Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (2.00 g, 8.45 mmol) in N,N-dimethylformamide (50 ml) was added 60% sodium hydride (0.34 g, 8.54 mmol), and the reaction mixture was stirred at room temperature until it became transparent. Then, ethyl bromoacetate (1.43 g, 8.54 mmol) was added and the resulting mixture was stirred at 50-60° C. for 4 hours. The reaction mixture was cooled to room temperature and poured into ice water, followed by extraction with ethyl acetate (three times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/95) to obtain ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.[C:11]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[F:34])(O)=[O:12].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[C:28]([F:34])[CH:29]=1
Reactant: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1C(=O)O
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1C(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
3-Morpholinopropylamine (290 mg, 2 mmol) was added to a solution of 6-carboxy-4-(4-chloro-2-fluoroanilino)-7-methoxyquinoline (200 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191 mg, 1 mmol) and 1-hydroybenzotriazole hydrate (135 mg, 1 mmol) in DMF (15 ml). The mixture was stirred at ambient temperature for 2 hours. The solution was partitioned between water (100 ml) and methylene chloride. The organic layer was washed with brine and dried by passing through phase separating paper. The solvent was removed by evaporation and the crude product was purified by flash chromatography eluting with methylene chloride/methanol (99/1 increasing to 90/10). The pure fractions were combined and the solvent was removed by evaporation. The remaining oil was dissolved in methanol and an ethereal solution of hydrogen chloride was added. The solvent was removed by evaporation and the solid was dried overnight in a vacuum 1 oven at 40° C. to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-(N-[3-morpholinopropyl]carbamoyl)quinoline (95 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[NH:34][CH2:35][CH2:36][N:37]=2)[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:21][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]5[NH:34][CH2:35][CH2:36][N:37]=5)[CH:28]=4)=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: Clc1ccnc(C2=NCCN2)c1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1CCc2ccc(Oc3ccnc(C4=NCCN4)c3)cc2C1
Yield: 67.4 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (64 mg, 0.17 mmol) and 4-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)pyridine (35 mg, 0.19 mmol) in DMF (1.70 mL) was added Cs2CO3 (170 mg, 0.52 mmol). The mixture was irradiated in a microwave for 200 sec at 200° C. Water was added, and the mixture was extracted with EtOAc. The organic solution was washed with water (3×) and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography. The product was dissolved in MeOH, and 2.0M HCl in Et2O was added. The solvents were evaporated to give I-36 as a white solid (59 mg, 58%). 1H NMR (300 MHz, CD3OD): δ 8.62 (d, 1H), 8.17 (d, 1H), 7.82-7.78 (m, 1H), 7.63 (d, 1H), 7.53 (d, 1H), 7.25 (d, 1H), 7.21-7.18 (m, 1H), 6.96-6.91 (m, 2H), 4.11 (s, 4H), 3.14-2.82 (m, 5H), 2.24-2.16 (m, 1H), and 2.01-2.90 (m, 1H). LCMS: (FA) ES+ 516.2, ES− 513.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH3:15])=[O:27])=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc([N+](=O)[O-])cc1)CC2

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methyl-isoquinoline (35.2 g, 0.17 m) in methylene chloride (50 ml) under nitrogen at ambient temperature was added p-nitrophenylacetic acid (31.4 g, 0.17 m) and then portionwise dicyclohexylcarbodiimide (37.0 g, 0.18 m) and the mixture stirred for 3 hr. The precipitated solid was removed by filtration and the filtrate evaporated to an oily residue. The residue was treated with 500 ml methanol and the solid precipitate collected by filtration to give, after drying, N-(4-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as a yellow solid, 66.0 g (100+% yield). The product contains a small amount of dicyclohexylurea.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:3]=1.[NH2:25][CH3:26]>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:25][CH3:26])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CN
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 67 °C

Procedure:
To 2-chloro-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonitrile (2.03 g) in THF (14 mL) was added H2NCH3 (13 mL, 2 M solution in THF). The reaction was heated to 67° C. in a closed vessel for 9 hours before concentrating. The product was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 10% EtOAc in hexane affording the title compound. HPLC/MS: 387.8(M+1), 389.8 (M+3); Rt=4.26 min.
Reaction SMILES: N[C@H:2]([C:5](O)=[O:6])C[SeH].[C:8]([CH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([OH:10])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(OCC)C>[C:5]([CH:11]1[C:12]2[C:13](=[CH:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)[C:14](=[O:15])[O:16][C:8]1=[O:10])(=[O:6])[CH3:2]
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Reactant: N[C@@H](C[SeH])C(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reaction time: 3 h

