Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:33])[CH:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]2[C:13]([CH3:32])=[C:14]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:5]=2[O:4]1.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:2][C:3]1([CH3:33])[CH:7]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[C:6]2[C:13]([CH3:32])=[C:14]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:5]=2[O:4]1
Reactant: Cc1c(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 4N hydrogenchloride in ethyl acetate (20 ml) was added to a solution of tert butyl 4-(2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazinecarboxylate (3.55 g, 8 mmol) obtained in Example 132 in THF (20 mL) and ethyl acetate (20 ml) and the mixture was stirred at 60° C. for 3 hours. The resulting mixture was cooled to 0° C. made to weakly alkaline using 1N sodium hydroxide aqueous, and extracted with ethyl acetate. The organic extract was washed using saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain 2.72 g (yield 100%) of the title compound as an amorphous powder.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[Cl:23].[CH3:24][S:25]SC.Cl>O1CCCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([S:25][CH3:24])[C:15]=1[Cl:23]
Reactant: CSSC
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1c(C(=O)O)ccc(Br)c1Cl
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
n-Butyllithium (2.5M in hexane; 8.8 ml) was added to a stirred cooled solution of di-isopropylamine (2.22 g) in dry tetrahydrofuran, maintaining the temperature below -40° C. The mixture was stirred for 0.5 hours then a solution of 4-bromo-3-chlorobenzoic acid (2.36 g) in dry tetrahydrofuran was added. The mixture was stirred at -40° C. for 6 hours. Dimethyl disulphide (2.82 g) was added and the mixture was stirred at -40° C. for 1 hour and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The organic layer was washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-bromo-3-chloro-2-methylsulphenylbenzoic acid (0.98 g) as a solid, m.p. 128°-130° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([OH:16])([CH3:15])[CH3:14].[B:17](OC)(OC)[O:18]C>C1COCC1>[CH3:14][C:13]1([CH3:15])[O:16][B:17]([OH:18])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: CC(C)(O)c1ccccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of n-BuLi (21.2 ml, 0.053 mol) in anhydrous THF (160 mL) at −78° C. under argon was slowly added a solution of 2-(2-bromophenyl)propan-2-ol (XCV) (0.0212 mol, 4.55 g) in anhydrous THF (50 mL) while maintaining the temperature below −65° C. After addition was complete, the reaction mixture was stirred at −75° C. for 30 min. To this mixture was added in portions trimethyl borate (0.032 mol, 3.3 g), and the reaction mixture was stirred at −78° C. for 30 min and then at room temperature overnight. The mixture was cooled to 0° C., carefully quenched with 1M aqueous HCl, and stirred at room temperature for 15 min. The mixture was acidified to pH 3 with 2M HCl and stirring was continued for 1 hour. The two phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over MgSO4. The crude product was purified by silica gel chromatography using DCM followed by DCM/MeOH 300/1 to give 3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVI) as a light yellow oil (1.37 g; 8.5 mmol, 40% yield). 1H NMR (CDCl3) δ ppm 1.54 (s, 6H), 7.25-7.29 (m, 1H), 7.33 (d, J=7 Hz, 1H), 7.45 (td, J=7 Hz, J=1 Hz, 1H), 7.68 (d, J=7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][C:25](F)=[CH:26][CH:27]=3)[C:22]2=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][OH:33].Cl.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[N:32][OH:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2Cc3ccc(F)cc3C2=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2Cc3ccccc3C2=NO)C1
Temperature: 100 °C

Procedure:
The title compound of Step A was dissolved into MeOH (2 mL), then NH2OH HCl (1 mmol) and K2CO3 (2 mmol) were added. The mixture was heated at 100° C. using a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (120 mg).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH3:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH3:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 102b (3 g, 5.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (3.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=3[CH:3]=2)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)OCC(=S)N2
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)OCC(=S)N2)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazin-3-thione and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 193-196° C. (diethylether)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:15])[N:10]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)sc1C
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(-c2c[nH]c(=O)n(C(=O)c3ccccc3)c2=O)sc1C
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
