Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[N:32]=[CH:33][S:34][C:35]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:35]4[S:34][CH:33]=[N:32][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1ncsc1C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2scnc2C)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 4-methylthiazole-5-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[N:9]=[CH:10][N:11]=1)=[CH2:5])C.C1COCC1>CO>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([N:12]2[C:8]3[N:9]=[CH:10][N:11]=[C:6]([C:4](=[O:3])[CH3:5])[C:7]=3[CH:14]=[CH:13]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: C=C(OCC)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Yield: 89 %

Procedure:
[7.25 g, 21.12 mmol] of 4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50 mL each of methanol and THF and stirred with 10 mL of 6N HCL for 4.0 hours at ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic fraction was brined and dried with anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude material was triturated with a mixture of MTBE and petroleum ether (1:4) for several hours and the solid finally isolated via suction filtration and air dried. The 5.95 g of pale yellow material, representing a 89% yield was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(Cl)s1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methyl 5-chloro-2-thiophenecarboxylate (7 g, 39.6 mmol) and aluminum trichloride (7.93 g, 59.4 mmol) in chloroform (79 ml) at 25° C. was added bromine (2.86 ml, 55.5 mmol). The resulting solution stirred at 25° C. for 2 h. Ice chips were added to quench and the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 5% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2-thiophenecarboxylate (7.2 g, 28.2 mmol, 71.1% yield) as a white solid; LCMS (ES) m/z=255, 257 (M, M+2)+.
Reaction SMILES: [C:1]([CH:5]1[O:19][CH:18]2[CH:7]([CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17]2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:5][O:6][CH:7]1[CH:18]([OH:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)C1OC2CCC=CCCC=CCCC2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)COC1CCC=CCCC=CCCC1O
Yield: 92 %

Procedure:
Preparation steps identical to those described in example 1(b) were carried out using 5.2 g of 14-tert-butyl-13,15-dioxabicyclo[10.3.0]pentadeca-4,8-diene and 32.8 ml of a 1.2M solution of DIBAH in toluene. After acidification, the reaction mixture was washed with ether, then with brine, dried, concentrated and distilled in a bulb-to-bulb apparatus. 4.82 g of 12-(2,2-dimethylpropoxy)-4,8-cyclododecadien-1-ol were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Reactant: NCc1ccc(N2CCCC2)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(F)cc1

Procedure:
Ethyl 3-(4-fluorophenyl)-2-hydroxyimino-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(Br)ccn1

Procedure:
In a manner similar to that describe in Preparation 34, 4-bromo-pyridine-2-carboxylic acid and 4-trifluoromethylaniline were converted to the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]([OH:21])=O)(=[O:12])=[O:11].C([N:24](CC)CC)C.ClC(OCC)=O.N>O1CCCC1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]([NH2:24])=[O:21])(=[O:11])=[O:12]
Reactant: O=C(O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1-(1H-Benzo[d]imidazol-2-ylsulfonyl)-2-piperidinecarboxylic acid (17.5 g) [see Preparation 16] was dissolved in tetrahydrofuran (180 ml) and cooled to −20° C. Triethylamine (10.2 ml) was added to the mixture followed by ethyl chloroformate (5.4 ml). The reaction mixture was stirred for 1 hour at −20° C. and 0.88 aqueous ammonia solution (25 ml) was added. The mixture was then stirred for a further 2 hours at room temperature. The organic solvent was removed under reduced pressure and ethyl acetate added. The organic layer was separated, washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidinecarboxamide (14.73 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][CH2:15]1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2CCNCC2)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(c2ccc(OC)cc2F)CC1

Procedure:
To a stirred solution of 4-(2-fluoro-4-methoxyphenyl)piperidine (40 mg; 0.19 mmol) in DMF (1 mL) under an atmosphere of N2 was added N,N-diisopropylethylamine (33 μL; 0.19 mmol), followed by ethyl bromoacetate (21 μL; 0.19 mmol). The resultant solution was stirred at room temperature for 2.5 h. The reaction was partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford ethyl [4-(2-fluoro-4-methoxyphenyl)piperidin-1-yl]acetate as a colorless oil. LCMS=295.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.14 (t, J=8.7 Hz, 1 H), 6.65 (dd, J=8.5, 2.5 Hz, 1 H), 6.58 (dd, J=12.43, 2.5 Hz, 1 H), 4.20 (q, J=7.1 Hz, 2 H), 3.77 (s, 3 H), 3.26 (s, 2H), 3.06 (d, J=11.4 Hz, 2 H), 2.80 (tt, J=12.1, 3.7 Hz, 1 H), 2.32 (t, J=11.2 Hz, 2 H), 1.87 (qd, J=12.3, 3.3 Hz, 2 H), 1.78 (d, J=12.1 Hz, 2 H), 1.29 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:9][C:6]=1[C:7]#[N:8].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(O)C>[OH:1][CH:2]([CH2:18][NH:28][CH2:27][CH2:26][O:25][C:24]1[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COCCOc1ccc(OCC2CO2)c(C#N)c1
Reactant: COc1ccc(OCCN)cc1
Solvent: CCO
Product: COCCOc1ccc(OCC(O)CNCCOc2ccc(OC)cc2)c(C#N)c1
Reaction time: 1 h

