Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[F:23])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=3[F:23])[O:24][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 3-[[5-(3,4-difluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-difluoro-phenol (70 mg, 0.19 mmol, 1.0 eq) in acetone (2 mL) was added Cs2CO3 (90 mg, 0.28 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 10 min then isopropyl bromoacetate (40 mg, 0.22 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 30 min then water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 20:1) to give the title compound as a colorless oil (73 mg, 82%).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:32]([NH:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][OH:37])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O>CO.Cl.[Pd]>[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([NH:16][C@H:15]([C:32]([NH:34][C@H:35]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:36][OH:37])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 84.1 %

Procedure:
Prepared according to the method described in Example 1(e) above from a batch of (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(S)-N-(2-hydroxy-1-phenyl-ethyl)ornithine amide (1.78 g; from step (c) above) and 10% Pd/C (200 mg) in 100 mL of MeOH and 1.0 mL of HCl (conc.), yielding 1.15 g of the sub-title compound as a white foam.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:36]([F:39])([F:38])[F:37])[O:20][N:19]=[C:18]([C:21]3[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH:28]4[CH2:32][O:31][NH:30][CH2:29]4)=[O:26])=[C:23]([CH3:35])[CH:22]=3)[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)C.[BH3-]C#N.[Na+]>CO>[Cl:15][C:13]1[CH:12]=[C:11]([C:16]2([C:36]([F:37])([F:39])[F:38])[O:20][N:19]=[C:18]([C:21]3[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH:28]4[CH2:32][O:31][N:30]([CH2:2][CH3:3])[CH2:29]4)=[O:26])=[C:23]([CH3:35])[CH:22]=3)[CH2:17]2)[CH:10]=[C:9]([Cl:8])[CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CNOC1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1CC(NC(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
Crude 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-isoxazolidin-4-yl-2-methyl-benzamide trifluoroacetic acid salt (0.16 mmol) was dissolved in MeOH (0.8 ml). Then acetaldehyde (0.090 ml, 10 equiv) was added at 0° C. under an argon atmosphere. After stirring for 1 hour at 0° C., NaBH3CN (20 mg, 2 equiv) was added. The reaction mixture was left to stir over the weekend. It was then evaporated. Flash column chromatography eluting with ethyl acetate/methanol (10/0 to 9/1) afforded 7.5 mg of the expected compound as a mixture of diastereomers. LCMS (Method E) 2.02 min, M+H 516/518. 1H-NMR (MeOD, 400 MHz): 7.70-7.53 (m, 5H), 7.52-7.37 (m, 1H), 4.92-4.85 (m, 1H), 4.40-4.22 (m, 2H), 4.00 (d, 1H), 3.83-3.62 (m, 1H), 3.29-2.52 (m, 4H), 2.43 (s, 3H), 1.16 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([C:11]#[N:12])=[C:6]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:7]=1
Reactant: COc1ccccc1-c1nc(N)nc(S(C)=O)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccccc1-c1nc(N)nc(OCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(2-methoxy-phenyl)-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=4[F:37])=[O:25])=[C:19]([F:38])[CH:18]=3)[C:11]([CH2:14][O:15][CH3:16])=[C:12](Br)[N:8]2[N:7]=[CH:6][N:5]=1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=4[F:37])=[C:19]([F:38])[CH:18]=3)[C:11]([CH2:14][O:15][CH3:16])=[C:12]([C:49]3[CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH2:47][CH:48]=3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Intermediate AAC, Step 1) (500 mg, 0.875 mmol, 1.0 eq) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (677 mg, 2.19 mmol, 2.5 eq) followed by 1,4-dioxane (5 mL). Nitrogen was bubbled through the solution for 15 min and then 2M Na2CO3 (6 eq) was added. Nitrogen again bubbled through solution for 15 minutes and [1,1′-Bis(dipheylphosphino)ferrocene] (143 mg, 0.2 eq) was added. N2 was bubbled through the solution for an additional 15 min and then the reaction was placed in a preheated 80° C. oil bath for 17 h. The reaction solution was allowed to cool to rt and was diluted with EtOAc and water. The organic layer was washed water and brine. The combined organic layers were dried (Na2SO4), filtered, condensed, and purified via flash column chromatography (1:1 tetrahydrofuran/hexanes). The purified fractions were collected, evaporated, and left under vacuum overnight to yield the title compound (520 mg, 88.2% yield). 1H-NMR (DMSO-d6) MS [M+H]+=674; LCMS RT=3.51 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]1[CH:21]2[N:16]([CH2:17][CH2:18][C:19](=O)[CH2:20]2)[CH2:15][CH2:14]1>>[CH2:13]1[CH:21]2[N:16]([CH2:17][CH:18]=[C:19]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=C1CCN2CCCC2C1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
The 5-nitro-1H-indole (4.48 g, 27.6 mmol) and 7-octahydroindolizinone (5.0 g, 35.9 mmol) were converted to product by the procedure of Preparation IV to yield 2.99 g. (38.5%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH3:21])[CH2:16][C:15]2=[O:22])[CH:11]=[N:10][CH:9]=1)(C)(C)C>CC(O)=O.C1COCC1.O>[OH:6][CH2:7][C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH3:21])[CH2:16][C:15]2=[O:22])[CH:11]=[N:10][CH:9]=1
Reactant: CCCC1CC(=O)N(Cn2cncc2C(C)(C)O[SiH2]C(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCC1CC(=O)N(Cn2cncc2CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-ylmethyl]-4-propyl-pyrrolidin-2-one a30 (0.5 g, 0.0014 mol) is heated at 80° C. in a AcOH/THF/H2O mixture (9 ml/3 ml/3 ml) for 9 h, then stirred overnight at room temperature and concentrated in vacuo. The residue is dry by azeotropic distillation with toluene, purified by chromatography on silicagel (CH2Cl2/MeOH) and the solid is recrystallized from AcOEt to give 1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one 80 (0. 1 14 g, 35%).
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)=[O:33])[CH2:28][CH2:27]1>>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([CH:37]2[CH2:38][CH2:39][N:34]([C:32]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:33])[CH2:35][CH2:36]2)=[CH:41][CH:42]=1
Reactant: CN1CCN(C(=O)N2CCC(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: CN1CCN(C(=O)N2CCC(c3ccc(N)cc3)CC2)CC1

