Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:41][C:40]=4[F:50])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[F:45][C:44]1[CH:43]=[C:42]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:41]=[C:40]([F:50])[C:39]=1[C:34]1[N:33]=[C:32]([C:30]([NH:29][C:12]2[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:31])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(C(C)(C)O)cc4F)n3)cnc3c2CCC3O)C1

Procedure:
The amide intermediate prepared as described above was treated with THF (6 mL), MeOH (6 mL) and 1.0 M aq. NaOH (7.39 mL, 7.39 mmol) at room temperature for 20 min. The volatile solvents were removed under reduced pressure. The residue was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under reduced pressure to give an alcohol intermediate, tert-butyl ((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:23][C:24]#[N:25])[CH2:16][N:15]([S:17]([CH:20]4[CH2:22][CH2:21]4)(=[O:19])=[O:18])[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:26]1([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[N:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[CH:20]1([S:17]([N:15]2[CH2:16][C:13]([CH2:23][C:24]#[N:25])([N:11]3[CH:12]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:35][C:34]5[CH:33]=[CH:32][C:31]([N:26]6[CH:30]=[CH:29][CH:28]=[N:27]6)=[CH:37][CH:36]=5)[N:7]=4)[CH:9]=[N:10]3)[CH2:14]2)(=[O:19])=[O:18])[CH2:22][CH2:21]1
Reactant: Nc1ccc(-n2cccn2)cc1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CN(S(=O)(=O)C2CC2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(-n5cccn5)cc4)n3)cn2)CN(S(=O)(=O)C2CC2)C1

Procedure:
A mixture of (3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile (30 mg, 0.08 mmol), 4-(1H-pyrazol-1-yl)aniline (18.9 mg, 0.119 mmol), and p-toluenesulfonic acid (12 mg, 0.067 mmol) in dry 1,4-dioxane (0.6 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC to give the desired product as a racemic mixture (17.6 mg, 44%). LCMS (M+H) 502.0.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl[C:13]1[C:18]2=[CH:19][N:20]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:21]=[C:17]2[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[N:20]1[CH:19]=[C:18]2[C:13]([NH:3][C:4]3[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][N:9]=3)=[N:14][CH:15]=[CH:16][C:17]2=[N:21]1
Reactant: N#Cc1ccc(N)nc1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc1
Yield: 51.5 %

Procedure:
Sodium hydride (12 mg, 0.30 mmol) was added to a solution of 6-amino-3-pyridinecarbonitrile (36 mg, 0.30 mmol) in DMF (2 mL) and the resultant mixture was stirred for 5 minutes before 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (80 mg, 0.27 mmol) was added. The reaction vial was sealed, purged with nitrogen and irradiated in a microwave at 150° C. for 10 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (53 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.57 (d, J=0.9 Hz, 1H), 8.98 (dd, J=2.3, 0.8 Hz, 1H), 8.47 (dd, J=8.7, 2.3 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.89-7.83 (m, 2H), 7.77 (dd, J=9.1, 7.2 Hz, 1H), 7.65-7.61 (m, 2H). LCMS (Method B): RT=3.05 min, m/z: 381 [M+H+].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[CH2:7]([O:9][P:10](Cl)Cl)[CH3:8]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[P:10]1[O:9][CH2:7][CH3:8]
Reactant: CNCCNC
Reactant: CCOP(Cl)Cl
Product: CCOP1N(C)CCN1C
Yield: 45.9 %

