Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:23])[CH2:18][CH2:19][N:20]=[C:21]=[S:22]>>[CH3:16][N:17]([CH3:23])[CH2:18][CH2:19][NH:20][C:21]([NH:3][CH2:2][CH2:1][NH:4][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[S:22]
Reactant: CN(C)CCN=C=S
Reactant: NCCN
Reactant: ClCc1nc2ccccc2[nH]1
Product: CN(C)CCNC(=S)NCCNCc1nc2ccccc2[nH]1

Procedure:
N-(2-Benzimidiazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 2-chloromethyl-benzimidazole by the procedure of Example 40, is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 to give the title compound.
Reaction SMILES: B(Br)(Br)Br.CSC.[C:8]([CH2:11][NH:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3([C:30]4[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=4)[CH2:29][CH2:28]3)=[O:26])=[CH:20][CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9].O>ClCCl>[C:8]([CH2:11][NH:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)=[O:26])=[CH:22][CH:23]=2)[CH2:14]1)(=[O:10])[CH3:9]
Reactant: COc1ccc(C2(C(=O)Nc3ccc(N4CCC(NCC(C)=O)C4)cc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)C3(c4ccc(O)cc4)CC3)cc2)C1

Procedure:
Boron tribromide-dimethyl sulfide (460 mg) was added to a solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (540 mg) in dichloromethane (5.5 ml) at 0° C. After a reaction time of 12 hours at room temperature, water was added to the mixture, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated and purified by chromatography (silica gel, toluene/ethanol/ethyl acetate 8:1:1 with addition of 0.1% triethylamine). This resulted in the product with the molecular weight of 393.49 (C23H27N3O3); MS(ESI): 394 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[F-].[K+].CC[N:31](C(C)C)[CH:32]([CH3:34])[CH3:33].CC(N)C>CS(C)=O.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:31][CH:32]([CH3:34])[CH3:33])[CH2:13][CH2:14]1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC(C)N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Nc1nc2cnccc2nc1N1CCN(Cc2ccc(F)cc2F)CC1
Temperature: 23 °C
Reaction time: 22 h
Yield: 60 %

Procedure:
To a flask charged with 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (2.34 g, 6.23 mmol) and potassium fluoride (0.470 g, 8.09 mmol) in DMSO (12 mL) was added DIPEA (2.169 mL, 12.45 mmol) and propan-2-amine (1.605 mL, 18.68 mmol) at 23° C. The reaction was stirred at 23° C. for 22 hr and diluted with water (48 mL) to furnish an orange, oily sludge. The crude product was extracted with EtOAc (25 mL) to furnish a suspension. The resulting solid was filtered, rinsed with EtOAc, and the filtrate was allowed to separate into two layers. The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a 20% to 100% gradient eluant of EtOAc in heptane on an NH 60 μM, size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (1.489 g, 60.0%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.4 Hz, 6H), 2.62 (t, J=4.9 Hz, 4H), 3.34-3.41 (m, 4H), 3.59 (s, 2H), 4.22-4.42 (m, 1H), 6.46 (d, J=7.8 Hz, 1H), 7.04-7.17 (m, 1H), 7.22 (td, J=10.0, 2.4 Hz, 1H), 7.40-7.44 (m, 1H), 7.49 (td, J=8.5, 6.8 Hz, 1H), 8.27 (d, J=5.9 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 399.0.
Reaction SMILES: [I:1]Cl.[N+:3]([C:6]1[C:7]([Cl:13])=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])([O-:5])=[O:4].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:12]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([Cl:13])[C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: Nc1cccc([N+](=O)[O-])c1Cl
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(I)c([N+](=O)[O-])c1Cl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Iodine monochloride (1.25 ml) was added to a solution of 3-nitro-2-chloroaniline (4265 mg) in glacial acetic acid (40 ml). The mixture was stirred for four hours at 70° C. After the mixture was allowed to cool to ambient temperature, saturated sodium sulphite solution (100 ml) was added. The solution was extracted with EtOAc (200 ml), volatile material was removed by evaporation and the residue was redissolved in EtOAc (150 ml), washed with saturated sodium bicarbonate solution (75 ml), brine (75 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography eluting with 5-15% EtOAc in hexane to give a mixture of the title compound and the starting material (1.933 g) (ratio 1:1.75). Iodine monochloride (0.28 ml) was added to a solution of the mixture (1919 mg) in glacial acetic acid (10 ml). The mixture was stirred for four hours at 70° C. After the mixture was allowed to cool to ambient temperature, saturated sodium sulphite solution (50 ml) added. The solution was extracted with EtOAc (100 ml), volatile material was removed by evaporation and the residue was partitioned between EtOAc (100 ml) and saturated sodium bicarbonate solution (50 ml). The organic phase was separated, washed with brine (50 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography eluting with 5-15% EtOAc in hexane to give the title compound (1286 mg) as a solid. NMR: 6.19 (s, 2H), 6.73 (d, 1H), 7.50 (d, 1H); m/z 297.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.Cl.C(Cl)Cl.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:36]>O.C(OCC)(=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:36])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1ccccc1C(=O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1C(=O)c1cnc2ccccc2c1
Reaction time: 45 h
Yield: 36 %

