Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[CH2:20]2.Cl>C1CCCCC1.O1CCCC1>[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([C:21]2([OH:27])[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[CH:8][CH:9]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OC1(c2ccc(-c3ccccc3)cc2)CN2CCC1CC2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
A solution of sec-butyllithium in cyclohexane (100 ml, 1.3M) was added dropwise with stirring to a solution of 4-bromobiphenyl (25 g) in dry tetrahydrofuran (240 ml) under an argon atmosphere at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (12 g) in dry tetrahydrofuran (100 ml) added during 20 minutes. Stirring was continued at -78° C. for 30 minutes and the mixture allowed to reach room temperature over 2 hours. 2M Hydrochloric acid (225 ml) was added keeping the reaction temperature below 10° C. The aqueous layer was separated and washed with diethyl ether (2×300 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH14. The mixture was extracted with ethyl acetate which had been heated to 50° C. and the ethyl acetate phase separated, dried (Na2SO4) and evaporated to yield a colourless solid which crystallised from ethyl acetate to give 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (11.0 g) m.p. 165°-166° C.; microanalysis, found: C, 81.1; H, 7.5; N, 5.2%; C19H21NO 0.1H2O requires: C, 81.1; H, 7.5; N, 5.0%; NMR (CDCl3 /CD3CO2D): 1.7-1.9(3H, m,), 2.5(1H, m), 2.5-2.7(1H, m), 3.2-3.5(4H, m), 3.7(1H, dd), 4.0(1H, dd) and 7.3-7.7(9H, m); m/z 279 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=1[N+:16]([O-:18])=[O:17]>C(N)CN>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([NH:4][CH2:5][CH2:6][NH2:16])[CH:8]=[C:7]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Solvent: NCCN
Product: NCCNc1cc(NCCO)c([N+](=O)[O-])c(NCCO)c1
Temperature: 0 °C

Procedure:
0.13 mole (36.5 g) of 2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)amino-4-chloronitrobenzene, whose synthesis was described in stage 1 of example 2, was heated for 2 hours at 130° C. in 150 ml of ethylenediamine, then the reaction medium diluted with 450 ml of ice water to precipitate out the desired product. After filtering and water washing to neutrality, the product obtained was dried under vacuum in the presence of P2O5. It was recrystallized from 96° ethanol and melted at 220° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:7][NH:8][C:9]2[C:13]([CH:14]=1)=[CH:12][C:11]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])([P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[CH:10]=2.[C:31]([O-:34])(=[S:33])[CH3:32].[Na+]>CC(C)=O>[C:31]([S:33][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:7][NH:8][C:9]2[C:13]([CH:14]=1)=[CH:12][C:11]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])([P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[CH:10]=2)(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(CCCCBr)CNC2=C1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(CCCCSC(C)=O)CNC2=C1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of dihydro-3-(4-bromobutyl)-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (5.0 mmol) is stirred in dry acetone (35 ml) and sodium thioacetate (5.2 mmol) is added. The mixture is stirred at 50° C. for 12 hours. After cooling to room temperature the solvent is removed under reduced pressure. The crude residue is dissolved in methylene chloride and washed with water. The organic layer is then dried and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[O:14])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCCCO
Product: O=Cc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 112.5 %

