Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.N1(O)C2C=CC=CC=2N=N1.[NH:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:29].C(N(C(C)C)CC)C>CN(C=O)C>[NH:2]([C:9]1([C:14]([NH:29][NH:28][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C1(Nc2ccccc2)CCCC1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NNC(=O)C1(Nc2ccccc2)CCCC1

Procedure:
1-Anilinocyclopentanecarboxylic acid hydrochloride and N-[3-(dimethylaminopropyl)]-N′-ethylcarbodiimide hydrochloride, 1H-1,2,3-benzotriazol-1-ol hydrate, tert-butyl hydrazinecarboxylate, N,N-diethylisopropylamine were stirred in DMF at room temperature to obtain tert-butyl 2-[(1-anilinocyclopentyl)carbonyl]hydrazinecarboxylate.
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][CH2:26][NH:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=5)=[C:20]([O:38][CH3:39])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:40]=O>C(O)=O>[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][CH2:26][N:27]([CH2:28][C:29]5[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=5)[CH3:40])=[C:20]([O:38][CH3:39])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCNCc1ccc(C(C)C)cc1
Solvent: O=CO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)Cc1ccc(C(C)C)cc1
Yield: 81 %

Procedure:
The product from Example H17 (12 mg) was dissolved in 37% formaldehyde (1 mL) and 88% formic acid (1 mL). The solution was refluxed for 2 h. The solvents were removed by rotary evaporation and the product was purified by silica gel column chromatography giving the title compound (10 mg, 81%). 1H NMR (CDCl3) δ 1.25 (6H, d), 2.40 (3H, s), 2.90 (2H, m), 3.65 (2H, m), 3.90 (3H, s), 4.21 (2H, m), 6.91-7.00 (3H, m), 7.19-7.34 (4H, m), 7.46 (2H, d, J=8.4 Hz). 7.55 (1H, s), 7.68 (2H, d, J=8.6 Hz), 8.15 (1H, s). LCMS m/z=574 (m+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:26](Br)[CH:27]=[CH2:28].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:28]([C@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:11]1=[O:25])[CH:27]=[CH2:26]
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one (1481 mg, 3957 μmol; Example 35, Step A) and allyl bromide (360 μl, 4155 μmol) in THF (16 mL, 0.25 M) was added dropwise lithium bis(trimethylsilyl) amide (1M solution in THF, 4352 μl, 4352 μmol) at −78° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19]([NH:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.C([Cl:42])(=O)OCC.[N+](=C)=[N-].CC[O:48][CH2:49][CH3:50]>O1CCCC1.Cl>[Cl:1][CH2:2][C:49]([CH2:50][Cl:42])=[O:48].[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:27])[C:19]([NH:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23])=[O:20])=[CH:28][CH:29]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCOCC
Reactant: CCOC(=O)Cl
Agent: C=[N+]=[N-]
Agent: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)N[C@@H](C)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[2-{4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy}propionylalanine (400 mg) was dissolved in 10 ml of tetrahydrofuran, added with 0.15 ml of triethylamine and cooled to 0° C. Ethyl chlorocarbonate (0.1 ml) was added and after 5 minutes, excessive diazomethane ether solution was added, and the mixture was stirred for one hour. Then, several drops of conc. hydrochloric acid were added and, after stirring for 10 minutes, the reaction mixture was washed with water, extracted with ether, and the extract dried over anhydrous magnesium sulfate. The oily product obtained by evaporation of the solvent under a reduced pressure was subjected to silica gel medium pressure column chromatography to obtain 300 mg of the title compound as a colorless oily product.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:15](=[N:18][OH:19])[C:16]#N)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[K+].[CH2:22]([OH:24])[CH3:23].Cl>C(OCC)(=O)C.CCCCCC>[C:1]([C:9]1[CH:10]=[C:11](/[C:15](=[N:18]/[OH:19])/[C:16]([O:24][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(=NO)c1cccc(C(=O)c2ccccc2)c1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
A mixture of 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile (14.5 g), 4N aqueous solution of potassium hydroxide (80 ml) and ethanol (80 ml) was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added to make the solution acidic and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in ethanol (150 ml) and concentrated sulfuric acid (catalytic amount) was added. The reaction mixture was heated under reflux for 15 hours, cooled to room temperature, poured into an aqueous saturated solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl Z-2-(3-benzoylphenyl)-2-(hydroxyimino)acetate (2.48 g, yield 14%) as a pale-brown oil from an ethyl acetate-hexane (1:2, v/v)-eluted fraction.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([CH:38]1[CH2:41][CH:40]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:39]1)[CH3:37].BrC1C=CC(C2CC(=O)C2)=CC=1.BrC1C=CC=CC=1C=O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:45]3[CH:44]=[CH:43][C:42]([CH:40]4[CH2:41][CH:38]([CH2:36][CH3:37])[CH2:39]4)=[CH:47][CH:46]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCC1CC(c2ccc(B(O)O)cc2)C1
Agent: O=C1CC(c2ccc(Br)cc2)C1
Agent: O=Cc1ccccc1Br
Product: CCC1CC(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)C1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-(3-ethyl-cyclobutyl)phenylboronic acid (41 mg, 0.2 mmol, prepared according to general procedure Y using 3-(4-bromophenyl)cyclobutan-1-one in stead of bromobenzaldehyde) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4′-(3-ethyl-cyclobutyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([O:34][CH3:35])[CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: COc1cc(N)ccc1-c1nc2ccccc2s1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)ccc1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (0.062 g, 0.336 mmol) and thionyl chloride (5 ml) was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and the excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, 2-(4-amino-2-methoxyphenyl)benzothiazole (0.086 g, 0.336 mmol) and Hunig's base (0.052 g, 0.403 mmol) in dry THF (5 ml) to give the title compound (0.105 g, 74%) as a pale yellow solid after work-up.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].CCN(CC)CC.[CH2:19]([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH3:21].C(Cl)Cl>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:23][O:22][CH2:19][CH2:20][CH3:21]
Reactant: CCCOCCNCCOCCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOCCN(CCOCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 72.8 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (2.94 g, 18.45 mmol) in DMF (30 mL) were added Et3N (3.11 g, 30.75 mmol) and bis(2-propoxyethyl)amine (1.16 g, 6.15 mmol) with stirring. The reaction mixture was heated at 90° C. overnight, then cooled to rt and poured into CH2Cl2 (100 mL). The organic phase was washed with water (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as yellow oil (1.47 g, 73%).
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17][CH:18]1[O:23][CH2:22][CH2:21][CH2:20][O:19]1>C(OC(=O)C)C>[Br-:15].[O:19]1[CH2:20][CH2:21][CH2:22][O:23][CH:18]1[CH2:17][CH2:16][N+:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: BrCCC1OCCCO1
Solvent: CCOC(C)=O
Product: C(=Cc1cc[n+](CCC2OCCCO2)cc1)c1ccccc1
Product: [Br-]
Yield: 90.5 %

