Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:28]#[N:29])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=3[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]21.[BH4-].[Na+]>O1CCCC1.CC(O)C.O>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=4[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([NH2:29])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 2.58 mL, 7.74 mmol) was added to a stirred solution of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (317 mg, 0.773 mmol) in tetrahydrofuran (7 mL) at 0° C. The resultant mixture was stirred at 60° C. for 1 hr. Ethylmagnesium bromide (3 M solution in diethyl ether, 2.58 mL, 7.74 mmol) was added to the reaction mixture at room temperature. The resultant mixture was stirred at 60° C. for 30 min. A suspension of sodium tetrahydroborate (585 mg, 15.5 mmol) in 2-propanol (7 mL) was added at room temperature. The resultant mixture was stirred at room temperature for 1 h, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a crude amorphous solid (392 mg).
Reaction SMILES: COC1C=CC([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])=CC=1>C(#N)C.O>[CH3:19][C:11]1([CH3:20])[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:9][C:10]1=[O:21]
Reactant: COc1ccc(N2C(=O)C(C)(C)C2c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC1(C)C(=O)NC1c1ccccc1

Procedure:
A solution of 24.4 g of N-(4-methoxy-phenyl)-3,3-dimethyl-4-phenylazetidin-2-one and 16.5 g of lithium 25 perchlorate in a mixture of 500 cm3 of acetonitrile and 50 cm3 of water, is subjected to electrolysis in a unseparated cell, using a graphite anode and a stainless steel grille as cathode and maintaining a constant potential difference of 1.5 V. At the end of the reaction the solution is concentrated to 1/4 of volume. An extraction is made with ethyl acetate and the organic phase is washed with a solution of aqueous sodium sulphite at 10% and then with water; it is dried with sodium sulphate and then evaporated. The raw product is purified on silica gel, using a mixture of ethyl acetate/hexane as eluant in a ratio of 3/7 and 15.4 g of 3,3-dimethyl-4-phenylazetidin-2-one are obtained (yield (98%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.CC(C)([O-])C.[Na+].N#N>CCOCC.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]1([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: Nc1nccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc2c(Nc3nccc4ccccc34)nccc2c1
Yield: 95 %

Procedure:
To a 100-mL round-bottom flask were added 1-chloroisoquinoline (2.84 g, 17.3 mmol), 1-aminoisoquinoline (2.5 g, 17.3 mmol), sodium tert-butoxide (2.33 g, 24.3 mmol), palladium (II) acetate (0.16 g, 0.69 mmol), bis(2-diphenylphosphinophenyl)ether(0.35 g, 0.65 mmol), and toluene (40 mL sparged with N2). The reaction mixture was heated at 105° C. for 18 h under an atm of N2. The reaction mixture was diluted with ether and THF, and washed with water. This solution was passed through a pad of celite to remove insoluble particles. The organic layer was dried over MgSO4 and then passed through a plug of SiO2 gel eluting with CH2Cl2:CH3CN 90:10. The volatile components were removed with a rotary evaporator to afford 4.46 g (94.9%) of bis(1-isoquinolyl)amine as an olive powder. Results of 1H NMR spectroscopy and electrospray mass spectroscopy are consistent with the product. 1H NMR (300 MHz, CDCl3): δ 6.93 (d, J=6.4 Hz, 2H), 7.63 (m, 7H), 7.71 (d, J=6.4 Hz, 2H), 9.11 (d, J=7.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) was cooled to 0° C. and treated dropwise with allyl chloroformate. After addition, the solution was stirred at ambient temperature for 2 h, diluted with dichloromethane, washed successively with 1N HCl and aqueous NaHCO3, dried over Na2 SO4, and concentrated to give the desired compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Cl:16])[N:6]=1>C(OC)(C)(C)C>[Cl:16][C:7]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]([Cl:11])=[C:5]([O:2][CH3:1])[N:6]=1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
10.8 g (0.06 mol) of 30% strength sodium methoxide solution were added to 15 g (0.06 mol) of 2,3,6-trichloro-5-trifluoromethylpyridine in 200 ml of methyl tert-butyl ether at 0-5° C. with stirring in the course of 20 minutes and the mixture was subsequently stirred at the same temperature for 30 minutes. After warming to 20° C., the resulting fine precipitate was filtered off with suction and washed with methyl tert-butyl ether. The organic filtrate was washed with water, dried and concentrated, 14.3 g (97% of theory) of the title compound of n25D =1.4890 being obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[O:7][C:6]2[C:8]([CH:13]([C:15]3[N:16]=[CH:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)O)=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[CH2:4][O:3]1>CO.[Pd].C(OCC)C>[CH3:1][C:2]1([CH3:39])[O:7][C:6]2[C:8]([CH2:13][C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: Cc1cc2c(c(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c1)OC(C)(C)OC2
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: Cc1cc2c(c(Cc3c[nH]cn3)c1)OC(C)(C)OC2