Procedure:
2.4 g of 2-(2,3-epoxypropoxy)-5-(2-methoxyethoxy)-benzonitrile and 8.35 g of 2-(4-methoxyphenoxy) ethylamine are dissolved in 30 ml of ethanol, the solvent is then evaporated and the resulting mixture stirred for 1 hour at 70°. The reaction melt is then dissolved in ether and allowed to crystallize under cooling. Purification is effected by recrystallization in benzene. The title compound is obtained (M.P. 95°-97°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30](C(OCC5C=CC=CC=5)=O)[CH2:29][CH2:28]4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCC3CCN(C(=O)OCc4ccccc4)CC3)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCC3CCNCC3)C2)CC1
Reaction time: 60 h
Yield: 32.5 %

Procedure:
To benzyl 4-(2-{(3R)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidin-1-yl}ethyl)piperidine-1-carboxylate (805 mg) was added 4M HCl in dioxane (5 ml). After removal of the solvent, 1-methyl-2-pyrrolidinone (5 ml) and zinc bromide (20 mg) were added, the mixture purged with Argon, 10% Pd/C (100 mg) added and stirred under hydrogen for 60 hours. Catalyst was filtered off through Celite, fresh catalyst and zinc bromide added and stirring continued for a further 48 hours under hydrogen. After filtration, the mixture was purified on a SCX2 50 g column, eluting sequentially with isohexane, ethyl acetate, 50% ethyl acetate/MeOH, MeOH and finally with 10% ammonia in MeOH to give the title compound (205 mg, 34%).
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](O)(=O)[CH2:34]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:33][CH3:34]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O

Procedure:
This compound was prepared as described above for (6) using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 91 mg (37%); Rhd f 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 12H, 6HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[CH:5].C[O:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13](Br)=[CH:12][N:11]=1)=[O:9].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:15]1[C:10]([C:8]([OH:9])=[O:7])=[N:11][CH:12]=[C:13]([C:5]#[C:4][CH2:3][O:2][CH3:1])[CH:14]=1
Reactant: COC(=O)c1ncc(Br)cc1Cl
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Product: COCC#Cc1cnc(C(=O)O)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 3-methoxy-propyne (421 mg, 6 mmol), bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol), copper(I) iodide (23 mg, 0.12 mmol) and N Eta (1.17 ml, 8.4 mmol) in THF (10 ml) under Argon was added 3-chloro-5-bromo-pyridine-2-carboxylic acid methyl ester (284 mg, 1.2 mmol) and the mixture was heated to 80° C. for 5 h. At 0° C. water (12 ml) was added and the mixture was extracted with EtOAc. The aq. Phase was acidified to pH 1 by addition of 1N HCl, extracted with DCM. The combined DCM extracts were washed with half-saturated aq. sodium chloride, dried with Na2SO4 and evaporated to provide the title compound as an off-white solid, which was used for coupling reactions without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:3](=[O:2])[CH2:4][CH:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]3[CH:23]4[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]3[CH2:25]5)[CH2:24]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1
Reactant: CN
Reactant: COC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Product: CNC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Yield: 37 %

Procedure:
(±)-2-Adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (33 mg, 0.075 mmol) was added to a solution of methylamine in alcohol (2 mL) at 0° C. The above mixture was heated under reflux overnight. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to obtain (±)-2-adamantyl 3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (12 mg, 37%). 1H-NMR (400 MHz, CD3OD): 8=-1.52-1.67 (m, 6H), 1.84 (m, 6H), 1.93 (m, 2H), 2.07 (M, 5H), 2.28 (m, 1H), 2.56 (m, 1H), 2.77 (m, 4H), 3.12 (br, 2H), 3.62 (m, 1H), 4.19 (br, 2H), 7.18 (m, 4H).
Reaction SMILES: C=O.[Br:3][C:4]1[CH:37]=[CH:36][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1>C(O)=O>[Br:3][C:4]1[CH:37]=[CH:36][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Yield: 88.3 %