Procedure:
4-styrylpyridine (1.81 g) and 2-(2-bromoethyl) 1,3-dioxane (1.95 g) were stirred and refluxed in ethylacetate (15 ml) solution for 15 hours. After cooling of the reaction mixture creamy crystals were separated by filtration, washed with ethyl ether and dried to give 3.4 g of N-[2-(1,3-dioxane-2-yl)ethyl]-4-styrylpyridinium bromide.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1.[CH3:19][C:20]([CH3:22])=O.[BH4-].[Na+].Cl>CO.CCOCC.O1CCOCC1>[ClH:2].[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][N:15]([CH:20]([CH3:22])[CH3:19])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1
Reactant: CC(C)=O
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CCc1cc(Cl)c2c(c1)[C@H]1CN(C(C)C)C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.6 %

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (Example 29) (19 mg, 0.066 mmol) in 2 mL of methanol was added acetone (0.015 mL, 0.20 mmol) followed by sodium borohydride (13 mg, 0.33 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 18 h. The reaction was concentrated and the residue was purified (ISCO, elution with 0-15% methanol/methylene chloride) to afford the free base. To the free base in 1 mL of ether was added 4N HCl in dioxane (0.05 mL). The mixture was concentrated in vacuo, triturated with ether, and dried in vacuo to afford 13 mg (60%) of the title compound of Example 64 as a white solid. 1H NMR (CD3OD): 7.36 (s, 1H), 7.07 and 7.02 (s, 1H), 4.27-4.21 and 4.16-4.11 (m, 1H), 3.88-3.35 (overlapping m, 6H), 2.70 (q, 2H), 1.48-1.42 (m, 6H), 1.26 (t, 3H). LRMS (ESI): 293.3/295.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.[Mg].[B:19](OC)([O:22]C)[O:20]C.Cl>O1CCCC1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][C:4]=2[F:17])=[CH:9][CH:10]=1)[CH2:15][CH3:16]
Reactant: CCCc1ccc(-c2ccc(Br)cc2F)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(B(O)O)cc2F)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
The product from step (ii) (10 g; 0.034 mol) in tetrahydrofuran (35 ml) was added dropwise to a suspension of magnesium turnings (0.88 g) in tetrahydrofuran (5 ml). The mixture was warmed to 75° C. when the Grignard reaction started. Further of the bromo compound was slowly added and the external heat source removed, a gentle reflux being maintained. After complete addition, the mixture was heated for 30 mins under reflux and then cooled to 15° C. A dry nitrogen atmosphere was introduced and trimethyl borate (3.77 g; 0.0363 mol) was slowly added and the mixture stirred at 15°-20° C. for 16 hrs. A 20% soln of hydrochloric acid (50 ml) was slowly added, the organic layer was separated, and the aqueous layer extracted with ether (2×50 ml). The combined organic layers were washed with brine and dried over sodium sulphate. Upon evaporation of the solvents a yellow solid was obtained. Yield 8.7 g; 100%.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1.[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)(Cl)Cl>[CH2:41]([C:42]1[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][O:8][CH2:13][CH2:12]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=1)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccccc1NCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Triethylamine (0.42 ml) was added to a solution containing N-(3-morpholinopropyl)-1,2-benzenediamine (0.640 g) in chloroform (3.5 ml), and then a solution containing stearoyl chloride (0.825 g) in chloroform (3.5 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (2.25 ml) was added to a solution containing the residue (1.442 g) in ethanol (15 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.296 g) was purified by silica gel column chromatography (silica gel 40 g, ethyl acetate), thereby yielding the entitled compound (1.088 g) as yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[Cl:23])[CH:8]=2)[N:3]=1.[NH2:24][C@H:25]1[C@H:29]([OH:30])[CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]1.C1CCN2C(=NCCC2)CC1>C(#N)C.CCOC(C)=O>[Cl:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[C:13]([Cl:23])[C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][C@H:25]1[C@H:29]([OH:30])[CH2:28][C@@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]1)[N:11]=[CH:10]2
Reactant: COC(=O)C1C[C@@H](N)[C@H](O)C1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1C[C@@H](O)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Temperature: 65 °C
Yield: 67.8 %

