Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16])=[O:4].[NH:17]1[CH2:21][CH2:20][NH:19][C:18]1=[S:22]>>[BrH:1].[Cl:16][C:6]1[CH:7]=[C:8]([Cl:15])[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]=1[C:3]1([OH:4])[CH2:2][S:22][C:18]2=[N:17][CH2:21][CH2:20][N:19]12
Reactant: S=C1NCCN1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Product: Br
Product: NS(=O)(=O)c1cc(C2(O)CSC3=NCCN32)c(Cl)cc1Cl

Procedure:
was obtained in a manner analogous to the method described in Example 4 e from 3.5 g of 2-bromo-2',4'-dichloro-5'-sulfamoylacetophenone and 1 g of imidazolidine-2-thione. Mp. 225° C (decomposition).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]#[N:19]>>[S:1]1[CH:5]=[C:4](/[CH:6]=[C:17](/[C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)\[C:18]#[N:19])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: N#CCc1cccs1
Reactant: O=Cc1csc2ccccc12
Product: N#C/C(=C\c1csc2ccccc12)c1cccs1
Yield: 30 %

Procedure:
Benzo[b]thiophene-3-carboxaldehyde (81 mg) was condensed with 2-thiopheneacetonitrile (62 mg) through Method B (production step 3), to thereby yield the target product (yield: 40 mg, 30%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3][CH2:2]1.Br[CH2:25][CH:26]([CH3:28])[CH3:27].BrCC1CC1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Reactant: CC(C)CBr
Agent: BrCC1CC1
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(CC(C)C)c1=O

Procedure:
The title compound from Example 242, step 1 was reacted in a manner similar to Example 242, step 2 except that 1-bromo-2-methylpropane was substituted for bromomethylcyclopropane to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.85-7.82 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 3.94 (d, J=7.2 Hz, 1H), 3.83 (d, J=7.2 Hz, 1H), 3.07 (s, 3H), 2.30-2.26 (m, 1H), 2.23 (s, 3H), 1.28-1.27 (m, 1H), 1.00 (s, 3H), 0.98 (s, 3H), 0.69-0.65 (m, 2H), 0.38-0.35 (m, 2H). LCMS: 390.2 (M+1)+
Reaction SMILES: [CH3:1][C:2](O)([CH3:4])[CH3:3].[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:15]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:16])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)O
Reactant: COc1cc(CC(NC(=O)OC(C)(C)C)C(=O)O)ccc1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C

