, 2H), 7.51-7.48 (m, 3H), 3.96 (s, 3H), 3.89 (s, 3H). MS (ESI) m/z: Calculated for C12H12N2O2: 216.09. found: 2168.8 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:7][C:8]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:9]=2[CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[F:16][C:11]1[C:9]2[CH:10]=[C:6]([CH2:5][OH:4])[O:7][C:8]=2[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: CC(=O)OCc1cc2c(F)ccc(F)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cc2c(F)ccc(F)c2o1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
252 mg of 2-acetoxymethyl-4,7-difluorobenzofuran was dissolved in 5 ml of methanol and 455 mg of potassium carbonate was added to the solution at room temperature. The resulting mixture was stirred at the same temperature for 2 hours, followed by the addition of ethyl acetate thereto. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was subjected to silica gel chromatography (developer: 5% ethyl acetate/n-hexane) to give 161 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=2)[N:25]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[CH2:10][C@@H:9]1[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-(2S)-2-isobutylpiperazine (384 mg, 1.6 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (219 mg, 32%) as a clear oil: 1H NMR and MS consistent.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12]([C:14]2[C:15](Cl)=[N:16][C:17]([Cl:21])=[C:18]([F:20])[CH:19]=2)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[Cl:21][C:17]1[N:16]=[C:15]2[C:14]([C:12](=[O:13])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:19][C:18]=1[F:20]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
7.0 g of ethyl 3-cyclopropylamino-2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)acrylate was dissolved in 35 ml of acetonitrile under heating to 75˜80° C. 8.56 g (2.0 eq.) of K3PO4 was added in portions to the reaction mixture, which was then stirred at the same temperature for 1.5 hours. The reaction mixture was filtered under a reduced pressure and washed with 77 ml of dichloromethane. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 77 ml of dichloromethane and then washed with water. The organic layer was concentrated under a reduced pressure to give 6.17 g of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (Yield: 98.5%).
Reaction SMILES: [F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[CH2:4][N:5]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[CH:15]=[CH2:16]>[Pd]>[NH2:12][C:8]1[C:7]([CH2:15][CH3:16])=[C:6]([N:5]([CH2:17][C:18]2[CH:35]=[CH:34][C:21]([O:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=2)[CH2:4][C:3]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:2]=2[F:1])[CH:11]=[CH:10][CH:9]=1
Reactant: C=Cc1c(N(Cc2ccc(Oc3cccc(OCC(=O)O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Agent: [Pd]
Product: CCc1c(N)cccc1N(Cc1ccc(Oc2cccc(OCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 87D (0.045 g, 0.0784 mmoles) in 1:1 ethyl acetate/TBF (4 mL) was added to a degassed flask charged with 10% palladium on carbon catalyst (0.050 g). Reaction mixture was degassed again and stirred vigorously at room temperature under an atmosphere of hydrogen for one hour. The reaction mixture was filtered through a pad of celite, and filtrate concentrated under reduced pressure to provide the title compound with no further purification (0.035 g, 82%). MS (ESI+) m/z 547 (M+H)+.
Reaction SMILES: [N:1]1([C:9]2([O:35][CH2:34][C@H:21]([O:22][CH2:23][P:24]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C@H:11]2[O:12]C(=O)C2C=CC=CC=2)[OH:10])[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N>CO>[N:1]1([C:9]2([O:35][CH2:34][C@H:21]([O:22][CH2:23][P:24]([O:26][CH:27]([CH3:29])[CH3:28])([O:30][CH:31]([CH3:32])[CH3:33])=[O:25])[C@H:11]2[OH:12])[OH:10])[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(=O)[nH]c2=O)[C@@H]1OC(=O)c1ccccc1)OC(C)C
Agent: N
Solvent: CO
Product: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(=O)[nH]c2=O)[C@@H]1O)OC(C)C
Yield: 95 %

Procedure:
A solution of 13 (2.03 g, 4.0 mmol) in MeOH saturated with ammonia (300 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to give compound 17 (1.52 g, 3.8 mmol) as a white powder in 96% yield which was characterized as follows:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[C:1]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of dimethyl malonate (6.24 g, 46.7 mmol) and potassium carbonate (6.51 g, 47.2 mmol) in DMF (20 ml) is added 2,4-difluoronitrobenzene (5.00 g, 30.8 mmol). The reaction is stirred at room temperature for 1 hour and then is brought to 60° C. After stirring for 1 hour, it is cooled to room temperature and 1 N HCl (100 ml) is added. The mixture is extracted with ethyl acetate (80 ml×2). The organic layers are combined, dried and concentrated. The desired compound is obtained after flash column chromatography purification (silica gel, eluted with hexanes-ethyl acetate): 1H NMR (CDCl3) δ 3.82 (s, 6H), 5.40 (s, 1H), 7.18-7.26 (m, 21), 8.16 (dd, 1H, J1=4.8 Hz, J2=8.8 Hz); LC-MS: 272.1 (MH+).