Procedure:
9.45 g (0.0183 mole) of alpha-(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl)-1-triphenylmethyl-1H-imidazole-4-methanol (prepared in Example 1.C.6.), dissolved in 300 ml of methanol, are subjected to hyrogeolysis in the presence of 0.6 g of 10% palladium on carbon for 4 hours at 80° C., under a hydrogen pressure of 2 hours. The catalyst is then filtered off and the solvent removed. The residue obtained is stirred in diethyl ether to remove the triphenylmethane, then chromatographed on 700 g of silica (10 μm) (eluent: 95:5 v/v dichloromethane-methanol). A 60:40 mixture of 4-[(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl)(methoxy)methyl]-1H-imidazole and 4-[(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl)methyl]-1H-imidazole is isolated and identified by NMR by the presence of a peak corresponding to the methoxy radical (DMSO: delta 3.13). The mixture is used as such in the following step.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[C:26]([O:30][C:31]([NH:33][NH2:34])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>>[NH2:20][C:18]([O:17][CH2:16][CH:15]1[C:6]2[C:4]([OH:5])=[C:3]([N:34]=[N:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:2]([CH3:1])=[C:8]([OH:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC12C(COC(N)=O)c3c(O)c(N=NC(=O)OC(C)(C)C)c(C)c(O)c3N1CC1NC12
Yield: 42.9 %

Procedure:
In a similar manner to that described in Example 17, mitomycin A (250 mg), tert-butoxycarbonylhydrazine (284 mg) and potassium carbonate (150 mg) are treated to obtain the desired product (138 mg) with a yield of 42.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=2[NH2:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=2[NH:17][C:25](=[O:26])[CH2:24][Cl:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of the product from Step B (1.79 g, 5.51 mmol) in 20 mL of EtOAc and 20 mL of saturated NaHCO3 solution at 0° C. was added chloroacetyl chloride (1.09 mL, 13.8 mmol). After one hour, the solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:25][CH3:26])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:39][SH:40].Cl>O.CN(C=O)C>[O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([S:40][CH2:39][C:38]([O:42][CH2:43][CH3:44])=[O:41])=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:25][CH3:26])[CH2:3]1
Reactant: CCOC(=O)CS
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC(=O)OCC)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 100.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 50 mg, 0.098 mmol) and Cs2CO3 (51 mg, 0.15 mmol) were added to DMF (2.0 ml) and ethyl thioglycolate (0.02 ml, 0.15 mmol) was added. The reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 150° C. for 5 min. The reaction mixture was diluted with water (100 ml), made acidic with HCl (1 M), extracted with DCM (3×10 ml) and the collected organic layers were dried (MgSO4) to give the crude title compound (54 mg). M/z 550.2.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][NH:25][CH2:24][CH2:23]2.C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl.CCCCCC>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][N:25]([S:12]([CH2:11][CH:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:5])=[O:16])(=[O:13])=[O:14])[CH2:24][CH2:23]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)CC(C(=O)O)C(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
2-Chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (1.0 ml of a 1M solution in dichloromethane) was added to a solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (230 mg) and triethylamine (0.31 ml) in dichloromethane (10 ml) and the mixture stirred at room temperature for 16 h. Trifluoroacetic acid was added (5 ml) and the reaction left to stir for 2 h then diluted with hexane (10 ml) and evaporated under reduced pressure. The residue was azeotroped with 1:1 dichloromethane-hexane (2×10 ml), dissolved in 1M sodium hydroxide and washed with diethyl ether (2×10 ml). The aqueous was acidified to pH=4 with citric acid and extracted with ethyl acetate (2 ×15 ml). The combined extracts were washed with water (10 mil) and brine (10 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give the title compound (93 mg, 25%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A 1 L single-necked round-bottomed flask was charged with 7 (61.4 g, 0.172 mol), benzyl amine (55.6 g, 0.519 mol, 3 eq), and anhydrous anisole (300 g) and then stirred at reflux until reaction was essentially complete (23 h, 165° C. oil bath temperature; internal temperature was 147° C.) and then allowed to cool to near room temperature. A portion (1 mL) of the reaction mixture was diluted with toluene (1 mL) resulting in the complete crystallization of that portion. This seed was then added to the reaction mixture and allowed to stand until the whole reaction mixture had crystallized to a single block. Toluene (150 mL) was added and the mixture swirled to break up the solid. Heptane/toluene (1:1, 100 mL) was added and the solid mixture broken up further. Finally, heptane (50 mL, then 25 mL) was added and the mixture broken up even further, allowing to stand an additional 30 min before filtering the solid. Filtration of the solid, washing with 2:1 toluene/heptane (300 mL), 1:2 toluene/heptane (300 mL), and then heptane (2×300 mL), and then drying (air, then high vac) gave 60.16 g (yield of 81%) of title product as a white solid (>98.9% AUC). Another 2.5 g of less pure (97.4%) material was obtained from the mother liquors.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[C:13]([C:14]([O:16]CC)=[CH2:15])=[C:12]([CH3:19])[N:11]=[C:10]([CH3:20])[N:9]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O>[CH3:15][C:14]([C:13]1[C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][CH:21]=2)=[N:9][C:10]([CH3:20])=[N:11][C:12]=1[CH3:19])=[O:16]
Reactant: C=C(OCC)c1c(C)nc(C)nc1NCc1ccc(Br)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1c(C)nc(C)nc1NCc1ccc(Br)cc1
Yield: 89.2 %