Procedure:
The procedure is carried out as in Example 1, starting with 189 mg of 2,6-dichloropurine, 5 ml of butanol and 149 mg of 4-aminoacetophenone. 308 mg of the expected product are thus obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:77]1[S:81][CH:80]=[N:79][CH:78]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:13]=[C:14]([C:77]2[S:81][CH:80]=[N:79][CH:78]=2)[CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Brc1cncs1
Reactant: CC1(C)OB(c2cc(CO[Si](C)(C)C(C)(C)C)cc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a flask containing the product of Step 4 (750 mg, 1.47 mmol), dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (70 mg, 0.15 mmol), Pd2(dba)3 (67 mg, 0.074 mmol), cesium carbonate (959 mg, 2.94 mmol) was added a solution of 5-bromothiazole in a degassed mixture of dioxane (2.7 mL) and water (2704). The solution was evacuated and then purged with argon 5 times and then heated at 90° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield N-[3-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (414 mg, 0.89 mmol, 60% yield). MS ESI: [M+H]+ m/z 381. 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.07 (s, 1H), 8.81 (d, J=4.9, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.69 (s, 1H), 7.28 (d, J=4.9, 1H), 7.26 (s, 1H), 4.72 (s, 2H), 0.91 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[CH3:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27]Cl)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][N:15]2[C:14](=[O:16])[O:13][N:12]=[C:11]2[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: Cc1ccc(C(=O)OCCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OCn2c(-c3cc(C(F)(F)F)ccn3)noc2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.29 g of chloromethyl 4-methylbenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.25 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 4-methylbenzoate (present compound (35)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.O.Cl>O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1
Reactant: C1COCCN1
Reactant: COCc1nccc(Cl)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCc1nccc(N2CCOCC2)n1
Yield: 53.2 %

Procedure:
A solution of morpholine (12.67 g) and 2-methoxymethyl-4-chloropyrimidine (7.69 g) in tetrahydrofuran (100 ml) was heated under reflux for 1 hour. On cooling, the mixture was treated with water (100 ml), the pH adjusted to 8 (conc HCl) and extracted with chloroform. After drying (K2CO3) the extracts were stripped, and the residue purified by chromatography (silica gel, CHCl3 /methanol) to give 2-methoxymethyl-4-morpholinopyrimidine (5.4 g) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](C(OC(C)(C)C)=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:30])[C:11]=2[CH2:31][O:32]C(=O)C)[CH:9]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:30])[N:16]([C:12]1[C:11]([CH2:31][OH:32])=[C:10]([C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=3)[CH:15]=[CH:14][CH:13]=1)[N:25]=[CH:24]2)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)cn1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(=O)O)c4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
To a solution of 4-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (136 mg, 0.24 mmol) in 5 mL of dioxane and 5 mL of water was added NaOH (40 mg) and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure. The residue was dissolved in 8 mL of water, and acidified with 1 N HCl to pH 3-4. The mixture was extracted with ethyl acetate (5 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid (99 mg, yield 100%). LC-MS calcd for C24H23N3O4 (m/e) 417.17, obsd 418 [M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[C@@H:11]([OH:12])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5].[C:13]1([C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH2:21][CH2:22]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:2][O:3][C:4]([C@H:6]1[C@@H:11]([OH:12])[CH2:10][CH2:9][N:8]([CH2:22][CH2:21][CH:20]=[C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:7]1)=[O:5]
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CNCC[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(CCC=C(c2ccccc2)c2ccccc2)CC[C@@H]1O