Procedure:
N-Boc-glycine (84.7 mg, 0.48 mmol) and EDCI HCl (92.6 mg, 0.48 mmol) were added to 6 mL of methylene chloride solution of (2-aminophenyl)-quinolin-3-yl-methanone (0.12 g, 0.48 mmol) under a nitrogen atmosphere at 0° C., followed by bringing back to room temperature and stirring for 45 hours. The resulting reaction solution was poured into 10 mL of ethyl acetate and 50 mL of water, and the aqueous layer was extracted with 100 mL of ethyl acetate, followed by washing the combined organic layer with 50 mL of brine and drying with magnesium sulfate. After filtering and concentrating, the resulting residue was purified by silica gel column chromatography to obtain {[2-(quinoline-3-carbonyl)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (0.07 g, yield: 36%), which was slightly yellow amorphous. Moreover, 1 mL of trifluoroacetic acid was added to this compound, followed by stirring at room temperature for 16 hours. The resulting reaction solution was poured into a mixture of 10 mL of ethyl acetate, 50 mL of saturated sodium bicarbonate water and 50 mL of water, the aqueous layer was extracted with 100 mL of ethyl acetate, and the combined organic layer was washed with 50 mL of brine, followed by extracting with magnesium sulfate. After filtering and concentrating, the resulting residue was dissolved in 10 mL of ethanol, and 0.5 g of acetic acid was added to the resulting solution. The solution was heated to reflux, and maintained for 30 minutes. The reaction solution was poured into a mixture of 100 mL of ethyl acetate, 50 mL of saturated sodium bicarbonate water and 50 mL of water, and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic layer was washed with 50 mL of brine, followed by drying with magnesium sulfate. After filtering and concentrating, the resulting residue was purified by silica gel column chromatography to obtain the target compound (0.03 g, yield: 61%), which was slightly yellow amorphous.
Reaction SMILES: [CH2:1]([CH2:13][CH2:14][NH2:15])[CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[C:16]([O:25][CH2:26][CH3:27])(=[O:24])/[CH:17]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[O:24]=[C:16]([CH2:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:15][CH2:14][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:17]([C:16]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:25][CH2:26][CH3:27]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NCCCCCCNCCCCCCN
Product: CCOC(=O)CC(NCCCCCCNCCCCCCNC(CC(=O)OCC)C(=O)OCC)C(=O)OCC
Yield: 100.7 %