Procedure:
A solution of 4-(4-bromobenzylamino)-2,6-dimethyl-5-(1-ethoxyvinyl)pyrimidine (2.72 g, 7.51 mmol), 1N HCl (8.3 mL), and acetone (8 mL) was heated under reflux for 2.5 h. The acetone was removed under reduced pressure and the aqueous phase was adjusted to pH 4 with 1N KOH. The resultant white precipitate was collected by filtration to give 2.24 g (89%) of product as a white solid. An analytical sample was recrystallized from hexane, mp 78°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:40][C:41]1[CH:74]=[CH:73][C:44]([O:45][C:46]2[C:55]3[C:50](=[CH:51][C:52]([O:58][CH2:59][CH:60]4[CH2:65][CH2:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:62][CH2:61]4)=[C:53]([O:56][CH3:57])[CH:54]=3)[N:49]=[CH:48][CH:47]=2)=[C:43]([F:75])[CH:42]=1>CN(C=O)C>[F:75][C:43]1[CH:42]=[C:41]([NH:40][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:74]=[CH:73][C:44]=1[O:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([O:58][CH2:59][CH:60]3[CH2:65][CH2:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:62][CH2:61]3)=[C:53]([O:56][CH3:57])[CH:54]=2)[N:49]=[CH:48][CH:47]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 mg, 0.06 mmol), HOBt (10 mg) and EDCI.HCl (20 mg, 0.10 mmol) in DMF (2 mL) was added a solution of tert-butyl 4-((4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yloxy)methyl)piperidine-1-carboxylate (35 mg, 0.07 mmol) in DMF (1 mL) at rt, and the reaction mixture was stirred overnight at rt. It was directly purified by preparative HPLC to afford the product (24 mg, 56%) as a white TFA salt solid. 1H NMR (CDCl3) δ 12.16 (s, 1H), 8.75 (d, 1H, J=7.7 Hz), 8.64 (d, 1H, J=5.5 Hz), 8.05 (d, 1H, J=12.1 Hz), 7.83 (s, 1H), 7.67-7.24 (m, 8H), 6.72 (d, 1H, J=6.1 Hz), 6.65 (t, 1H, J=6.6 Hz), 4.22-4.11 (m, 2H), 4.07 (s, 3H), 3.48 (s, 2H), 2.78 (m, 2H), 2.13 (m, 1H), 1.87 (m, 2H), 1.47 (s, 9H), 1.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:20]=2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: COc1ccc(CN)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc(C)c2[N+](=O)[O-])cc1OC1CCCC1
Temperature: -10 °C
Yield: 82.3 %