Procedure:
[4-(4-Amino-phenyl)-piperidin-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (4-Methyl-piperazin-1-yl)-[4-(4-nitro-phenyl)-piperidin-1-yl]-methanone.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([N:14]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:42])[C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16])=[O:13])C1C=CC=CC=1>C(O)C.CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([N:14]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:42])[C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=4)[CH2:29][CH2:30]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16])=[O:13]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3cccc(OCc4ccccc4)c3)CC2)cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3cccc(O)c3)CC2)cc1OC
Yield: 78.3 %

Procedure:
1-(3-Benzyloxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (6 g) was dissolved in a mixture of ethanol (100 ml) and DMF (50 ml), and 10% palladium on carbon (1 g) was added thereto. The mixture was hydrogenated at 50° C. After completion of reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:ethyl acetate:methanol=100:2) to give 1-(3-hydroxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[NH:19]>C1(C)C=CC=CC=1>[CH:20]1([C:18]2[N:19]=[C:13]([CH:12]=[CH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:15][N:17]=2)[CH2:22][CH2:21]1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: N=C(NO)C1CC1
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(C3CC3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 2.74 g (13.2 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 20 mL of toluene, 2.18 g (13.4 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-cyclopropanecarboximidamide (compound of Example 35; 2.1 g, 26.9 mmol) in 10 mL of toluene was added to the above reaction mixture as one portion at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 20 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 10 mL of toluene. The organic layers were combined and washed with 20 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]([C:13]2[N:17]3[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)[CH3:12])=[C:9]([F:25])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:26].[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH:11]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:25])[N:6]([CH3:26])[N:5]=[CH:4]4)[CH3:12])=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Reactant: NOCCO
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 42.8 %

Procedure:
A solution of 1-(3-(1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (110 mg, 0.31 mmol) and 2-(aminooxy)ethanol (intermediate S) (35.1 mg, 0.31 mmol) in 10 mL of MeOH was stirred at it overnight. Solvent was evaporated and the residue was partitioned between water and EtOAc. Aqueous layer was extracted with EtOAc twice. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 55 mg (43%) of the title compound as white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.01 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.16 (d, 1H), 5.16 (m, 1H), 4.29 (m, 2H), 3.99 (s, 3H), 3.82 (m, 2H), 2.17 (s, 3H), 1.95 (d, 3H). LCMS (method B): [MH]+=415.0, tR=2.64 min. Chiral separation (method G) provided enantiomeric pure compounds example 51-R and example 51-S.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1OC

