Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[F:20][CH2:21][C@@H:22]([O:25][CH2:26][C:27](N(OC)C)=[O:28])[CH:23]=[CH2:24].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:20][CH2:21][C@@H:22]([O:25][CH2:26][C:27]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:28])[CH:23]=[CH2:24]
Reactant: C=C[C@@H](CF)OCC(=O)N(C)OC
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C[C@@H](CF)OCC(=O)c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of n-butyllithium in hexane (2.50 M; 176.52 mL, 441.29 mmol) was added dropwise over 20 mins to a solution of 2-bromofluorobenzene (49.00 mL, 451.88 mmol) in THF (670 mL) under a N2 atmosphere at −78° C. The temperature of the reaction was kept below −60° C. during the addition. The yellow solution was stirred at −78° C. for 30 mins. (S)-2-((1-fluorobut-3-en-2-yl)oxy)-N-methoxy-N-methylacetamide (67.50 g, 353.03 mmol) was added dropwise as a solution in THF (100 mL) keeping the internal temperature below −60° C. The reaction was stirred at −78° C. for 45 mins. Aqueous NH4Cl (200 mL) was added to the reaction solution and was allowed to warm up to RT and EtOAc (700 mL) was added. The two layers were separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic portions were washed with water 9300 mL), dried over MgSO4, (40 g) and concentrated. The crude product was purified by silica gel column chromatography (1% to 10% EtOAc in hexanes) to obtain the title compound as a yellow liquid (63.78 g, 80%). 1H-NMR (400 MHz, CDCl3) δ ppm 4.16-4.31 (m, 1H) 4.42-4.51 (m, 1H) 4.54-4.61 (m, 1H) 4.67-4.88 (m, 2H) 5.35-5.52 (m, 2H) 5.80 (ddd, J=17.43, 10.29, 7.26 Hz, 1H) 7.11-7.19 (m, 1H) 7.24-7.31 (m, 1H) 7.49-7.60 (m, 1H) 7.92-8.00 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:30][N:29]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCCC2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 66 using 5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 67.1) and (2-aminopyrimidin-5-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=445.3 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.84 (m, 4H) 3.18-3.26 (m, 4H) 6.77 (s, 2H) 7.34 (d, J=8.31 Hz, 2H) 7.86 (d, J=9.29 Hz, 2H) 7.95 (d, J=2.45 Hz, 1H) 8.27 (s, 2H) 8.71 (d, J=2.45 Hz, 1H) 10.12 (s, 1H).
Reaction SMILES: O=C1N2C3C=CC(N4CCOCC4=O)=CC=3OC[C@@H]2[C@@H](CCS([O-])(=O)=O)O1.O([CH2:36][C@H:37]1[C@@H:45]2[N:40]([C:41]3[CH:49]=[CH:48][C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][C:51]4=[O:56])=[CH:46][C:42]=3[O:43][CH2:44]2)[C:39](=[O:57])[O:38]1)[Si](C(C)(C)C)(C)C.[K].[C:59]1(=[O:69])[NH:63][C:62](=[O:64])[C:61]2=[CH:65][CH:66]=[CH:67][CH:68]=[C:60]12>>[O:57]=[C:39]1[N:40]2[C:41]3[CH:49]=[CH:48][C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][C:51]4=[O:56])=[CH:46][C:42]=3[O:43][CH2:44][C@@H:45]2[C@H:37]([CH2:36][N:63]2[C:59](=[O:69])[C:60]3[C:61](=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:62]2=[O:64])[O:38]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@H]12
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C1COCCN1c1ccc2c(c1)OC[C@@H]1[C@@H](CCS(=O)(=O)[O-])OC(=O)N21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@H]12
Yield: 82.1 %

Procedure:
Using compound ((3R,3 aR)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methylmethanesulfonate (2.98 g, 7.48 mmol) prepared above in (a) and phthalimide potassium (2.08 g, 11.22 mmol) as starting materials, preparation following the method as described in Example 1 (d) afforded white solid 2.76 g, yield: 82.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+].Cl>CO.ClCCCl>[NH2:20][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1
Reactant: [BH3-]C#N
Reactant: COc1cccc2c1CCC(=O)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: ClCCCl
Product: COc1cccc2c1CCC(N)C2
Reaction time: 48 h