Procedure:
2,4-Dichloro-5-nitro-6-methylpyrimidine (2.0 g) was dissolved in tetrahydro-furan (14 ml) and added with a solution of 3-cyclopentyloxy-4-methoxybenzylamine (2.25 g) dissolved in tetrahydrofuran (7 ml) with stirring and cooling on a salt-ice bath (−10° C.). Then, the mixture was added dropwise with triethylamine (1.4 ml), and stirred for 30 minutes on a salt-ice bath (−10° C.). The reaction mixture was further added with saturated brine, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was suspended and washed in a mixed solvent of ether and hexane (50:50) to obtain 3.11 g of the title compound.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH:24]1([C:27]2[O:31][C:30]([NH2:32])=[N:29][N:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[O:31][C:30]([NH:32][C:8]([CH:10]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:17][C:16]4[C:11]3=[CH:12][CH:13]=[CH:14][CH:15]=4)=[O:9])=[N:29][N:28]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: Nc1nnc(C2CC2)o1
Product: O=C(Nc1nnc(C2CC2)o1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 246-248° C. and MS: m/e=333.1 (M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine [J.Med.Pharm.Chem. 5, 617(1962)].
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([CH:6]=[N:7]O)=[CH:4][C:3]=1[CH3:12]>C(O)(=O)C.[Zn]>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([OH:1])=[C:10]([CH3:11])[CH:9]=1
Reactant: Cc1cc(C=NO)cc(C)c1O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(CN)cc(C)c1O
Yield: 98.2 %

Procedure:
A solution of 4-Hydroxy-3,5-dimethyl-benzaldehyde oxime (1.0 grams, 6.06 mmole) in acetic acid (30 ml) and Zn dust (4.0 grams, 61.2 mmole) was stirred at ˜60° C. for 2 hours. The mixture was filtered through celite, basified by aqueous ammonium hydroxide and extracted with chloroform. The combined extracts were dried over MgSO4, filtered, and concentrated to give a foam (0.90 g). MW 151; MS (m/e) 151 (M+).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]([C:20]1[C:29]([CH3:30])=[C:28](O)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:32])[CH:26]=2)[CH:21]=1)=[O:19].N1C=CC=CC=1.O>ClCCl.CCCCCC.C(OCC)(=O)C>[CH3:16][O:17][C:18]([C:20]1[C:29]([CH3:30])=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:32])[CH:26]=2)[CH:21]=1)=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (3.52 mL, 20.8 mmol) was added drop-wise over a period of 30 minutes to a 0° C. solution of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (3.75 g, 16.0 mmol) in dichloromethane (120 mL) and pyridine (1.95 mL, 24.2 mmol). The resulting mixture was allowed to warm slowly to room temperature with stirring, and the reaction mixture was stirred at room temperature for 3.5 hours. After this time, the reaction mixture was cooled to 0° C. Water (150 mL) was added, and the organic phase was separated. The organic phase was dried over Na2SO4, filtered, and concentrated to afford a brown solid. Flash chromatography (Aspire FlashReady™, 50 μm, 10%-18% ethyl acetate in hexane) gave 6-fluoro-3-methyl-4-trifluoromethane-sulfonyloxynaphthalene-2-carboxylic acid methyl ester as 4.52 g (77%) of a yellow, crystalline solid. HRMS (EI+) cald. for C14H10F4O5S [M+] 366.0185, obsd. 366.0186.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:52][C:53]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: COc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)N2CCc3cc(-c4csc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-methoxyphenylacetic acid (62.2 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-(1-{[3-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (69.4 mg) as a white solid. LC/MS (ES) m/z=416.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22 (t, J=8.34 Hz, 2H) 3.75 (s, 3H) 3.86 (s, 2H) 4.23 (t, J=8.46 Hz, 2H) 5.54 (br. s., 2H) 6.84 (dd, J=8.21, 2.40 Hz, 1H) 6.87-6.91 (m, 2H) 7.21-7.27 (m, 2H) 7.29 (d, J=5.56 Hz, 1H) 7.33 (s, 1H) 7.44 (s, 1H) 7.83 (d, J=5.81 Hz, 1H) 8.17 (d, J=8.34 Hz, 1H).