Procedure:
t-BuOH (5.17 g, 6.67 mL, 69.8 mmol) was added to a stirred suspension of 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid (1.55 g, 4.98 mmol) in dry toluene (25 mL). The mixture was brought to reflux to give a homogeneous solution. N,N-dimethylformamide dineopentyl acetal (3.46 g, 4.17 mL, 15.0 mmol) was added dropwise over 1 h at reflux. After heating at reflux to 3-4 h, the reaction mixture was cooled to room temperature and a saturated solution of NaHCO3 (40 mL) was added. The mixture was extracted with CH2Cl2 (3×40 mL) and the combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 4536 mL) to afford tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoate. Rf=0.42 (20% EtOAc/hexanes). LCMS calc.=390.2; found=389.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 6.82 (d, J=7.9 Hz, 1 H); 6.87-6.63 (m, 2 H); 5.54 (s, 1 H); 4.97 (d, J=7.8 Hz, 1 H); 4.40 (q, J=6.7 Hz, 1 H); 3.86 (s, 3 H); 2.98 (d, J=6.0 Hz, 2 H); 1.42 (s, 9 H); 1.41 (s, 9 H).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH:9](NC)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[CH2:15][N:16](CC)CC.[N+:21]([C:24]1[C:25](SC#N)=[N:26][C:27]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][C:39]([F:42])([F:41])[F:40])=[N:28][CH:29]=1)([O-:23])=[O:22]>CCO>[N:1]1([C@H:6]2[CH2:7][CH2:8][C@H:9]([CH2:15][NH:16][C:25]3[C:24]([N+:21]([O-:23])=[O:22])=[CH:29][N:28]=[C:27]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][C:39]([F:41])([F:42])[F:40])[N:26]=3)[CH2:10][CH2:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CNC1CCC(n2ccnc2)CC1
Reactant: N#CSc1nc(NCc2ccccc2OC(F)(F)F)ncc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (4-imidazol-1-yl-cyclohexyl)-methylamine (32 mg, 0.18 mmol) and Et3N (76 μL, 0.54 mmol) in EtOH (1 mL) was added (5-Nitro-4-thiocyanato-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (71 mg, 0.19 mmol). The mixture was stirred at room temperature for 14 h before concentrating in vacuo. The residue was partially purified by column chromatography using a 12 g ISCO combi-flash cartridge (silica gel, 95:4.75:0.25 DCM/MeOH/NH4OH) then re-purified by semi-preparative HPLC. The isolated TFA salt was converted to the free base by partitioning between sat. NaHCO3 and EtOAc. Concentration of the organic layer in vacuo afforded 29 mg of the title compound as an off-white solid, m/z 492 [M+1]+
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][C:13]1([CH3:20])[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[O:14]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[S:1]1[C:2]([CH:10]=[CH:19][C:15]2[O:14][C:13]([CH3:20])([CH3:12])[C:17](=[O:18])[CH:16]=2)=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1cc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cc3ccccc3s2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a solution of 2-benzothiophenecarboxaldehyde (1.5 g, 9.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.6 g, 9.2 mm) in ethanol (100 mL), was added 1 N aqueous sodium hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred at room temperature for one day, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The residue was purified by chromatography (silica gel, hexane-ethyl acetate) to afford a yellow solid (2.2 g, 58% yield), m.p. 103.5°-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].ClC1C=C(NC2C3C(=CC=C(OCC(NO)=O)C=3)N=CN=2)C=CC=1F>>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: CCOC(=O)CCCCCBr
Reactant: C#Cc1cccc(Nc2ncnc3ccc(O)cc23)c1
Agent: O=C(COc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1)NO
Product: C#Cc1cccc(Nc2ncnc3ccc(OCCCCCC(=O)OCC)cc23)c1
Product: C#Cc1cccc(Nc2ncnc3ccc(OCCCCCC(=O)[O-])cc23)c1
Yield: 64 %