Procedure:
First, 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (17.6 g, 0.1 mol) is dissolved in methanol (800 ml) and 1,2-dichloroethane (200 ml), then it is mixed with ammonium acetate (77 g) and sodium cyanoborohydride (5.4 g) and stirred for 2 days at laboratory temperature. The reaction mixture is adjusted to pH 2 with concentrated hydrochloric acid and the solvent is distilled off in vacuo. The residue is dissolved in ethyl acetate/water. The aqueous phase is separated off, made alkaline with 50% sodium hydroxide solution with cooling and extracted twice with methylene chloride. The extract is dried, treated with Fuller's earth/activated charcoal and concentrated by evaporation. The residue is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid. Yield: 2 g. Mp: 260°-262° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[NH:20][C:19]4=O)[CH2:14][CH2:13]3)[C:6]=2[N:5]=[C:4]([O:28][CH3:29])[C:3]1=[O:30].N1CCC(N2C3C=CC=CC=3N[C:38]2=[O:46])CC1.C1(N2C3(CCNCC3)C(=O)NC2)C=CC=CC=1>>[CH3:29][O:28][C:4]1[C:3](=[O:30])[N:2]([CH3:1])[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][C:15]4([N:18]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=5)[CH2:19][NH:20][C:38]4=[O:46])[CH2:14][CH2:13]3)[C:6]=2[N:5]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Agent: O=C1NCN(c2ccccc2)C12CCNCC2
Product: COc1nc2c(N3CCC4(CC3)C(=O)NCN4c3ccccc3)ncnc2n(C)c1=O

Procedure:
6-methoxy-8-methyl-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)pteridin-7(8H)-one was prepared in an analogous fashion to 8-methyl-6-(methyloxy)-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one, in which the 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one was replaced with commercially available 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.37 (s, 1H), 7.08 (t, 2H), 6.66 (t, 1H), 6.61 (d, 1H), 4.99 (d, 2H), 4.60 (s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 2.63 (m, 2H), 1.76 (d, 2H); MS (EI) for C21H23N7O3; 422 (MH+).
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])[N:9]=C(SC)C=C2OC1C=CC(NC(C2(C(NC3C=CC(F)=CC=3)=O)CC2)=O)=CC=1F.CS[C:43]([S:54][CH3:55])=[C:44]1[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]1=[O:53].COC1C=C(C=CC=1OC)N>CCO>[CH3:14][O:13][C:12]1[CH:11]=[C:10]([NH:9][C:43]([S:54][CH3:55])=[C:44]2[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]2=[O:53])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Agent: COc1ccc(N)cc1OC
Solvent: CCO
Product: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Yield: 83 %

Procedure:
Synthesis of N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3×). 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=O)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=[N:30]/[OH:31])=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)c1cc(OC)ccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)ccc1F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of the product from Step 3 (1.6 g, 4.0 mmol), hydroxylamine hydrochloride (2.8 g, 40 mmol) and sodium acetate (3.3 g, 40 mmol) in ethanol (40 mL) was stirred in a sealed tube at 60° C. for 48 h. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the oxime product.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OC2CCCCO2)c1
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: Ic1ccc(NCc2cccc(OC3CCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of 4-iodoaniline (11.80 g, 53.9 mmol) and 3-(tetrahydro-pyran-2-yloxy)-benzaldehyde (11.68 g, 56.6 mmol) in 100 mL methylene chloride was added magnesium sulfate (64.9 g, 539 mmol). The reaction mixture was stirred in darkness under nitrogen at room temperature overnight. The magnesium sulfate was filtered off and replaced each day for 3 days. On the fourth day, the reaction mixture was filtered and concentrated in vacuo. The resulting residue (16.45 g) was dissolved in 100 mL ethanol and 50 mL methanol and was treated with sodium borohydride (7.68 g, 202.1 mmol) which was added in portions. The reaction mixture was stirred at room temperature for 4.5 hr. at which time saturated aqueous sodium bicarbonate was added. The reaction mixture was extracted with methylene chloride and the organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (10% methanol/methylene chloride) afforded 6.81 g (41%) of the title compound of Step A.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1.[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[OH:10]/[N:9]=[C:8](\[Cl:15])/[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(trifluoromethoxy)benzaldehyde oxime (9.5 g, 46 mmol) in DMF (80 ml) was added N-chlorosuccinimide (8.0 g, 60 mmol) and the resulting mixture was stirred at RT for 5 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc, and washed with H2O, brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The solid residue was used without further purification for the following step. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=7.2 Hz, 2H), 7.13 (d, J=6.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1C(NCC1CCCCN1)=O.C1(C=CC(O)=CC=1)O.FC(F)(F)S(OCC(F)(F)F)(=O)=O>>[F:1][C:2]([F:27])([F:28])[CH2:3][O:4][C:5]1[CH:6]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=1
Reactant: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Oc1ccc(O)cc1
Product: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1

