Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: COCCN
Product: COCCNc1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(2-methoxy-ethyl-amino)-nicotinamide was prepared starting from intermediate E and 2-methoxyethylamine. MS calcd. for C25H23ClN4O3 [(M+H)+] 463.2, obsd. 463.0.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:23][C:24]1[CH:25]=[C:26]([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:30]([NH:33][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=3)=[CH:16][CH:17]=2)([CH3:31])[CH3:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CCCCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC(C)(N)c1cccc(Cl)c1
Product: CCCCCCc1ccc(C#Cc2ccc(CNC(C)(C)c3cccc(Cl)c3)cc2)cc1
Yield: 80 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-[(4-hexylphenyl)ethynyl]benzaldehyde and 1-(3-chlorophenyl)-1-methylethylamine gave the title compound as a brown oil (80%). HPLC (Condition A), Rt: 4.73 min (HPLC purity: 98.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+].ClCCl>[Cl:10][CH2:11][C:12]([NH:5][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)cc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)CCl)c1
Reaction time: 18 h
Yield: 94.1 %

Procedure:
3,5-Dimethylaniline (Acros, 10.50 mL, 84.05 mmol) in 2N sodium hydroxide (200 mL) was treated with chloroacetyl chloride (Acros, 10.00 mL, 125.7 mmol) as a solution in dichloromethane (200 mL) drop wise. After 18 hours, the layers were separated. The organic phase was washed with 1N hydrochloric acid, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide 15.64 g (94%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 6H), 4.21 (s, 2H), 6.73 (s, 1H), 7.20 (s, 2H), 10.11 (br s, 1H); MS (DCI/NH3) m/e 198 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH2:5][C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[C@H:3]1[C:12]([O:14]C)=[O:13].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:16])[C@@H:4]([CH2:5][C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@@H]1[C@H](CC2(C)OCCO2)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C[C@H]2[C@@H](C(=O)O)C2(C)C)OCCO1
Temperature: 51 °C
Yield: 59.9 %

Procedure:
To a solution of 0.8 g of methyl (1R,cis)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-ylmethyl)cyclopropanecarboxylate in 5 ml of methanol, was added 1.6 ml of a 10% aqueous sodium hydroxide solution. The mixture was heated at 51° C. for 16 hours. The resulting mixture was diluted with water, acidified to pH 3 with 1 N hydrochloric acid, extracted with diethyl ether, and the extract was dried over magnesium sulfate and stripped to give 0.45 g of the desired product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (181 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (250 mg, 0.65 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (399 mg, 0.85 mmol) in chloroform (8 mL). DIEA (620 μL, 3.55 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=587 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=4)=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[C:14]([NH:16][C@@H:17]([C:19]([O:21]C(C)(C)C)=[O:20])[CH3:18])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1.CS(C)=O>C(Cl)Cl.O>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=4)=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[C:14]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N[C@H](C)C(=O)O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)-D-alaninate (375 mg, 0.495 mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was azetroped with toluene (2×30 mL) to give a viscous oily solid. DMSO (5 mL) was added and the solution was sonicated. To this solution was added water (60 mL) and the mixture was sonicated for 5 mins then stirred at room temperature for 20 mins. The white solid was isolated by filtration and washed with additional water (20 mL) and isohexanes (30 mL). The material was dried under vacuum, suspended in ACN (20 mL), then diluted with diethyl ether (30 mL) and stirred for 20 mins. The suspension was filtered and the wet solid was dried under vacuum to give 189.3 mg (55%) of ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine Compound 327 as a white powder. LCMS-ESI (m/z) calculated for C38H46N4O5S: 670.3. found 671.0 [M+H]+, tR=13.32 min (Method 10). The chiral purity was calculated at >99% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.16 (s, 2H), 8.56 (d, J=8.8 Hz, 1H), 8.48 (d, J=7.4 Hz, 1H), 8.35-8.26 (m, 2H), 7.84-7.76 (m, 2H), 7.70 (d, J=3.