Procedure:
2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (0.576 g, 1.558 mmol), methyl (3R,4R)-3-amino-4-hydroxycyclopentane-1-carboxylate (0.372 g, 2.337 mmol) were taken up in acetonitrile (3 ml) and DBU (0.470 ml, 3.12 mmol) was added. The reaction was purged with N2 for 5 minutes then heated to 65° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified via flash chromatography (0-100% Hex/EtOAc; 12 g column), and (1S,3R,4R)-methyl 3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-hydroxycyclopentanecarboxylate (0.520 g, 1.056 mmol, 67.8% yield) was recovered. MS (ES+) C23H23Cl2N3O5 requires: 492, found: 493 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].BrC1C=CC(S(O[CH2:35][CH2:36][C@@H:37]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[OH:38])(=O)=O)=CC=1.C(OCC)C>CN(C)C=O.O>[NH3:5].[CH:39]1([CH:37]([OH:38])[CH2:36][CH2:35][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)[CH3:1])[CH2:4]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=S(=O)(OCC[C@H](O)C1CCCCC1)c1ccc(Br)cc1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCC(O)C3CCCCC3)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) in N,N-dimethylformamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and (S)-3-cyclohexyl-3-hydroxypropyl 4-bromobenzenesulfonate (J. A. Werner et al, J. Org. Chem., 1996, 61, 587) (0.08 ml, 0.89 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (90 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([N+:12]([O-])=O)[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([NH:26][CH:27]([CH2:31][CH2:32][CH3:33])[C:28](O)=[O:29])=[O:25])[CH:19]=[C:20]([F:22])[CH:21]=1>>[CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:25])[CH2:23][C:18]3[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([F:15])[CH:17]=3)[CH2:31][CH2:32][CH3:33])[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1
Reactant: CC1(Cn2cnc([N+](=O)[O-])c2)COC1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CC2(C)COC2)cn1

Procedure:
1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole was reduced and then coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 421.3 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=O)[S:28][CH:29]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:30]([C:27]3[S:28][CH:29]=[C:25]([Br:24])[CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3cc(Br)cs3)nn12

Procedure:
The title compound, MS m/e (%): 375 (M++1, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 4-bromothiophene-2-carboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][C:16]2[CH:35]=[CH:34][C:19]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[O:14])[CH2:9]1.[NH:36]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:3][C:2]1[N:36]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]4)=[CH:34][CH:35]=3)=[O:14])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)[C@H]3CCNC3)cc2)CC1
Product: Cc1ccc(N2CC[C@H](C(=O)Nc3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-bromo-6-methylpyridazine for 3-bromopyridine and (S)-tert-butyl 4-(4-(pyrrolidine-3-carboxamido)phenoxy)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[C:33]([CH:41]2[CH2:43][CH2:42]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[C:33]([CH:41]2[CH2:42][CH2:43]2)=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: Nc1cccc2c1c(C1CC1)nn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3c(C3CC3)nn4Cc3ccccc3)cnc2c1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a magnetically stirred, ice cooled, suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (29.5 mg, 0.125 mmol) (prepared as in Example 1, steps A-D) in dichloromethane (1 mL) was added N,N-dimethylformamide (5 μL) followed by oxalyl chloride (79.7 μL, 0.159 mmol; 2M solution in dichloromethane). The mixture was stirred in a sealed vial and allowed to warm to ambient temperature. The vial was occasionally vented to allow gases to evolve. After 30 minutes a solution of 1-benzyl-3-cyclopropyl-1H-indazol-4-amine (35.0 mg, 0.133 mmol) in dichloromethane was added followed by triethylamine (27.8 μL; 0.199 mmol). The mixture was stirred for 24 hours and then concentrated under reduced pressure. The material was purified by preparative thin layer chromatography, eluting with 10% methanol in dichloromethane. Further purification was carried out eluting with hexane/ethyl acetate (3:1). The desired band was isolated and concentrated to give N-(1-benzyl-3-cyclopropyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (17.5 mg). MS (APCI), positive scan, m/z=482.3 (M+H).