(5-(4,5-dimethyl-1,3-thiazol-2-yl)-2,4(1H,3H)-pyrimidinedione) (Prep 15, 100 mg) suspended in Pyridine (2 mL) was slowly added to a stirring solution of benzoyl chloride (0.156 ml, 1.344 mmol) in Pyridine (1 mL) under nitrogen atmosphere. The resulting yellow solution was stirred at rt for 5.5 hours. Water was added (3 mL) and the mixture was extracted with EtOAc (10 mL). The organic was washed with NH4Cl saturated aqueous solution (2×2 mL) dried (Na2SO4, vacuo) to afford 340 mg of a yellowish solid that was dissolved in EtOAc (30 mL) and washed with NaHCO3 aqueous saturated solution. The organic was dried (Na2SO4, vacuo) to afford the title compound as a yellowish solid (180 mg)
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[N:24](/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C1COCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27]
Reactant: Clc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)/N=N\C(=O)OC(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a stirred solution of 2.5 M Butyllithium in hexanes (13.79 mL, 34.47 mmol) at −20° C. was added dropwise 2,2,6,6-tetramethylpiperidine (5.82 mL, 34.47 mmol) in THF (30 mL). This was stirred for 30 minutes. This solution was cooled down to −78° C., and a solution of 1-bromo-3-chlorobenzene (6 g, 31.34 mmol) in THF (20 mL) was added dropwise so as to maintain the temperature at <−70° C. After 2 hours (Z)-di-tert-butyl diazene-1,2-dicarboxylate (10.82 g, 47.01 mmol) in THF (30 mL) added dropwise at −78° C. Stirred at this temperature for 2 hours, then allowed to warm to room temperature overnight. Water (150 mL) added. The mixture was extracted with EtOAc (2×300 mL). The extracts were combined, washed with brine (100 mL), dried (MgSO4) and reduced go give a residue which was purified by flash silica chromatography, elution gradient 0-10% EtOAc in hexane. Fractions containing suspected product were combined, and reduced to give di-tert-butyl 1-(2-bromo-6-chlorophenyl)hydrazine-1,2-dicarboxylate (9.59 g, 72.5%) 1H NMR (400 MHz, DMSO) δ 1.30-1.50 (18H, s), 7.28 (1H, m), 7.55 (1H, dd), 7.67 (1H, dd), 9.18 (1H, s). m/z (ES+) (M+Na)+=443; HPLC tR=10.76 min.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[CH:39]2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:41]1[C:42]2[C:38](=[CH:37][C:36]([NH:35][C:1]([C:4]3[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]4[N:18]=[C:17]([N:19]5[C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=6[N:21]=[CH:20]5)[CH:16]=[CH:15][N:14]=4)[CH3:11])[CH:7]=[CH:8][CH:9]=3)=[O:2])=[CH:44][CH:43]=2)[CH:39]=[CH:40]1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (19.2 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (37 μL) was added followed by 5-aminoindole (19.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.3 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 30 min then eluted on silica gel column (2-4%MeOH in CH2Cl2) then on one 250 μm silica gel plate (1:1 hexanes:acetone) to yield 3.7 mg of the title compound. 1H NMR (500 MHz, CDCl3,partial): δ 8.50 (br s, 1H); 8.40 (d, J=5.5 Hz, 1H); 8.22 (br s, 1H); 8.03 (s, 1H); 7.96 (br s, 1H); 7.87 (s, 1H); 7.64 (d, J=7.8 Hz, 1H); 7.51 (t, J=7.8 Hz, 1H); 7.25 (m, 1H); 6.81 (d, J=5.5 Hz, 1H); 6.56 (br s, 1H); 5.89 (br s, 1H); 5.29 (br s, 1H); 1.69 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 474.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccnc(N3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
A mixture of 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and morpholine (0.087 ml, 1.0 mmol) in DMSO (0.5 ml) is heated at 80° C. for 6 h. The resulting mixture is diluted with CH2Cl2 (2 ml), washed with 0.01 N NaOH, and dried over sodium sulfate. After evaporation to dryness, the residue is purified by column chromatography on silica gel (50% EtOAc in hexane) to give 3-fluoro-5-morpholin-4-yl-N-{4-[(2-morpholin-4-ylpyrimidin-4-yl)oxy]-1-naphthyl}benzamide as a white solid (25 mg). Mp: 104-106° C.; 1H NMR (300 MHz, CDCl3) δ 3.26 (bs, 4H), 3.64 (bs, 8H), 3.87 (bs, 4H), 6.07 (d, J=4.5 Hz, 1H), 6.77 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.32 (bs, 2H), 7.52-7.59 (m, 2H), 7.89-8.00 (m, 3H), 8.12-8.19(m, 2H); MS: 530 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][O:19][CH2:20][CH3:21].C(N(CC)CC)C.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][O:19][CH2:20][CH3:21])[N:4]([CH2:3][C:2]([NH:1][C:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:38])([CH3:22])[CH3:23])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.552 g, 4.94 mmol) in dichloromethane (50 mL) was cooled to 0° C. Triethylamine (1.38 mL, 9.92 mmol) and cyclohexylcarbonyl chloride (661 μL, 4.94 mmol) were added sequentially. Two (2) days later the reaction mixture was cooled and additional cyclohexylcarbonyl chloride (40 μL) was added. The reaction mixture was stirred overnight and then diluted with saturated sodium bicarbonate and dichloromethane (50 mL). The layers were separated. The organic layer was washed sequentially with water (×2) and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (4×13 cm silica gel column, eluting with 3% methanol in chloroform). The purified material was dissolved in refluxing propyl acetate (80 mL) with the aid of methanol, the methanol was boiled off, and the solution was allowed to slowly cool. The resulting precipitate was isolated by filtration, rinsed with cold propyl acetate, and dried under high vacuum at 70° C. to provide 1.37 g of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a colorless crystalline solid, mp 210-211° C. Anal. calcd for C23H32N6O2: % C, 65.07; % H, 7.60; % N, 19.80. Found: % C, 64.93; % H, 7.76; % N, 19.97.