Procedure:
2-Chloro-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine, 3,4-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[C@H:46]([CH3:47])[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH3:48])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:14]([C:49]2[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=2)[O:52][CH2:53][CH2:54]OS(C)(=O)=O)[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[C@H:42]([CH3:48])[CH2:43][CH2:44][CH2:45][C@@H:46]5[CH3:47])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:14]([C:49]2[CH:62]=[CH:61][CH:60]=[C:51]([O:52][CH2:53][CH2:54][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:50]=2)[N:13]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCN(C)CC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
1-Methylpiperazine (48 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. 1-Methylpiperazine (48 μL, 0.43 mmol) was added and the reaction continued for a further 24 h. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O to give the title compound (42 mg, 38%) as an off-white solid. LCMS (Method 5): Rt 3.76 min, m/z 775.6 [MH+]. 1H NMR (400 MHz, do-DMSO): 0.60 (3H, d, J=6.0 Hz), 0.63 (3H, d, J=6.0 Hz), 1.28 (9H, s), 1.36-1.62 (3H, m), 1.65-1.75 (2H, m), 1.76-1.99 (3H, m), 2.03-2.12 (2H, m), 2.14-2.26 (3H, m), 2.34-2.61 (5H, m, obscured by solvent), 2.63-2.74 (3H, m), 3.11-3.24 (2H, m), 3.28-3.38 (2H, m), 4.1 (2H, t, J=5.8 Hz), 4.78-4.87 (1H, m), 5.50-5.56 (1H, m), 6.33 (1H, s), 6.93-7.00 (1H, m), 7.05-7.13 (3H, m), 7.20 (1H, dd, J=9.9, 2.4 Hz), 7.23-7.31 (2H, m), 7.34 (2H, t, J=8.0 Hz), 7.40 (1H, t, J=8.0 Hz), 7.67 (1H, d, J=9.9 Hz), 7.87-7.91 (1H, m), 8.11 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:16]Br>FC(F)(F)C(O)=O.C(Cl)Cl>[Br:16][C:7]1[C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[C:9]([S:11][C:12]([F:15])([F:13])[F:14])[CH:8]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(Br)cc(SC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
24 g of finely powdered 2-nitro-4-trifluoromethylmercapto-aniline were dissolved in 50 ml of trifluoroacetic acid, and 18 g of bromine were metered in at 20° C. The mixture was then subsequently stirred at 20° C. for 3 hours and at 40° C. for a further 30 minutes and poured onto water, and the product was taken up in methylene chloride. After removal of the solvent, 31 g of 6-bromo-2-nitro-4-trifluoromethylmercapto-aniline were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][CH:5]([CH2:13][CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][CH:5]([CH2:13][CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)butanoic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)butanoate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:12]=1[C:13]([C:15]1C=CC=CC=1)=[O:14].O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[C:13]([C:12]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:11]=1[NH:10][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])(=[O:14])[CH3:15]
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: O=C(O)c1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(C)=O)c(NC(=O)c2ccccn2)c1
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a suspension of 2-picolic acid (3.73 g, 30.3 mmol) and 2-amino-4-methoxybenzophenone (5.0 g, 30.3 mmol) at −30° C. dissolved in pyridine (150 mL) was added POCl3 (3.7 mL, 45.4 mmol) in 5 min. the reaction mixture was stirred for 3 hr at the temperature, and stirred at rt overnite. The reaction mixture was poured into cold water and extracted with EtOAc (3×). The combined extract was dried to provide the product (7.67 g, 93%): 1H NMR (methanol-d4) δ ppm 2.65 (s, 3H), 3.92 (s, 3H), 6.78 (m, 1H), 7.60 (m, 1H), 8.00 (m, 1H), 8.06 (m, 1H), 8.21 (d, J=7.63 Hz, 1H), 8.59 (t, J=2.29 Hz, 1H), 8.76 (d, J=3.97 Hz, 1H). LC-MS (retention time: 1.56, Method D), MS m/z 271 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:30]3[CH2:31][CH2:32][N:27]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:28][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 44.1 g (0.250 mole) of N-benzylpiperazine, followed by 14.2 g (0.0750 mole) of titanium tetrachloride. The mixture was heated under reflux for 3 hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted further with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was taken up in 50 ml of hot methanol, from which 7.00 g (59%) of product crystallized. Recrystallization from a solution of dichloromethane (10 ml) to which methanol (50 ml) was added afforded the analytical sample, mp 129°-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(F)c(C)c2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.