Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH3:9]
Reactant: Cc1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(F)cc(F)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a stirred solution of 2,4-difluorotoluene (25.0 g, 195.3 mmol) in conc. H2SO4 (60 mL) was added fuming HNO3 (30 mL) drop wise at the rate that temperature was maintained between 40-50° C. over a period of 1.5 h. The reaction mixture was stirred at 40° C. for an additional 1 h. The reaction mixture was poured into ice-cold water (500 mL) and the solid precipitated was filtered and washed with water (2×50 mL). The solid residue was dissolved in EtOAc (200 mL), washed with aq. NaHCO3 (2×200 mL). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to afford 1,5-difluoro-2-methyl-3-nitrobenzene (21.0 g, 62%) as a light brown liquid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:21]1[C:20]2[O:26][C:16]([CH2:15][C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)=[N:18][C:19]=2[CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH:30]=[CH2:31]
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Yield: 52 %

Procedure:
A solution of N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline (38.1 g, 0.092 mol) in 200 ml of diphenyl ether was heated under nitrogen at 180° for 8 hours. Protracted heating resulted in reduced yields. The reaction mixture was diluted with 500 ml of petroleum ether, applied to a column packed with 500 g of flash chromatography silica gel and eluted with petroleum ether followed by methylene chloride. Fractions of 800 ml were collected. The material from fractions 9-14 weighed 30 g (80% of theoretical). This material was recrystallized from hexane to give 19 g (52%) of the title compound, mp 43-44° C., which was greater than 98.3% pure by HPLC.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Product: COC(=O)[C@H]1C[C@@H](O)CN1c1ccccc1[N+](=O)[O-]
Yield: 97.2 %

Procedure:
The same procedures used in Reference Example 1 were repeated except for using the cis-4-hydroxy-D-proline methyl ester hydrochloride prepared in Reference Example 4 and 1-fluoro-2-nitrobenzene to give the title compound. Yield 97.2%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:14](=O)[CH3:15])[C:6](=O)[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].O.[NH2:19][NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:19][NH:20][C:14]=1[CH3:15])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)COC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(COC(C)(C)C)n[nH]c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester [0.325 g, Reference Example 46] in acetic acid (3 ml) was added hydrazine hydrate (71 μL). The mixture was stirred at ambient temperature for 16 hours and then evaporated to remove the acetic acid. The residue was dissolved in ethyl acetate and the solution was washed with 5% sodium hydrogen carbonate solution, then with water, then dried over magnesium sulfate, and then evaporated to yield 3-tert-butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.258 g) as a yellow oil which was used without further purification. LC-MS (METHOD B): RT=3.22 minutes; 241 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:20]([C:21](=[O:23])[CH3:22])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6′-acetylamino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-5b (36.9 mg, 0.11 mmol) and 1-bromomethyl-3-chloro-benzene (15.8 μL, 0.12 mmol) in DMF (1.1 mL) at room temperature was added 60% NaH in mineral oil (5 mg, 0.13 mmol). After stirring at room temperature for 4 h, the reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with H2O (3×10 mL), brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude material was purified by preparative TLC using 50% ethyl acetate/ether with 1% NH4OH to afford the title compound I-5c (27.1 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:9]2[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C:11]=3[C:12](=[O:13])[N:7]([OH:6])[C:8]2=[O:21])=[CH:31][CH:30]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2oc3ccccc3c2n(Cc2ccc(Br)cc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 4-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.52 (s, 2H); 7.29-7.40 (m, 3H); 7.52 (d, J=8 Hz, 2H); 7.60 (dd, J=8 Hz, 1H); 7.75-7.81 (m, 2H); Ret. time=2.70 min., m/z=387.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:7][C:6]4[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Fc1ccc(C(F)(F)F)c(CCl)c1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (40% yield). 1H NMR (300 MHz, CDCl3) δ 7.95-8.01, 7.57-7.68, 7.04, 6.95, 3.79, 3.71, 3.56, 2.64, 1.51, 0.68-0.82, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: O=Cc1ccccc1-c1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1-c1cnccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-pyrazin-2-ylbenzaldehyde (9.9 mmol from the previous step) in absolute MeOH (100 mL) at 0° C. was added sodium borohydride (420 mg, 11.1 mmol) in portions. The mixture was allowed to warm to room temperature and stirred under N2 atmosphere for 2 h. The solvent was removed in vacuo and the residue was treated with saturated aqueous NH4Cl. The mixture was extracted twice with EtOAc and the combined organic extracts were washed successively with H2O and brine, dried (MgSO4), filtered and concentrated to give a brown oil. Silica gel chromatography (70% EtOAc-hexanes) afforded the title compound as a pale red-brown oil. 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1 H), 8.65–8.61 (m, 2 H), 7.62–7.46 (m, 4 H), 5.18 (t, J=7.2 Hz, 1 H), 4.49 (d, J=7.2 Hz, 2 H). LCMS (M+H): 186.9.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[C:5]=12.[K+].[Br-]>>[CH3:10][C:6]1[C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccn2ccnc12
Agent: [Br-]
Agent: [K+]
Product: Cc1cccn2ccnc12
Yield: 10 %