Procedure:
The title compound ethyl 6-(4-(3-ethynylphenylamino)quinazolin-6-yloxy)hexanoate (0212-23) (0.3 g, 64%) was prepared from compound 4-(3-ethynylphenylamino)quinazolin-6-ol (0211) and ethyl 6-bromohexanoate using a procedure similar to that described for compound 0210-13 (Example 9): LC-MS m/z 404 [M+1].
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C:12]#[N:13]>[Fe].CC1C=CC=CC=1>[ClH:3].[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: N#CC(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cl
Product: N#CC(c1ccc(N)cc1)c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
20 parts of iron-powder are added to 190 parts of ammonium chloride solution 0.78N at reflux temperature. Then there is added dropwise a solution of 20 parts of 2,4-dichloro-α-(4-nitrophenyl)benzeneacetonitrile in 180 parts of methylbenzene. Upon completion, stirring is continued overnight at reflux. The reaction mixture is cooled at 60° C and filtered over hyflo. The filter-cake is washed with tetrahydrofuran. The filtrate is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2,2'-oxybispropane, methanol and 2-propanol. The salt is filtered off and dried, yielding α-(4-aminophenyl)-2,4-dichlorobenzeneacetonitrile hydrochloride; mp. 207.2° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:21]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CN(Cc1cscn1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)CN(Cc1cscn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) solution of 4-{isobutyl-[(thiazol-4-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (540 mg, 1.53 mmol, 1 eq.) in anhydrous dichloromethane (3 ml), is added anisole (2.5 g, 23 mmol, 15 eq.) and trifluoroacetic acid (2.6 g, 23 mmol, 15 eq.). The reaction is allowed to warm to room temperature and stirred for 4-5 hours. The reaction mixture is loaded on a SCX-2 column. The column is first washed with methanol and then the base eluted with 20% 2N NH3 in methanol in dichloromethane. The solvents are removed in vacuo to afford isobutyl-(piperidin-4-yl)-[(thiazol-4-yl)methyl]-amine (387 mg). m/z=254 (M+1); 1H NMR (CDCl3): δ=8.27 (1H, d), 7.22-7.21 (1H, m), 3.86 (2H, d), 3.15 (2H, brd), 2.62-2.49 (3H, m), 2.30 (2H, d), 2.03 (1H, brs), 1.78 (2H, d), 1.66-1.59 (1H, m), 1.50-1.40 (2H, m), 0.86 (6H, d).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[N:29]=1>C(O)(C)C>[ClH:1].[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[S:27][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CSc1nc2ccccc2[nH]1
Product: Cl
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A suspension of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyrid-azine (0.39 g, 0.95 mmol) and 2-mercapto-1H-benzimidazole (160 mg, 1.05 mmol) in isopropanol (50 ml) is heated under reflux for 7 h. After cooling to room temperature, the precipitate is filtered off, washed with isopropanol and dried at 40° C. in vacuo. The title compound (0.46 g, 86%) is isolated as a beige solid. M.p. 200-207° C (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].[Br:35]N1C(=O)CCC1=O.O.C(Cl)Cl>C(#N)C>[NH2:1][C:2]1[C:33]([Br:35])=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:5]
Reactant: Cc1ccc(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(Br)c(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 75 °C
Yield: 71.4 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-methyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (60 mg, 0.128 mmol) was dissolved in acetonitrile (2 ml) and N-bromosuccinimide (23 mg, 0.128 mmol) was added. The reaction was heated to 75° C. for 4 h. The reaction mixture was cooled to RT and partitionated between water and methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (50 mg, 71%) as a light brown oil. MS (ISP) 547.3 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[H][H].[CH3:27]I>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([N:15]([CH3:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:13])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CI
Reactant: CC(C)(CCCO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C(C)(C)CCCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 750 mg of 12b in 4 ml of DMF was treated with 200 mg of 60% NaH (dispersion in mineral oil) and heated under N2 at 50° C. for 10 min, after which time evolution of hydrogen gas ceased. The reaction mixture was cooled to 0° C. and 500 μl of methyl iodide was added. The reaction mixture was stirred for an additional 2 hr and quenched by pouring into ice-water (caution excess NaH). The product was extracted with ethyl acetate and the extract was washed with water, dried, concentrated and the crude material was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 550 mg of 12c as colorless oil; Rf 0.50 (heptane/ethyl acetate 3/1). NMR (CDCl3) δ 0.05 (s, 6, Si(CH3)2), 0.89 (s, 9, tertC4H9Si), 1.32 (s, 6, C(CH3)2) 1.42 (s, 9, tertC4H9+m, 2, CH2), 1.72 (m, 2, CH2), 2.88 (s, 3, NCH3), 3.60 t, 2, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[N:13]=2)=[CH:5][CH:4]=1.[CH2:21]=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[CH2:21][NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[C:12]3=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc(-c2nc(-c3ccccc3N)c[nH]2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Reaction time: 0.03 h

Procedure:
2-(4-Methoxyphenyl)-4-(2-aminophenyl)imidazole (5 g) is dissolved in acetic acid (20 ml) and formaldehyde (37% in water, 1.53 ml) is added. The reaction is stirred for 2 min., diluted with ethyl acetate (100 ml), and extracted with 5%HCl (250 ml). The aqueous layer is basified with K2CO3, then extracted with ethyl acetate. The organic layer is evaporated under reduced pressure and the residue is recrystallized from dichloromethane to afford 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (3 g) as a light brown solid. m.p. 190-191° C.
Reaction SMILES: [Cl-].[Na+].[Na+].[Na+].[Cl-].[Cl-].[I:7][C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[O:11][C:12]=1[C:13]([OH:15])=O.[O-:23][N+:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[C:26]([C@H:34]([NH2:36])[CH3:35])[CH:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[I:7][C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[O:11][C:12]=1[C:13]([NH:36][C@@H:34]([C:26]1[CH:25]=[N+:24]([O-:23])[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:27]=1)[CH3:35])=[O:15]
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: Cc1ccc(-c2nc(I)c(C(=O)O)o2)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc(I)c(C(=O)N[C@H](C)c3ccc(C(F)(F)F)[n+]([O-])c3)o2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of tri sodium chloride salt of iodo-2-(4-methylphenyl)-1,3-oxazole-5-carboxylic acid (55.2 mg, 0.11 mmol) in DMF (1.1 mL) were added (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (27.9 mg, 0.12 mmol), EDC (36.7 mg, 0.19 mmol), HOAT (7.45 mg, 55.0 μmol) and triethylamine (61 μL, 0.44 mmol). The mixture was stirred at 50° C. After 30 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (41 mg). MS 517.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=3)[C:14]=2[O:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:41].B(Br)(Br)Br>C(OCC)(=O)C.C(OCC)C>[ClH:41].[F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([O:25][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:39][CH:40]=3)=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]3)[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)c(S(C)(=O)=O)c(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1c(F)cc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Temperature: 0 °C
Yield: 20 %