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.13-7.05 (m, 2H), 6.92 (d, J=3.8 Hz, 1H), 4.86-4.77 (m, 1H), 4.29-4.18 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.20-3.10 (m, 1H), 3.08-2.94 (m, 1H), 1.80-1.68 (m, 2H), 1.51-1.22 (m, 20H), 0.94-0.83 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:15]2=[O:29])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[CH3:1][C:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:23]3[CH2:28][CH2:27][N:26]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:25][CH2:24]3)[C:15]2=[O:29])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(Cn2c(=O)n(C3CCNCC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(Cn2c(=O)n(C3CCN(C(=O)OCc4ccccc4)CC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a mixture of 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-(3-piperidin-4-yl)-1,3-dihydrobenzimidazol-2-one prepared in Example 579 (90 mg, 0.23 mmol) and methylene chloride (5 ml), triethylamine (75 mg, 0.74 mmol) and benzyl chloroformate (126 mg, 0.74 mmol) were added in this order with cooling on ice-bath followed by stirring at room temperature for 3 hours. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=1/1) to afford benzyl 4-[3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]piperidine-1-carboxylate (25 mg, yield 21%) as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[Si:63]([O:70][CH2:71][CH2:72][N:73]1[CH:77]=[CH:76][C:75]([NH2:78])=[N:74]1)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64]>>[C:66]([Si:63]([CH3:65])([CH3:64])[O:70][CH2:71][CH2:72][N:73]1[CH:77]=[CH:76][C:75]([NH:78][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:11](=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:74]1)([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-amine (WO2009127544) (0.16 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as a off white foam (Yield 0.1 g, 33%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[C:45]([F:47])[C:44]([OH:48])=[C:43]([F:49])[CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[C:45]([F:47])[C:44]([OH:48])=[C:43]([F:49])[CH:42]=2)[CH2:37][CH2:36][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:34][CH2:33]1
Reactant: Oc1c(F)cc(CCCC2(O)CCNCC2)cc1F
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3cc(F)c(O)c(F)c3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-hydroxy-4-(3-(3,5-difluoro-4-hydroxyphenyl) propyl)piperidine.HCl (from EXAMPLE 83, Step B) using procedures analogous to those described in EXAMPLE 71, Steps A and B. For the title compound: 1H NMR (500 MHz) 8 0.95-3.42 (35H), 5.16 (ABq, J=12.0, 2H), 6.56 (d, J=8.0, 2H), 7.21-7.30 (5H); ESI-MS 571 (M+H).
Reaction SMILES: Cl[CH:2]([Cl:23])[B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:8])[C:5]([CH3:22])([CH3:21])[O:4]1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1.C(OCC)(=O)C>[Cl:23][CH:2]([B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])([CH3:8])[C:5]([CH3:21])([CH3:22])[O:4]1)[CH2:24][CH3:25]
Reactant: CC(CCC1(C)OB(C(Cl)Cl)OC1(C)C)CC(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
0.86 g (2.3 mmol) of tert-butyl 5-[2-(dichloromethyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to -78° C. under a nitrogen atmosphere. 2.6 ml (2.6 mmol) of 1 M ethylmagnesium bromide in tetrahydrofuran were added dropwise, the resulting solution wasstirred for 16 hours while slowly warming to room temperature and then diluted with ethyl acetate and extracted with 2M hydrochloric acid and brine. The organic phase was dried over sodium sulphate and then evporatedunder a vacuum to give 0.83 g of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=1)=O.[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:43]=1[C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:43]=1[C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:15][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=2)=[CH:51][CH:50]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (89 mg, 0.42 mmol) was added to a DCE solution (1 mL) of ethyl 3-(5-(2-formyl-4-methoxyphenyl)picolinamido)propanoate (100 mg, 0.28 mmol), 2′,4′-dichloro-[1,1′-biphenyl]-4-amine (100 mg, 0.42 mmol), and AcOH (0.02 mL, 0.28 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH:13]=1>C(O)C.[Pd]>[O:12]1[C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[CH3:1])=[CH:13][C:9]=2[N:10]=[CH:11]1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccc2ocnc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1Oc1ccc2ocnc2c1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of 5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole (1.65 g, 6.12 mmol) in ethanol was added Pd/C (0.130 g, 0.122 mmol). After stirring under hydrogen atmosphere for 16 hours, the mixture was filtered and the filtrate was concentrated to provide the product (0.81 g, 55%) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33]Cl>>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1