Procedure:
Following a literature procedure (Ind. J. Chem. Sec. B, 1986, 25B, 640-643), 2-carboxymethyl-4-methoxybenzoic acid (1.0 g; 4.8 mmol) was dissolved in a mixture of pyridine (1.4 mL) and acetic anhydride (8.6 mL; 9.3 g; 91 mmol) then stirred for 3 hours, during which time a solid had formed. The suspension was diluted with diethyl ether, filtered and the filter cake washed with diethyl ether. Yield: 905 mg (81%) of 4-acetyl-6-methoxyisochroman-1,3-dione.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].CC#N.O>C1(C)C=CC=CC=1.C(O)C.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:31])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3,7-dimethylnaphthalen-2-yl)acetic acid (78) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using trimethylboroxine and K2CO3 instead of triethylamine, and toluene, ethanol, water as a solvent mixture. 1H-NMR: 400 MHz, (CD3OD) δ: 7.65 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.53 (m, 3H), 7.27 (m, 2H), 6.98 (s, 1H), 5.15 (s, 1H), 2.56 (s, 3H), 2.30 (s, 3H), 0.96 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=4.06.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5](=[O:22])[CH2:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=1>C1COCC1>[F:15][C:10]1[C:11]([O:13][CH3:14])=[N:12][C:7]([CH2:6][C:5]([O-:22])=[O:4])=[N:8][C:9]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1.[Na+:2]
Reactant: COC(=O)Cc1nc(OC)c(F)c(N2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nc(CC(=O)[O-])nc(N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.9 ml of 2N sodium hydroxide are added to a solution of 3.46 g of (5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid methyl ester in 36 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5 so as to give 3.7 g of sodium (5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.C([O-])(O)=O.[Na+].[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][C@H:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1>Cl.CCO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C@H:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][CH:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1
Reactant: Cc1cccc2cc(C(C)Nc3nc(Cl)nc4c3ncn4C3CCCCO3)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc([C@H](C)Nc3nc(Cl)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1cccc2cc(C(C)Nc3nc(Cl)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
3-(1(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H-one (compound 5303) (172 mg, 0.33 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH=7-8, and then extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and recrystallized from ethyl acetate and hexanes. The solid was collected by filtration and dried in vacuo to afford the desired product, 3-(1-(2-chloro-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5304) (128 mg, 90% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[CH3:18])[CH:7]=1.[CH:21](O)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:1][C:2]1[C:3](=[O:20])[N:4]([CH:21]([CH3:23])[CH3:22])[C:5](=[O:19])[N:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[CH3:18])[CH:7]=1
Reactant: CC(C)O
Reactant: Cc1ccc(C(F)(F)F)cc1-n1cc(I)c(=O)[nH]c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)cc1-n1cc(I)c(=O)n(C(C)C)c1=O
Temperature: 25 °C

Procedure:
To a solution of 5-iodo-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 118) (645 mg) in THF (20 ml) were added isopropyl alcohol (0.25 ml), triphenylphosphine (855 mg), diethyl azodicarboxylate (2.2 M toluene solution, 1.48 ml), and the resulting mixture was stirred at room temperature for twenty-five minutes. The reaction solutions were concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-iodo-3-isopropyl-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (548 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][NH2:8].[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]#[N:33])=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][NH:8][C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]#[N:33])[CH:22]=[CH:23][C:12]=1[N+:9]([O-:11])=[O:10])[CH3:19]
Reactant: NCC1OCCCO1
Reactant: CC(Oc1cc(Oc2ccc(F)cc2C#N)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(F)cc2C#N)ccc1[N+](=O)[O-])C(=O)NCC1OCCCO1
Temperature: -15 °C

Procedure:
N-(1,3-Dioxan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-cyano-4-fluorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2-[2-nitro-5-(2-cyano-4-fluorophenoxy)phenoxy]propionamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH:18]1[CH2:19][O:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1ccc(OCC2CO2)c(C(C)(C)C)c1

Procedure:
The title compound was prepared from 2,4-di-tert-butyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][NH2:13])=[O:11].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O.Cl>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]1[O:11][C:10]([CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:12][N:13]=1
Reactant: O=C(Cl)CCCCl
Reactant: NNC(=O)Cc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Cc2nnc(CCCCl)o2)c(F)c1
Reaction time: 1 h