Procedure:
From 4a (yield: 10%); mp: 150-152° C.; IR (KBr) 2100, 1700, 1600, 1280 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.41 (t, 3H, J=7 Hz), 4.39 (q, 2H, J=7 Hz), 6.83 (t, 1H, J=7 Hz), 7.57 (d, 1H, J=1 Hz), 7.61 (d, 1H, J=1 Hz), 7.76 (s, 1H), 8.06 (dd, 1H, J=7, 1 Hz), 8.17 (dd, 1H, J=7, 1 Hz). MS m/z 257 (M+, 1), 229 (61), 183 (100), 155 (31), 129 (23), 104 (14). Further elution gave 8-methylimidazo[1,2-a]pyridine (yield: 10%-Kaiser, C. and al. J. Med. Chem. 1992, 35, 4415-4424).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH3:30].[Li+].[Br-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)([OH:16])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: -90 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a solution of 11.7 g (32.0 mmol) of 17 in 260 mL of THF, 37 mL (33.6 mmol) of 0.91 M MeLi*LiBr in THF was added dropwise with vigorous stirring for 20 min at −90° C. The reaction mixture was slowly warmed to room temperature and 50 mL of water was added. The organic solvent was evaporated using a rotary evaporator. The crude product was extracted from the residue with 2×100 mL of dichloromethane. The combined extract was dried over Na2SO4 and then evaporated to dryness. This procedure gave 12.0 g (98%) of 18.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[C@@H:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12]>CC(O)=O>[F:8][C:7]1[C:2]2[NH:1][C:10]([C@@H:11]([NH2:13])[CH3:12])=[N:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(F)c1N
Solvent: CC(=O)O
Product: C[C@H](N)c1nc2cccc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of (S)-tert-butyl 1-(2-amino-3-fluorophenylamino)-1-oxopropan-2-ylcarbamate (2.08 g, 7.00 mmol) in AcOH (30 mL) was heated at 65° C. for 2 h, cooled to rt. After being concentrated under reduced pressure, the residue was subjected to 4 M HCl in 1,4-Dioxane (20 mL). The resultant mixture was stirred at rt for 40 min. The mixture was concentrated under reduced pressure and dissolved in water (10 mL) and then basified with 1 N NaOH to pH 9.5. The mixture was concentrated under reduced pressure. The residue was triturated with MeOH-DCM (1:1). The crude product was purified by column chromatography on a silica gel column using DCM-MeOH—NH4OH (9:1:0.05) as eluent to give (S)-1-(7-fluoro-1H-benzo[d]imidazol-2-yl)ethanamine: LC-MS (ESI) m/z 180.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8](Br)([CH3:10])[CH3:9].[Cl:14][C:15]1[C:20]([OH:21])=[CH:19][C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[C:17]([F:35])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([O:21][C:20]1[CH:19]=[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:17]([F:35])=[CH:16][C:15]=1[Cl:14])([CH3:10])[CH3:9]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)CCNC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCNC(=O)C(C)(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 63.8 %

Procedure:
3-(2-Bromo-2-methylpropionylamino)propionic acid methyl ester (224 mg) and 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-1H-pyrimidin-2,4-dione (250 mg) were dissolved in acetonitrile 5 ml. After addition of K2CO3 (204 mg), the reaction mixture was heated for 12 hours under reflux, cooled and diluted with ethyl acetate (50 mL). After washing with water (50 mL), thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (240 mg).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])(C)(C)C.[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([O:21]C)=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C1COCC1>[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH2:2][C:1]#[N:3])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc2cnccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of ACN (1.8 g, 43 mmol) in 90 mL of THF at −78° C. was added tert-butyllithium (25 mL, 1.7 M in heptane). After 20 minutes, methyl isoquinoline-6-carboxylate (2.0 g, 11 mmol) was added slowly in 10 mL of THF. After 1 hour, the reaction was quenched with 100 mL of aqueous NH4Cl and warmed to room temperature. The biphasic mixture was extracted twice with 100 mL of EtOAc, and the combined organic extracts were washed with 100 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded 3-(isoquinolin-6-yl)-3-oxopropanenitrile (2.1 g, 100% yield crude). The product thus obtained was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].C(N(C(C)C)C(C)C)C.Cl[CH2:23][O:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:23][O:24][CH3:25]
Reactant: COCCl
Reactant: Oc1cccc2c(F)cccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc2c(F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of 0.257 g of 5-fluoro-1-hydroxynaphthalene in 6 ml of dry dichloromethane was cooled in an ice/salt bath after which was added 0.36 ml (2.07 mmol) of ethyl diisopropylamine followed by 0.15 ml (0.16 g, 1.96 mmol) of chloromethylmethyl ether. The mixture was stirred at 0° C. for 0.5 h after which it was allowed to warm to RT and stirred at RT for 11 h. The mixture was poured into saturated sodium carbonate solution, extracted twice with dichloromethane, dried, filtered and concentrated to an oil. The material was dissolved in a minimum volume of dichloromethane and flash chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 0.260 g (79%) of 5-fluoro-1-methoxymethyloxynaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=4)=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=4)=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-{[3-(4-fluorophenyl)-1H-indazol-5-yl]carbonylamino}benzoate (112 mg, 0.29 mmol) in methanol (20 mL) and water (20 mL) was added sodium hydroxide (25 mg, 0.64 mmol). The solution was stirred at room temperature for 2 hours when it was acidified and the methanol removed under vacuo. The resulting solid was filtered and dried to recover the product (55 mg, 51%). 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 12.8 (br s, 1H), 10.6 (s, 1H), 8.69 (s, 1H), 8.12 (dd, 2H), 8.0 (d, 1H), 7.94 (s, 4H), 7.70 (d, 1H), 7.41 (t, 2H); ES-MS (m/z) 376 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[C:36](O)(=O)[CH3:37]>>[CH3:18][N:15]1[C:14]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:36]1[CH3:37])=[N:10][C:11]=2[N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Yield: 21.1 %