Procedure:
Substantially the same procedure was followed as in Example 1, with 3.00 grams (34 mmol) N,N'-dimethylethylenediamine and 4.55 grams (31 mmol) ethylphosphorodichloridite to produce 2.31 grams of 1,3-dimethyl-2-ethoxy-1,3-diaza-2-phosphacyclopentane, ##STR25## as phosphorus amide catalyst.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:12][C@@H:13]1[C:18]2=[C:19]3[C:28](=[C:29]([O:31][CH3:32])[CH:30]=[C:17]2[O:16][C:15]([CH3:40])([CH3:39])[C@@H:14]1[OH:41])[C:27](=[O:33])[C:26]1[C:21](=[CH:22][CH:23]=[C:24]2[CH:37]=[CH:36][CH:35]=[CH:34][C:25]2=1)[N:20]3[CH3:38]>N1C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[C:1]([O:41][CH:14]2[C:15]([CH3:39])([CH3:40])[O:16][C:17]3[C:18](=[C:19]4[C:28](=[C:29]([O:31][CH3:32])[CH:30]=3)[C:27](=[O:33])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]5[CH:37]=[CH:36][CH:35]=[CH:34][C:25]5=3)[N:20]4[CH3:38])[CH:13]2[OH:12])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(O)C(OC(=O)/C=C/c1ccccc1)C(C)(C)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1.33 mmol of cinnamoyl chloride are added to a previously cooled solution of 0.30 mmol of the compound of Example 4 in 4 ml of pyridine. After stirring at 0° C. for 90 minutes, the reaction mixture is evaporated under reduced pressure. Chromatography over silica gel (cyclohexane, and then cyclohexane/acetone: 94/6 to 90/10) allows the expected product to be isolated.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10])[CH2:3][CH3:4].[BH4-].[Li+]>C1COCC1>[CH3:1][C@@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:13]=[CH:14][CH:15]=1)[CH2:3][CH3:4]
Reactant: CC[C@@H](C)Oc1cccc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C)Oc1cccc(CO)c1
Temperature: 50 °C

Procedure:
To a solution of methyl 3-{[(1R)-1-methylpropyl]oxy}benzoate (3.50 g, 16.8 mmol) in THF (67 mL) was added 2M lithium borohydride solution in THF (25.2 ml, 50.4 mmol). The reaction was heated to 50° C. overnight. The reaction was quenched with MeOH and the solvents were concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3. The aqueous phase was extracted with dichloromethane and the organics were combined, washed with H2O (2 times) dried with MgSO4, filtered, and concentrated. The residue was purified on a silica gel cartridge (10% EtOAc/hexanes to 20% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (500 mg, 1.16 mmol) (obtained as described in Reference Example 77(2)) in methylene chloride (25 ml) were added methanesulfonyl chloride (269 μl, 3.48 mmol) and triethylamine (488 μl, 3.48 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 3 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (546 mg, yield 92%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)/[CH:5]=[N:6]/[S@@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[Li][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:6][S@@:7]([C:9]([CH3:11])([CH3:12])[CH3:10])=[O:8])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cccc(Br)c1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
(R,E)-N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide, 24-b, (12 g, 41.64 mmol) was dissolved in anhydrous THF (120 ml). The mixture was then cooled to −78° C. and PhLi (41 ml, 83.28 mmol) was added dropwise. After addition the mixture was allowed to stir at −78° C. for additional 2 h and warmed to room temperature for another 2 h. The mixture was quenched with saturated NH4Cl followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to provide the product, 24-c, (11.8 g, 77%). HPLC indicated that the diastereomer ratio is 90:10 and the product was used for the next step directly.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:38][Si](C(C)(C)C)(C)C)[C:22]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:23][C:4]=2[N:3]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([OH:38])[C:22]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]3)=[CH:23][C:4]=2[N:3]=1
Reactant: Cc1nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(O[Si](C)(C)C(C)(C)C)cc2n1Cc1ccc(C#N)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(O)cc2n1Cc1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-methyl-6-(tert-butyldimethylsilyl)oxy-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (3 g) in THF (50 mL) was added Bu4NF (4 mL, 1M)) at ambient temperature. After stirring at ambient temperature for 30 minutes the solvent was removed. The reaction was worked up between ethyl acetate and H2O. The organic layer was dried, concentrated and purified by silica gel chromatography (hexane/ethyl acetate/CH2Cl2 /methanol, gradient) to afford 2-methyl-6-hydroxy-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole.
Reaction SMILES: [F:1][S:2]([O-:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[NH2:21][NH2:22]>CO>[F:1][S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][C:16](=[N:21][NH2:22])[CH:15]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: O=S(=O)([O-])F
Reactant: COc1cc[n+](-c2ccc(Cl)cc2)cc1
Solvent: CO
Product: NN=c1ccn(-c2ccc(Cl)cc2)cc1
Product: O=S(=O)(O)F
Reaction time: 8 h