Reactant: CN(C)CCCl
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OCCN(C)C
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 37, 6-hydroxy-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-dimethylaminoethyl chloride to give 6-(2-dimethylaminoethoxy)-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 47% yield, m.p. 125°-126° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11].N1C=CC=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1CCN
Solvent: O
Solvent: c1ccncc1
Product: COc1ccccc1CCNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 2-(2-methoxyphenyl)ethylamine (1510 mg, 10 mmol, Aldrich), pyridine (10 mL), 4-(trifluoromethyl)benzoyl chloride (2 mL, 10 mmol, Fluka). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaHCO3 (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/CH2Cl2 to give N-(2-methoxyphenethyl)-4-(trifluoromethyl)benzamide. MS (ESI pos. ion) m/z: 324 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([OH:20])=[O:19])=O)(C)(C)C.[C:21](=O)([O-])[O-].[K+].[K+].IC.[ClH:29].O1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[ClH:29].[CH:9]1([C:18]([O:20][CH3:21])=[O:19])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2C1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1NCCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 2-(tert-butyoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (0.500 g, 1.80 mmol), potassium carbonate (0.324 g, 2.34 mmol), and iodomethane (0.384 g, 2.70 mmol) in 3 mL of DMF was stirred at rt for 3 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. To a solution of the resultant residue (0.400 g, 1.37 mmol) was added 4 N HCl in dioxane (2.06 mL, 8.22 mmol). After 2 hours, the reaction was concentrated in vacuo to provide the title compound as a beige solid that gave a mass ion (ES+) of 192.2. This crude intermediate was used to prepare Example 12, by the procedure described for Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][CH2:22]C(OCC)=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.CC1C2N3C=CN=C3C(=O)[NH:37]C=2C2C=CC=CC1=2.[H-].[Na+].C[Si](Cl)(C)C.BrCCCC#N>CN(C)C=O>[CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]#[N:37])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CCCCC1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: C[Si](C)(C)Cl
Agent: N#CCCCBr
Agent: [H-]
Solvent: CN(C)C=O
Product: CC1(CCCC#N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 2 h

Procedure:
The process is performed as in Example 50 for the preparation of ethyl 5-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)-valerate but starting with 1.42 g of 10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 75 ml of dimethylformamide, 1 g of sodium hydride, 0.84 ml of trimethylsilyl chloride and 0.76 ml of 4-bromo-butyronitrile. The product is first purified by crystallization from acetonitrile, then by heating of the crystals to reflux in an ethyl acetate/methanol mixture (9/1 by volume). After allowing to stand for 2 hours at a temperature in the region of 20° C., the suspension is filtered and the solid is washed with ethyl acetate and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 0.83 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)-butyronitrile is obtained in the form of an off-white solid melting above 260° C. (Analysis, % calculated C: 71.04, H: 5.30, N: 18.41, O: 5.26, % found C: 70.7, H: 5.5, N: 18.6).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH2:33]Br)[CH:26]=1>CC(C)=O>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH2:33][O:1][C:2]2[CH:3]=[C:4]([C:8]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH:26]=1
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Reactant: BrCC#Cc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(OC)(c1cccc(OCC#Cc2cccnc2)c1)c1nccs1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.25 g), potassium carbonate (0.28 g), 3-(3-pyridyl)prop-2-yn-1-yl bromide hydrobromide (0.28 g) and acetone (5 ml) was stirred and heated to reflux for 17 hours. The mixture was cooled to ambient temperature, filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with hexane/ethyl acetate (1:1 v/v) to give 2-[1-[3-(3-(3-pyridyl)prop-2-yn-1-yloxy)phenyl]-1-methoxypropyl]thiazole as an oil (0.217 g, 59%).