Procedure:
A mixture of 2-(2,4-difluorophenyl)acetohydrazide (570 mg, 3.06 mmol) and DIPEA (0.553 ml, 3.2 mmol) in dry DCM (30 ml) was added to 4-chlorobutyryl chloride (0.343 ml, 3.06 mmol) in dry DCM (5 ml) over 15 min. An immediate white precipitate formed. After stirring for 1 h, 2M HCl (20 ml) was added and the solid 2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole was filtered off, washed with water and dried (726 mg).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]([C@H:14]2[O:23][C@@H:17]3[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]3[CH2:15]2)[CH2:12][CH3:13])=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:22][C:19]1([CH3:21])[O:18][C@H:17]2[O:23][C@H:14]([C@@H:11]([OH:10])[CH2:12][CH3:13])[CH2:15][C@H:16]2[O:20]1
Reactant: CC[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a solution of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl] 4-nitrobenzoate (compound 6d, 100 g, 285 mmol) in methanol (1200 mL) was added K2CO3 (78.7 g, 570 mmol). After being stirred at room temperature for 10 minutes, the resulted mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:8 EtOAc in petroleum ether) to afford 54.7 g of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6e) as a slight yellow solid.
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])C.S([O-])([O-])=[O:21].[Na+].[Na+].Cl>O.O1CCOCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([OH:5])=[O:21])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: O=S([O-])[O-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 64.7 g (1.61 mol) of soda in 560 ml water is prepared at 0° C. 69.9 g (0.44 mol) of bromine then 260 ml of 1,4-dioxane are added successively. A yellow solution is obtained which is cooled down to 0° C. and which is added over 10 minutes, without exceeding 10° C., to a suspension of 28 g (0.12 mol) of 4'-acetyl-4-methoxybiphenyl in a mixture of 750 ml of 1,4-dioxane and 510 ml water. The reaction medium is agitated for 1 hour at approximately 20° C., a solution of 15.5 g of sodium sulphite in 160 ml water is added and taken to reflux for 10 minutes. 76 ml of concentrated hydrochloric acid is added and the reaction medium is left under agitation whilst being cooled down, for 1 hour. After drying, washing with water and drying at 50° C., 25.5 g of 4'-methoxy-4-biphenyl carboxylic acid is obtained in the form of a white powder (yield: 93%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:5]([O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:4]([C@H:5]([O:7][Si:8]([C:21]([CH3:22])([CH3:24])[CH3:23])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[C:3]([OH:33])=[O:2])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 98.7 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester (3.56 g, 7.55 mmol) was taken up in a mixture of tetrahydrofuran (10 mL) and water (3 mL) and cooled using an ice bath. Lithium hydroxide monohydrate (1.27 g, 30.2 mmol) was then added and the reaction was left to stir overnight. The solution was acidified using hydrochloric acid (2 M) until the solution was pH 2. The solution was then extracted with ethyl acetate. The organics were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (3.41 g, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.02-1.11 (m, 21H), 4.26-4.35 (m, 1H), 4.41-4.51 (m, 1H), 5.34 (d, J=9.0 Hz, 1H), 7.35-7.49 (m, 6H), 7.63-7.77 (m, 4H). LCMS (m/z) 458.1 [M+H], Tr=3.68 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH2:34]([NH2:36])[CH3:35]>C(O)CCC>[CH2:34]([NH:36][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1)[CH3:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: CCN
Solvent: CCCCO
Product: CCNc1cc2c(cn1)cc(-c1cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
N-[3-(7-Chloro-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (50 mg, 0.106 mmol) is mixed with ethylamine (0.14 mL 70% in water, 2.2 mmol) in a sealed tube. 1 mL of n-butanol is added and the reaction is stirred at 100° C. for 16 hours. After cooling and removal of solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product as white solid: 1H NMR 400 MHz (DMSO-d6) δ 10.47 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 8.25 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J=7.8 Hz), 7.78 (m, 2H), 7.66 (m, 2H), 7.26 (d, 1H, J=9.0 Hz), 6.46 (s, 1H), 3.57 (s, 3H), 3.39 (q, 2H, J=7.1 Hz), 2.13 (s, 3H), 1.22 (t, 3H, J=7.1 Hz); MS m/z 481.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]([CH3:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:21]O.C(Cl)(Cl)Cl.O1CCCC1.CS(Cl)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]([CH3:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:21][N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: Cc1c(CO)nc2n1-c1ccccc1N(C)c1ccccc1-2
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(CN2CCN(C)CC2)nc2n1-c1ccccc1N(C)c1ccccc1-2
Temperature: -20 °C

Procedure:
A sampmle of 3,9-dimethyl-2-hydroxymethyl-9H-dibenzo[b,f]-imidazo[1,2-d] [1,4]diazepine is suspended in a chloroform/tetrahydrofuran mixture and treated with triethylamine. After cooling to -20° C. methanesulfonyl chloride is added with stirring at -20° C. The mixture is treated with 4-methylpiperazine and warmed gradually to room temperature. Work-up from an aqueous base followed by the usal purification techniques affords the product 3,9-dimethyl-2-(4-methyl-1-piperazinyl)methyl-9H-dibenz[b,f]-imidazo[1,2-d][1,4]diazepine as a yellow oil.