Procedure:
Dissolve the compound of Example 79 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry int vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the 6-(3,5-difluoro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL) and ethyl acetate (6.0 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to give 31 mg of the title compound (20%): mass spectrum (ion spray): m/z: 554.3 (M+H—HCl).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Reactant: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(-n2cncn2)ncc1Br
Temperature: 120 °C

Procedure:
In a microwave tube were charged with compound 23B (100 mg, 0.2 mmol), 1H-1,2,4-triazole (42 mg, 0.6 mmol), triethylamine (84 μL, 0.6 mmol) and DMF (0.6 mL, The mixture was heated up to 120° C. for 15 min in a Microwave Synthesizer. After cooled down, it was partitioned between ethyl acetate and 5% of LiCl aqueous solution. The organic layer was separated and concentrated. The residue was purified on silica gel chromatography eluting with ethyl acetate and hexanes to afford the title compound. MS (m/z) 481.21 [M+H]+.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[C-:8]#[N:9].[Na+].O.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[C:2]([NH:6][NH:7][C:12]1([C:8]#[N:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: [C-]#N
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NNC1(C#N)CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a rapidly stirred solution of 24.8 g. (0.2 m.) tert.-butylhydrazine hydrochloride and 9.8 g. (0.2 m.) sodium cyanide in 100 ml. of deionized water in a 250 ml. 4 neck round bottom flask, was added a solution of 19.6 g. (0.2 m.) of cyclohexanone in 15 ml. of ethanol. The reaction was stirred for 5 hours at room temperature and the allowed to stand overnight. The next morning the reaction was stirred an additional hour and filtered. The product was dried at 30° C. in a vacuum oven. The yield was 36.3 g. (93.5%) of a white solid melting at 70°-73° C. The white solid evolves HCN on exposure to air over extended periods. The infra-red spectrum contained strong NH bands, a cyano band and did not contain any carbonyl or imino bands. Thus the infra-red spectrum was consistent with the structure of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([O:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])([CH3:35])([CH3:34])[CH3:33].C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:42])[CH2:38][C:39]([O:29][C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:30][CH3:31])=[O:40]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
A suspension of 6-(4-chlorophenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxy-phenyl)-thieno[3,2-d]pyrimidin-4(3H)-one (100 mg; 0.219 mmol) (Example 82), 3-tert-butoxy-3-oxopropanoic acid (83 uL; 0.538 mmol), diisopropylcarbodiimide (83 uL; 0.538 mmol) and 4-N,N-dimethylaminopyridine (27 mg; 0.219 mmol) in 1 mL of CH2Cl2 was stirred at rt for 17 h. Additional 3-tert-butoxy-3-oxopropanoic acid (83 uL; 0.538 mmol) and diisopropylcarbodiimide (83 uL; 0.538 mmol) were added and the suspension stirred at rt for 3 h. The suspension was diluted with CH2Cl2, filtered and the filtrate washed with 1N HCl, saturated aq. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 1:1 gradient) to afford 104 mg (79%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.64 (s, 6H), 3.23 (s, 2H), 3.87 (s, 3H), 4.20 (s, 2H), 6.91 (dd, J=8.24 Hz, 2.20 Hz, 1H), 6.95 (d, J=2.20 Hz, 1H), 7.02 (d, J=8.24 Hz, 1H), 7.44 (d, J=8.24 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.80 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 23.37, 27.92, 44.04, 56.23, 74.44, 81.83, 82.01, 111.53, 114.75, 119.20, 120.87, 123.22, 127.65, 129.47, 130.51, 131.54, 135.67, 148.19, 149.30, 150.49, 151.63, 156.79, 157.40, 165.85, 166.20; HPLC (Method #1) 4.46 min retention time, (97%); MS (ES): m/z 599 [M+H]+.