Procedure:
Analogously to (1), 154 g (0.72 mol) of bis(hexamethylene)triamine and 246 g (1.42 mol) of diethyl maleate were used to obtain 400 g of the product as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=3[F:31])[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:22]=2[CH3:39])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COc1cc(-c2ncc(Br)cc2N)c(F)cn1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c(F)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-amine (54.1 mg, 0.18 mmol) in dry DMF (3 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (22.1 mg, 0.55 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (55.7 mg, 0.19 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted 5 times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a yellow residue as N-(5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine that was used without further purification.
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]5)[CH2:25][O:24]6)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].O1CCCC1.C(O)C>O>[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]5)[CH2:25][O:24]6)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)OC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A flask was charged with methyl 2-(1-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (0.040 g, 0.034 mmol), lithium hydroxide monohydrate (0.043 g, 1.040 mmol), tetrahydrofuran (1 ml), ethanol (0.3 ml) and water (0.3 ml), and stirred at 50° C. for 2 hours. The mixture was purified by HPLC (0.1% NH4OH, 10-50% acetonitrile/water, 20 minutes run, retention time ˜7 minutes) to afford {1-[4′-(5-cyclobutyl-[1,3,4]oxadiazol-2-ylamino)-biphenyl-4-yl]-2-oxa-bicyclo[2.2.2]oct-4-yl}-acetic acid (6 mg, 39%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.89 (m, 5H) 1.89-2.00 (m, 1H) 2.00-2.14 (m, 5H) 2.26-2.39 (m, 5H) 3.62-3.73 (m, 1H) 3.86 (s, 2H) 7.43 (d, J=8.40 Hz, 2H) 7.55 (d, J=8.50 Hz, 2H) 7.62 (s, 4H) 10.39-10.59 (br. s, 1H). LC/MS, [MS+] 459.22, RT: 2.61 (Condition M).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[C:11]1[C:16]([CH:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:15][N:14]=[C:13]2[S:27][C:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:12]=12.O1CCC[CH2:35]1>>[CH3:35][C:15]1[N:14]=[C:13]2[S:27][C:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:12]2=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]=1[CH:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(OC(C)(C)C)c1cnc2sc3c(c2c1I)CCCC3
Reactant: C1CCOC1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Oc1ccccc1)CCCC3
Temperature: 100 °C
Yield: 39 %

Procedure:
Phenol (11.93 mg, 0.127 mmol) was placed in a 2 ml biotage tube, dissolved in tetrahydrofuran (300 μl) and sodium hydride (60%, 5.07 mg, 0.127 mmol) was added. The tube was purged with nitrogen and sealed. After 10 min. a solution of Methyl 2-[4-iodo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (50 mg, 0.106 mmol) in tetrahydrofuran (300 μl) was added dropwise and the mixture was heated in a sand bath at 100° C. overnight. After cooling, the mixture was partitioned between water and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane to provide 18 mg (39%) of the title compound as an oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[NH:17][C:18]([CH2:23][OH:24])=[C:19](CO)[N:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.COC(O)C>O1CCOCC1>[CH2:9]([C:16]1[NH:17][C:18]([CH2:23][OH:24])=[C:19]([Br:1])[N:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1nc(Cc2ccccc2)[nH]c1CO
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)O
Solvent: C1COCCO1
Product: OCc1[nH]c(Cc2ccccc2)nc1Br