Procedure:
37% Aqueous formaldehyde (3.5 ml, 42 mmol) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (3.49 g, 6.22 mmol), (prepared as described for the starting material in Example 1), in formic acid (35 ml). After heating at 95° C. for 4 hours the volatiles were removed under vacuum. The residue was suspended in water and the mixture was adjusted to pH10.5 by slow addition of a solution of 2N sodium hydroxide. The suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried MgSO4 and evaporated to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (2.61 g, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C@@:8]2([CH3:33])[N:12]3[C:13]([C:16]([NH:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:9]2=[O:32])=[CH:5][CH:4]=1)#[N:2].[N:36]1[NH:37][N:38]=[N:39][C:40]=1[C@@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1.CCN(CC)CC.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C@@:8]2([CH3:33])[N:12]3[C:13]([C:16]([NH:18][C@@H:19]([CH3:23])[C:20](=[O:22])[N:43]4[CH2:44][CH2:45][CH2:46][C@@H:41]([C:40]5[N:36]=[N:37][NH:38][N:39]=5)[CH2:42]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)[C:9]2=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: C1CNC[C@H](c2nn[nH]n2)C1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2nn[nH]n2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
To a solution of (S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (60 mg, 0.117 mmol) and (R)-3-(2H-tetrazol-5-yl)-piperidine (35.8 mg, 0.234 mmol) in anhydrous DMF (1 mL) was added Et3N (33.8 μl, 0.234 mmol) at 0° C. HOAt (47.8 mg, 0.351 mmol) was then added to the reaction. After 10 min of stirring at 0° C., HATU (53.4 mg, 0.140 mmol) was added. The reaction was slowly warmed to 25° C. and stirred overnight. The crude reaction was purified by reverse phase HPLC to afford 55 mg of (3R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-N-{(1S)-1-methyl-2-oxo-2-[(3R)-3-(2H-tetrazol-5-yl)piperidin-1-yl]ethyl}-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide as a white solid, m/z 647.5 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[CH:6]2.[Li]C.I[CH2:15][CH2:16][CH3:17].[NH4+].[Cl-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6]2
Reactant: CCCI
Reactant: COc1ccc2c(c1)C=CC2
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC1C=Cc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.3 %

Procedure:
A solution of 5-methoxy-1H-indene (0.895 g, 6.12 mmol) in anhydrous Et2O (7.5 mL) was treated with 1.4M MeLi in Et2O (4.7 mL, 6.58 mmol) added dropwise over 10 minutes. The resulting hazy solution was stirred at room temperature an additional 15 minutes, then cooled in an ice bath and treated with iodopropane (1.00 mL, 10.3 mmol). The mixture was stirred at ice bath temperature with gradual warming to room temperature. After stirring at room temperature overnight, the mixture was treated with saturated aq. NH4Cl (10 mL) and Et2O (15 mL) and shaken. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to afford a mixture (1.248 g) of 5-methoxy-1-propyl-1H-indene and 6-methoxy-1-propyl-1H-indene as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[CH:13]=[CH:14][C:15]=1[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:20]=2)=[CH:11][C:10]=1[NH:9][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccs1
Yield: 33.4 %

Procedure:
Thiophene-2-carbonyl chloride (0.069 g) was added to a stirred suspension of N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (0.104 g), triethylamine (0.15 ml) and methylene chloride (20 ml) and the resultant mixture was stirred at ambient temperature for 4 hours. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was dissolved in methylene chloride (2 ml) and diethyl ether (20 ml) was added to give a precipitate which was isolated by filtration, washed with diethyl ether and dried. There was thus obtained the title compound (0.047 g); NMR Spectrum: (DMSOd6) 2.18 (t, 3H), 3.18 (t, 4H), 3.76 (t, 4H), 7.14 (d, 1H), 7.20 (m, 2H), 7.38 (m, 2H), 7.41 (s, 1H), 7.58 (m, 1H), 7.78 (s, 1H), 7.82 (d, 1H), 7.98 (d, 1H), 9.93 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]([CH3:26])=[O:25]>>[CH2:15]([O:14][C:12]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:23][CH:24]3[CH2:26][O:25]3)[CH:3]=2)[NH:7][C:6]=1[CH3:11])=[O:13])[CH3:16]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(C)[nH]c2ccc(OCC3CO3)cc12
Temperature: 25 °C

Procedure:
A solution of 2.19 g (10 mmol) of ethyl 5-hydroxy-2-methyl-indole-3-carboxylate, 2.6 g (10 mmol) of 2S(+)glycidyl-3-nitrobenzenesulfonate and 1.5 g (11 mmol) of potassium carbonate in 25 mL reagent grade acetone was refluxed overnight. The mixture was then allowed to cool to room temperature and the solids were removed by vacuum filtration. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organics were washed once with water, twice with brine, dried over sodium sulfate and concentrated in vacuo. Then the solid was dried under vacuum to give 2.65 g of the title compound as a dull tan solid; mp 93–94° C.; 1H NMR (300 MHz, CDCl3) δ 1.44 (t, J=5.3 Hz, 3H), 2.71 (s, 3H), 2.74–2.80 (m, 1H), 2.92 (t, J=4.7 Hz, 1H), 3.37–3.43 (m, 1H), 4.00–4.06 (m, 1 H), 4.27–4.31 (m, 1H), 4.37 (q, J=5.3 Hz, 2H), 6.86 (dd, J=5.5, 3.0 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.67 (d, J=3.0 Hz, 1H), 8.32 (s, 1H); MS (ES) m/z: 275.9 (MH+); HRMS Calcd. for C15H18NO4(MH+): 276.1236. Found: 276.1228.