Procedure:
A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (177 mg, 0.368 mmol) in acetic acid (1.5 mL) was stirred at reflux for 5 hours. The reaction mixture was then concentrated and then purified first by flash chromatography (10% MeOH in DCM containing 1% 2 M ammonia in MeOH), followed by RP-HPLC to give 157 (0.0373 g, 21.1%). LCMS: M+H+=505.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.09 (m, 1H), 7.60 (m, 1H), 7.25 (m, 2H), 4.26 (s, br, 4H), 4.02 (s, 1H), 3.83 (s, 3H), 3.78 (m, 4H), 3.73 (s, 2H), 2.90 (m, 2H), 2.84 (s, 3H), 1.99 (m, 2H), 1.66 (m, 2H), 1.21 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34]>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCCO
Solvent: OCCOCCO
Product: Cc1cc(F)ccc1N1CCc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in diethylene glycol(10 ml) and 4-amino-1-butanol(4 ml) was added. The reaction mixture was reacted at the same condition of Step 3 in the Example 42 to obtain 550 mg of desired compound as solid in 86% of yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: Fc1cccc2cc[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1cccc2c1NCC2
Reaction time: 1 h
Yield: 54.2 %

Procedure:
7-fluoroindole (2.0 g, 14.8 mmol) was dissolved in acetic acid (6 mL) and sodium cyanoborohydride (1.87 g, 29.6 mmol) was added in 5 portions. The mixture was stirred for 1 hour then poured into 150 mL of 2N NaOH. The mixture was extracted with methylene chloride. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give 7-fluoroindoline (1.1 g).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=1)[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1
Reactant: COc1cccc(C(N)COc2noc3ccc(Cl)cc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(COc1noc2ccc(Cl)cc12)c1cccc(O)c1

Procedure:
To a solution of 2.3 g of 3-[2-amino-2-(3-methoxyphenyl)ethoxy]-5-chloro-1,2-benzoisoxazole in 20 ml of methylene chloride is dropwise added 22 ml of a methylene chloride solution (1.0M) of boron tribromide over 15 minutes with ice-cooling, and they are subjected to reaction at the same temperature for 30 minutes. Subsequently, insolubles are removed by filtration, and water and ethyl acetate are added to the filtrate. The pH is adjusted to 8.5 with a 10% aqueous sodium hydroxide solution, and after shaking, the crystals precipitated are collected by filtration. The organic layer of the filtrate is separated, and the organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The crystals obtained are combined with the crystals previously obtained by filtration and dried, to obtain 2.0 g of colorless, crystalline 3-[2-amino-2-(3-hydroxyphenyl)ethoxy]-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of 4-trifluoromethyl-phenylamine (2.6 mL, 21 mmol) and 3-nitro-benzaldehyde (3.44 g, 23 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 3 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford (3-nitro-benzylidene)-(4-trifluoromethyl-phenyl)-amine (5.88 g, 95%) as a light yellow oil: LC/MS m/e calcd for C14H9F3N2O2 (M+H)+: 295.24, observed: 295.1.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]3[O:15][CH2:14][CH2:13][N:9]3[C:10](=[O:12])[NH:11][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:18]=1.Cl.O1CCOCC1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:2]3[C:7]4[CH:8]5[O:15][CH2:14][CH2:13][N:9]5[C:10](=[O:12])[NH:11][C:6]=4[N:5]=[CH:4][CH:3]=3)=[CH:22][CH:21]=2)=[O:36])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:27]=1
Reactant: O=C1Nc2nccc(Cl)c2C2OCCN12
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Nc2ccnc3c2C2OCCN2C(=O)N3)cc1)c1ccc(F)cc1C(F)(F)F
Reaction time: 1 h

Procedure:
42 (16 mg, 0.07 mmol), N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl) benzamide (22 mg, 0.07 mmol), and 4.0M HCl in dioxane (18 μl, 0.07 mmol) were suspended in a sealed tube, and placed in microwave at 140° C. for 1 h. The crude product was purified directly via HPLC to provide 43. LC-MS (M+H=488, obsd.=488).