Procedure:
Similarly, a mixture of 1.63 g. (0.00835 mole) of cis-4-hydroxy-3-piperidinecarboxylic acid methyl ester, hydrochloride, 3 g. (0.0104 mole) of 4,4-diphenyl-3-butenyl bromide, 1.5 g. of potassium carbonate and 0.2 g. of potassium iodide in 50 ml. of dimethylformamide was reacted as described above to give 1-(4,4-diphenyl-3-butenyl)-cis-4-hydroxy-3-piperidinecarboxylic acid methyl ester. This ester (1.4 g., 0.0038 mole) was hydrolyzed in 50 ml. of hot 6 N hydrochloric acid to obtain 1-(4,4-diphenyl-3-butenyl)-cis-4-hydroxy-3-piperidinecarboxylic acid hydrochloride, m.p. 174°-177° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=1>CCO>[Cl:18][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)=[CH:16][C:15]=1[OH:17]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: COc1ccnc(Cl)n1
Solvent: CCO
Product: COc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Temperature: 90 °C
Yield: 57 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-4-methoxypyrimidine (87 mg, 0.60 mmol) and 5-amino-2-chlorophenol (86 mg, 0.60 mmol) in 10% aqueous EtOH (3 mL) was heated at 90° C. for 18 h. The title compound was obtained in 57% yield a (87 mg) and used for the next step without additional purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C@H:8]([C:45]1[C:53]2[S:52][C:51](=[O:54])[NH:50][C:49]=2[C:48]([OH:55])=[CH:47][CH:46]=1)[CH2:9][N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]2[CH2:44][CH2:43][C:31]3([O:36][CH2:35][CH2:34][N:33](C(=O)C(F)(F)F)[CH2:32]3)[CH2:30][CH2:29]2)=[CH:21][CH:20]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>O.CO>[O:36]1[C:31]2([CH2:43][CH2:44][N:28]([CH2:27][CH2:26][O:25][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:10]([CH2:9][C@H:8]([OH:7])[C:45]4[C:53]5[S:52][C:51](=[O:54])[NH:50][C:49]=5[C:48]([OH:55])=[CH:47][CH:46]=4)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CNCCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of potassium carbonate (240 mg) in water (35 mL) was added to a solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(4-(2-(4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)benzyl)carbamate (examples 223-263, step a) (725 mg) in MeOH (35 mL). The resulting mixture was stirred at RT for 5 h. Methanol was removed by evaporation under a stream of nitrogen keeping the reaction mixture at 25° C. Water (20 mL) and brine (30 mL) were added and the mixture was extracted with ethyl acetate (7×30 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-20% (2M NH3 in MeOH)/DCM to give the subtitled compound as a white solid. Yield 385 mg.
Reaction SMILES: [CH2:1]=[N:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:10][N:11]([CH3:23])[C:12](=[O:22])[CH:13]=[C:14]1[C:18](=[O:19])OC(C)(C)[O:15]1>CO>[Cl:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:10][N:11]([CH3:23])[C:12]([C:13]1[CH2:1][N:2]([CH2:3][CH2:4][OH:5])[C:18](=[O:19])[C:14]=1[OH:15])=[O:22]
Reactant: C=NCCO
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCO)C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyleneamino-ethanol (1 mL, 0.1 mmol) in MeOH (1 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (0.036 g, 0.1 mmol). The mixture was stirred at 55° C. for 1 h, cooled and purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA). The title compound was isolated as a white foam (0.018 g, 49% yield). HRMS (M−H) calcd for C15H15N2Cl2O4: 357.04089. found: 357.0396.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[F:16].O1CCOCC1.[NH3:23]>O>[NH2:23][C:4]1[C:3]([F:16])=[C:2]([NH2:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Reaction time: 1.33 h
Yield: 100.1 %