Procedure:
In still another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. Hydroquinone is contacted with 2,2,2-trifluoroethyl trifluoromethanesulfonate under conditions to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Subsequently, the 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Finally, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].[ClH:11].[CH2:12]([OH:14])[CH3:13]>C(Cl)(Cl)Cl>[ClH:11].[CH2:12]([O:14][C:1](=[NH:10])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:13]
Reactant: CCO
Reactant: N#Cc1ccccc1C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccccc1C#N
Temperature: 0 °C

Procedure:
A suspension of phthalonitrile (70 g, 0.55 mol) in ethanol (100 ml) and chloroform (200 ml) was warmed and then cooled to 0° C. The reaction mixture was saturated with HCl (g) and then aged at 0° C. for 2 weeks. The resultant precipitate was filtered and washed with chloroform. Dilution of the filtrate with ether produced additional 2-cyano-benzimidic acid ethyl ester hydrochloride.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[NH2:17][C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:17][C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cn1nnc(N)n1
Solvent: Cc1ccccc1
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
A solution (70 ml) of 3,5-bis(trifluoromethyl)benzaldehyde (6.71 g) and 5-amino-2-methyltetrazole (3.30 g) in toluene was heated under reflux for 4 hr. The reaction solution was concentrated and the obtained residue was dissolved in ethanol (70 ml), and sodium borohydride (2.10 g) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 30 min, and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was recrystallized from isopropanol-water (3:7, 50 ml) to give the title compound.
Reaction SMILES: [ClH:1].C(O)(C(F)(F)F)=O.C(OC([N:16]1[CH2:20][C@@H:19]([CH3:21])[CH2:18][C@H:17]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37]#[C:38][C:39]2[NH:43][C:42]([C@@H:44]4[CH2:49][C@@H:48]5[C@@H:46]([CH2:47]5)[N:45]4C(OC(C)(C)C)=O)=[N:41][CH:40]=2)[CH:31]=[CH:30]3)[N:26]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:21][C@@H:19]1[CH2:20][NH:16][C@H:17]([C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]#[C:38][C:39]3[N:43]=[C:42]([C@@H:44]5[CH2:49][C@@H:48]6[C@@H:46]([CH2:47]6)[NH:45]5)[NH:41][CH:40]=3)[CH:31]=[CH:30]4)[N:26]=2)[CH2:18]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc4cc(C#Cc5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc4cc(C#Cc5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6)n5)ccc4c3)c[nH]2)C1
Reaction time: 8 h
Yield: 148.1 %

Procedure:
2M HCl (0.33 mL, 0.66 mmol) in dioxane was added to a solution of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-((6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (115 mg, 0.131 mmol) in dioxane (2 mL) and the reaction was stirred vigorously overnight. The reaction was concentrated to yield an HCl salt of (1R,3S,5R)-3-(4-((6-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (87 mg) which was used without further purification. LC-MS retention time 2.793 min; m/z 449.41 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=O)[CH3:9])=[O:6])[CH3:3].Cl.[CH3:15][C:16](=[CH2:19])[CH2:17][NH2:18].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O1CCCC1>[CH3:9][C@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:3])[CH3:13])[C:10]([NH:18][CH2:17][C:16]([CH3:19])=[CH2:15])=[O:12]
Reactant: C=C(C)CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a cooled (0° C.) mixture of 18.9 parts of (S)-N-[(1,1-dimethylethoxy)carbonyl]alanine, 10.8 parts of 2-methyl-2-propen-1-amine monohydrochloride, 27.0 parts of 1-hydroxy-1H-benzotriazole hydrate and tetrahydrofuran, there were added 10.1 parts of N-methylmorpholine and, after 20 min, 20.6 parts of N,N-methanetetraylbis[cyclohexanamine] under a nitrogen atmosphere. The whole was kept at 0° C. for 1 hour and at room temperature for 12 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and NaHCO3 (sat.). The organic layer was separated, washed with NaCl (sat.), dried, filtered and evaporated, yielding 24.2 parts (99.9%) of (1,1-dimethylethyl) (S)-[1-methyl-2-[(2-methyl-2-propenyl)amino]-2-oxoethyl]carbamate (interm. 63).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][CH2:12][C:13]([N:15]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][CH2:12][C:13]([N:15]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCCCN(C(=O)CCC(=O)Nc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCC(=O)N(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1)Nc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 42 h
Yield: 71.2 %