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].N1C(C)=CC(C)=CC=1C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[Cl:21][CH2:22][C:23]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])=[O:24]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(C=O)cc1OC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture containing 108 g. (710 mmol.) of 3-hydroxy-4-methoxybenzaldehyde, 500 ml. of chloroform, and 125 ml. of collidine was kept below 10° C., treated dropwise with 70 ml. (800 mmol.) of chloroacetyl chloride over a 1-hour period, and then stirred 2 hours at 25° C. The solution was serially extracted with 500-ml. portions of water, 0.3N HCl, and water (2×). Chloroform was evaporated and crude 3-chloroacetoxy-4-methoxybenzaldehyde was recrystallized from diethyl ether (147 g., 91%), m.p. 88°-89° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17]C(=O)OC(C)(C)C)[CH2:11]3)=[CH:6][C:5](=[O:25])[NH:4]1)[CH3:2].F[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH2:17])[CH2:11]3)=[CH:6][C:5]([O:25][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:4]1)[CH3:2]
Reactant: CCn1[nH]c(=O)cc1-c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1ccc2c(c1)CC(N)C2
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 56.7 %

Procedure:
A mixture of tert-butyl [5-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-2-yl]carbamate (28 mg, 0.082 mmol) in DMSO (1 mL) was treated with fluoro-4-(trifluoromethyl)benzene (100 mg, 0.609 mmol) and K2CO3 (20 mg, 0.15 mmol). The suspension was stirred for 40 min at 140° C. until no SM remained. Significant Boc thermolysis was observed under these conditions. The reaction was cooled, diluted with DCM, extracted with 1 N NaOH, water, dried (Na2SO4), concentrated. The residue was dissolved in 0.9 mL of DCM and 0.1 mL of TFA, then stirred for 1 hour, diluted with DCM, extracted with 1 N NaOH, water, dried (Na2SO4), and finally concentrated to give 5-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}-2,3-dihydro-1H-inden-2-amine (18 mg, 57%): MS cal'd for C21H21F3N3O [M+H]+388.2. found 388.1.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][N:33]1[C:37]([CH:38]=O)=[CH:36][N:35]=[CH:34]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:37]4[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cn1cncc1C=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cncn4C)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 1-methyl-1H-imidazole-5-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[C:1]1([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccoc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccoc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of phenylboronic acid (15 g, 123.02 mmol) in dioxane (150.0 mL) and water (3.0 mL) was added 3-bromofuran (16.3 g, 110.91 mmol), K3PO4 (43 g, 202.57 mmol) and Pd(PPh3)4 (6.0 g, 5.19 mmol) with stirring for 2 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 3-phenylfuran as a white solid (15 g, 85%).
Reaction SMILES: [Li][CH3:2].[CH3:3][C:4](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:5]([OH:7])=O.Cl>CCOCC>[CH3:3][C:4](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:5](=[O:7])[CH3:2]
Reactant: CC(=CC(C)C)C(=O)O
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=CC(C)C

Procedure:
Under an atmosphere of N2, a 1.6 M solution of MeLi in Et2O (500 ml, 800 mmol) was added during 105 min. dropwise with stirring between 0-10° C. to a solution of 2,4-dimethylpent-2-enoic acid (41.0 g, 320 mmol) in Et2O (1.6 L). The reaction mixture was heated to reflux for 1 h, and then between 5-15° C. 5 N HCl (200 ml) was added dropwise. The organic layer was separated, the aqueous one extracted with Et2O (200 ml). The combined organic solutions were washed with water (200 ml) and brine (100 ml), dried (Na2SO4) and concentrated in a rotary evaporator to afford crude 3,5-dimethylhex-3-en-2-one, which was taken up in Et2O (160 ml). Under N2 at room temp., this solution was added dropwise with stirring to a suspension of LAH (3.34 g, 880 mmol) in Et2O (320 ml) during 1 h. The reaction mixture was refluxed for 2 h, and then quenched between 0-5° C. by addition of water (10 ml) and brine (20 ml). The organic layer was separated and the aqueous one extracted with Et2O (100 ml). The combined ethereal extracts were washed with water (100 ml) and brine (50 ml), dried (Na2SO4), and concentrated under reduced pressure. Silica-gel FC (pentane/Et2O, 4:1, Rf=0.40) of the resulting residue provided 34.7 g (85% over 2 steps) of 3,5-dimethylhex-3-en-2-ol.