Procedure:
To a stirred solution of methyl 4-amino-2,3-difluoro-5-nitrobenzoate (4) (33.0 g, 142.15 mmol) in 1,4-dioxane (165 mL, 1.93 moles), in a 250 mL glass pressure vessel, was added an aqueous solution of ammonia (39 g, 711 mmol, 42.9 mL, 16.5 M). The vessel was then heated in an immersion bath at a bath temperature between 79 and 105° C., for 80 minutes, over which time the internal pressure ranged between 0.2 and 2.7 bar. The pressure was then released slowly and the mixture was treated with water (330 mL, 10 vol). The resultant suspension was stirred for 20 minutes and then filtered under vacuum, and the solid was washed with water (33 mL, 1 vol). The solid was sucked dry, then dried in a vacuum oven at 50° C. to provide methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (32.6 g, 92% yield) as a yellow solid. 1H NMR (500 MHz, d6 DMSO) δ 3.83, (3H, s, OMe), 7.20 (2H, br, NH2), 7.37 (2H, br, NH2), 8.47 (1H, s, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 52 (CH3), 101 (C), 122 (C), 126 (CH), 134 (C), 137 (C), 142 (C), 166 (C═O). νmax/cm−1 3474, 3358, 1697, 1633, 1528, 1435, 1317, 1285.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 4-Fluoro-3-nitro aniline (0.5 g, 3.2 mmol), 4-bromobenzoyl chloride (0.702 g, 3.2 mmol), diisopropylethylamine (0.56 ml, 3.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hr. The mixture was diluted with dichloromethane (50 mL) and washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound as a yellow solid (0.89 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C[Al](C)C.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:30]=[CH:29][NH:28][C:27]=2[C:31](OC)=[O:32])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:31]([C:27]1[NH:28][CH:29]=[CH:30][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=1)=[O:32]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Agent: C[Al](C)C
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2[nH]ccc2-c2ccc([N+](=O)[O-])cc2)c(OC)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To 2.435 cm3 (15.84 mmol) of 2,4-dimethoxybenzylamine dissolved in 65 cm3 of toluene are added, at a temperature in the region of 20° C. under an argon atmosphere, 10.3 cm3 (20.59 mmol) of a 2M solution of trimethylaluminium in toluene, followed by addition of 1.95 g (7.92 mmol) of methyl 3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate. After stirring for 1 hour at a temperature in the region of 20° C. and then for 16 hours at a temperature in the region of 60° C., the reaction mixture is diluted with 170 cm3 of ethyl acetate. The resulting solution is washed successively with three times 70 cm3 of saturated aqueous ammonium chloride solution and twice 50 cm3 of water and then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a yellow solid, which is then stirred in 20 cm3 of acetonitrile at a temperature in the region of 5° C. for 30 minutes. After filtering through a No. 3 sinter funnel, the solid is washed with 10 cm3 of ice-cold acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 3 hours to give 1.96 g of 2-(2,4-dimethoxybenzylamino)carbonyl-3-(4-nitrophenyl)-1H-pyrrole in the form of a yellow solid; ES+: m/z=382: [M+H]+; ES−: m/z=380: [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][CH3:21])=[N:3]3)=[CH:15][CH:16]=1
Reactant: COc1ccccc1CN
Reactant: Fc1ccc(COc2cccc3nc(Cl)ccc23)cc1
Product: COc1ccccc1CNc1ccc2c(OCc3ccc(F)cc3)cccc2n1

Procedure:
2-Chloro-5-(4-fluoro-benzyloxy)-quinoline (100 mg, 0.35 mmol) and 2-methoxybenzylamine (144 mg, 1.05 mmol) were stirred in a sealed tube at 150° C. for 16 hours. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). 5-(4-Fluorobenzyloxy)-quinolin-2-yl-(2-methoxy-benzyl)-amine was obtained as a yellow oil (57 mg, 42%), MS: m/e=389.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:3]1[C:4]1[N:5]=[N:6][N:7](CC3C=CC(OC)=CC=3)[C:8]=1[CH2:9]2>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:3]1[C:4]1[N:5]=[N:6][NH:7][C:8]=1[CH2:9]2
Reactant: COc1ccc(Cn2nnc3c2CC2CCCC3N2C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C2CCCC1c1nn[nH]c1C2
Yield: 64.7 %

Procedure:
12-Methyl-5-(4-methoxybenzyl)-3,4,5,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (0.5 g, 1.7 mmol) in trifluoroacetic acid (TFA) (6 mL) was heated at 65° C. overnight. The solvent was removed and the residue was purified by prep HPLC to afford the product (200 mg, 1.1 mmol, 65% yield) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]1COCC1.[Si](C=[N+]=[N-])(C)(C)C.C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([N:23]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH3:41])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N[C@@H]2C(=O)NS(=O)(=O)c2ccc(F)cc2)ccn1
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(=O)[C@H]1NC(=O)[C@@H]1Cc1ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 98 (18 mg, 1.0 eq.) in MeOH: THF (1 mL: 300 uL) was added 2.0M TMSCHN2 in hexanes (266 uL, 17 eq.). After 15 minutes, TLC showed complete conversion of starting material. The reaction was poured into ethyl acetate and then washed with 0.2N HCl, 1N NaHCO3 and brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo. The product was then purified via reverse phase HPLC (C18, acetonitrile/water with 0.1% TFA) to yield 99 (11.9 mg, 65%) as a clear oil.