Procedure:
Methyl 4-[3-[N-[3-(4-chlorophenylcarbamoyl)propionyl]-N-(4-chlorophenyl)amino]propoxy]benzoate (1.50 g) was dissolved in methanol (20 ml), and thereto was added 1N aqueous sodium hyroxide solution (4.83 ml), and the mixture was heated with stirring at 60° C. for 42 hours. After the reaction mixture was cooled, a neutralizing amount of conc. hydrochloric acid was added thereto, and the mixture was concentrated under reduced pressure. The resultant was suspended in 10 % aqueous methanol, and collected by filtration to give the desired product (1.04 g). mp. 197°-201° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:10](=[C:11]([CH3:23])[N:12](COCC[Si](C)(C)C)[N:13]=3)[CH:9]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)=[CH:4][C:3]2[CH:33]=[CH:34][CH:35]=[CH:36][C:2]1=2.B([O-])[O-].C(OC([N:47]1[C:55]2[CH:54]=[N:53][C:52]([N:56]=CN(C)C)=[N:51][C:50]=2[C:49](I)=[CH:48]1)=O)(C)(C)C>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:49]3[C:50]4[N:51]=[C:52]([NH2:56])[N:53]=[CH:54][C:55]=4[NH:47][CH:48]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[C:11]3[CH3:23])=[CH:4][C:3]2[CH:33]=[CH:34][CH:35]=[CH:36][C:2]1=2
Reactant: CN(C)C=Nc1ncc2c(n1)c(I)cn2C(=O)OC(C)(C)C
Reactant: Cc1c2cc(B3OC(C)(C)C(C)(C)O3)cc(-c3cc4ccccc4s3)c2nn1COCC[Si](C)(C)C
Agent: [O-]B[O-]
Product: Cc1n[nH]c2c(-c3cc4ccccc4s3)cc(-c3c[nH]c4cnc(N)nc34)cc12
Yield: 18.9 %

Procedure:
A mixture of 7-benzo[b]thiopen-2-yl-5-bromo-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (Preparation #24, 1.0 g, 2.18 mmol) in tetrahydrofuran (15 mL) was cooled to about −65° C. then a solution of n-butyllithium (1.6 M, 1.5 mL, 2.4 mmol) was added dropwise. After about 5 minutes methyliodide (0.37 g, 2.6 mmol) was added then the solution was warmed to about −20° C. Saturated ammonium chloride (1 mL) was added then the mixture was diluted with ethyl acetate (25 mL) and water (10 mL). The layers were separated then the organic layer was dried over magnesium sulfate, filtered and evaporated to give the crude 7-benzo[b]thiophen-2-yl-5-bromo-3-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole which was converted to 7-benzo[b]thiophen-2-yl-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (0.29 g, 25% over 2 steps) using general procedure E. The boronate (200 mg, 0.385 mmol) was coupled with 2-(dimethylamino-methyleneamino)-7-iodo-pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester (0.135 g, 0.32 mmol) using general procedure F and the resulting product deprotected using general procedure G to give 7-(7-benzo[b]thiophen-2-yl-3-methyl-1H-indazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamine (24 mg, 19%); (DMSO-d6, 400 MHz) δ 12.48 (bs, 1H), 11.44 (s, 1H), 8.50 (m, 3H), 8.18 (d, 1H), 8.07 (bs, 1H), 8.02 (d, 1H), 7.90 (d, 1H), 7.43 (m, 2H), 5.94 (bs, 2H), 2.61 (s, 3H); RP-HPLC (Table 1, Method e) Rt 1.76 min; m/z: (M−H)− 394.9.
Reaction SMILES: COC1C=[C:5]([CH2:11][CH2:12][CH2:13][C:14](=O)C=C)[CH:6]=[C:7]([O:9]C)C=1.C[O:19]C1C=C(CCCC(=O)CCN(CC)CC)C=C(OC)C=1>[OH-].[K+]>[CH2:13]([CH:12]1[C:7](=[O:9])[CH2:6][CH2:5][C:11]1=[O:19])[CH3:14]
Reactant: C=CC(=O)CCCc1cc(OC)cc(OC)c1
Reactant: CCN(CC)CCC(=O)CCCc1cc(OC)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux 6-(3,5-dimethoxyphenyl)hex-1-en-3-one, containing a small amount of 6-(3,5-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolic potassium hydroxide (10 cc) for 10 hours. Work up the reaction mixture as for the preparation of 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione to obtain 2-[6-(3,5-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione as a viscous gum; infrared absorption peaks at 5.80, 6.25 μ (split peak).