Procedure:
3.56 Grams (20 mmol) of the N-bromosuccinimide was added to a solution consisting of 4.86 g (20 mmol) of the 2-benzyl-4,5-bis(hydroxymethyl) imidazole, 80 mol of methoxyethanol and 30 ml of dioxane maintained at a temperature of 45° to 50° C. with stirring. The mixture was further reacted at the same temperature for 24 hours with stirring and, then, the solvent was distilled off under reduced pressure. The obtained reaction product was washed with water and was recrystallized from acetonitrile to obtain a 2-benzyl-4-bromo-5-(hydroxymethyl) imidazole in an amount of 2.1 g (yield, 39%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1.CCOCC>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:7]1[C:2]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Yield: 81.4 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (10.6 g), p-tolylboronic acid (19.69 g) and tetrakis(triphenylphosphine)palladium (O) (0.16 g) in 2N sodium carbonate solution (100 ml) and dimethoxyethane (100 ml) was heated to reflux under nitrogen. After 64 h the mixture was cooled then filtered through hyflo eluting with more dimethoxyethane. The filtrate was evaporated in vacuo to give an oil which was redissolved with ether (300 ml) and washed with 5N sodium hydroxide solution (300 ml). The aqueous portion was further extracted with ether (300 ml×2). The combined organic extracts ware washed with water (200 ml), 1N hydrochloric acid (2×100 ml) and saturated brine. were dried (MgSO4) and evaporated in vacuo. The resultant crystalline solid was triturated with hexane to give the title compound as a yellow crystalline solid (11.66 g). T.l.c.(Hexanelethylacetate (2:1)), Rf 0.52,
Reaction SMILES: O[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Cl
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Ethyl 5-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazole-4-carboxylate (i.e. the product of Step B, 10.0 g, 36.1 mmol) was suspended in anhydrous toluene (300 mL) under a nitrogen atmosphere. Phosphorus pentachloride (8.3 g, 39.8 mmol) was added and the mixture was stirred at 40° C. for 90 min. during which time a clear yellow solution was formed. The reaction was concentrated under reduced pressure to remove most of the toluene. The resulting residue was diluted with diethyl ether (150 mL) and washed with saturated aqueous sodium bicarbonate solution (70 mL) and water (70 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was recrystallized twice from hexanes (200 mL, 100 mL) to afford the title compound (6.0 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:3]=1.[BH4-].[Na+].S(Cl)(Cl)=O.[CH3:23][N:24]1[CH:28]=[C:27]([CH2:29][C:30]2[C:31](=[O:37])[NH:32][C:33](=[S:36])[NH:34][CH:35]=2)[CH:26]=[N:25]1>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][S:36][C:33]3[NH:34][CH:35]=[C:30]([CH2:29][C:27]4[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=4)[C:31](=[O:37])[N:32]=3)=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: O=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4cc(Cl)ccn4)cc3)nc2=O)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 4-[(4-chloro-2-pyridinyl)oxy]benzaldehyde (120 mg, 0.514 mmol), (which may be prepared according to procedures described in the International Patent Application Publication No. WO 199847869) in methanol (2.0 mL) was added NaBH4 (23.32 mg, 0.616 mmol). After the suspended solution turned clear, it was quenched with water. The mixture was extracted with EA and concentrated. After removing the solvent, thionyl chloride (0.187 mL, 2.57 mmol) and DCM (2 mL) was added, and stirring continued overnight. Then 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (114 mg, 0.514 mmol) was added. The reaction mixture was heated at 60° C. for 0.5 h. Purification via MDAP then afforded the title compound (132 mg, 58.4% yield). LCMS: rt=2.84 min, [M+H+]=440
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][C:9]2[O:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)[Cl:18]>S(Cl)(Cl)=O.CN(C=O)C>[ClH:18].[N:2]1([CH2:8][C:9]2[O:13][C:12]([C:14]([Cl:1])=[O:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(CN2CCOCC2)o1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CN2CCOCC2)o1
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid hydrochloride in thionyl chloride with 2 drops of DMF was refluxed under N2 for 3 hours, then cooled to room temperature. Dry CH2Cl2 was added and solvents were evaporated in vacuo. The residue was triturated with dry CH2Cl2, and the resulting solid was filtered, washed with dry CH2Cl2 and dried in vacuo to give 373 mg (83% yield) of 5-morpholin-4-ylmethyl-furan-2-carbonyl chloride hydrochloride as a white solid. 1H-NMR (d6-DMSO) δ: 11.54 (broad s, 1H), 7.26 (d, 1H), 6.92 (d, 1H), 4.49 (s, 2H), 3.94 (m, 2H), 3.74 (m, 2H), 3.28 (m, 2H), 3.09 (broad s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][C@@H:33]1[O:37][C:36](=[O:38])[NH:35][CH2:34]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:35]5[CH2:34][C@H:33]([CH3:32])[O:37][C:36]5=[O:38])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: C[C@H]1CNC(=O)O1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(S(C)(=O)=O)c2)C(=O)O1
Yield: 62.1 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (400 mg) described in Preparation Example 89 and (S)-5-methyloxazolidin-2-one (80.2 mg) described in Preparation Example 42, the title compound (258.4 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:18][CH2:17]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17]1
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CC2)C1C
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC1)C(C)C(C)C(=O)N2C
Yield: 70.5 %

Procedure:
A mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-cyclopropyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-46), 0.10 g (0.0006 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.145 g of (rac)-4-(9-cyclopropyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-46a) as an off-white solid.