Procedure:
To a suspension of 3.2 g. (0.01 mole) of 1-(4-chlorophenyl)-4-methoxypyridinium fluorosulfonate, prepared by the process set forth in Example 1, in 20 ml. methanol was added 0.4 g. anhydrous hydrazine. The mixture was heated to boiling for a few minutes and the resulting clear orange solution was kept overnight at room temperature. The product, in the form of orange crystals, was obtained in two crops. The total weight was 2.97 g. (93%). The product was recrystallized from methanol, m.p. 174°-176° C. The elemental analyses for C, H, N and Cl were within ±0.4% of the theoretical values.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.C([NH:26][CH2:27][CH2:28][NH2:29])(OC(C)(C)C)=O.Cl>>[NH2:26][CH2:27][CH2:28][NH:29][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Agent: Cl
Product: COc1ccc2c(c1)CCn1c-2cc(NCCN)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and N-Boc-ethylenediamine as in Example 1 d, followed by treatment with HCl. 1H-NMR as mixture of two isomers (400 MHz, d6-DMSO) δ 9.25-8.40 (1H), 8.32 and 7.70 (d, 1H), 8.12 and 8.02 (br, 3H), 7.07-7.00 (m, 2H), 6.80 and 6.33 (s, 1H), 4.04 and 3.98 (t, 2H), 3.88 and 3.85 (s, 3H), 3.80 and 3.61 (q, 2H) and 3.08-2.94 (4H); MS (ESI) (M+H)+ 287. The spectrum acquired at 333K showed single isomers.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][C:41]12[CH2:48][CH:45]([NH:46][CH2:47]1)[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:46]1[CH2:47][C:41]3([CH3:40])[CH2:48][CH:45]1[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42]3)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester (890 mg, 3.8 mmol) in dry DMF (10 mL) at room temperature under an inert atmosphere of nitrogen was added HOBt (570 mg, 4.2 mmol) and EDAC (951 mg, 4.9 mmol), and the resulting solution was stirred for 30 min. 1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane hydrochloride (796 mg, 4.2 mmol) was added to the solution followed by DIPEA (1.98 mL, 11.4 mmol), and the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3×50 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by silica gel chromatography using a mixture of ethyl acetate and heptane (1:2) as eluent. Pure fractions were collected, the solvent evaporated in vacuo and dried in vacuo at 50° C. affording 800 mg (57%) of the title compound as a solid. MS-ESI m/z 369; 1H NMR (300 MHz, CDCl3) δ 0.94 (d, 3H), 1.04 (d, 3H), 1.14-1.19 (m, 4H), 1.24-1.29 (m, 2H), 1.39-1.45 (m, 4H), 1.58-1.63 (m, 1H), 1.76-1.79 (m, 1H), 3.25-3.30 (m, 1H), 3.35 (d) and 3.65 (d, 1H), 4.06-4.09 (m) and 4.64-4.67 (m, 1H), 4.42 (q, 2H), 7.27 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (d, 1H), 9.05 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:32])[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=1>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[CH:24][CH:23]=2)[CH:27]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)C=CNCc1ccc(C)cc1
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccc(C)cc3)C=C1C(C)=O)C2=O

Procedure:
The title compound 57 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 58 (110 mg, 0.57 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 57 as a yellow oil. (Yield 63.0 mg, 37%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=CC=CC=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccccc3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and aniline (9.1 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18 mg, 60%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccs1
Yield: 69.7 %

Procedure:
To a solution of 10.0 g (41.5 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 27.7 ml (200 mmol) of triethylamine in 100 ml of methylene chloride, 5.35 ml (50.0 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:20) to obtain powder. The powder was recrystallized from methanol/ethyl acetate (=1:20) to obtain 8.05 g of the desired compound (yield: 70.5%, yellow prisms).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].Cl>N1C=CC=CC=1>[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:26])=[CH:23][CH:22]=1)=[O:19]
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Yield: 18.9 %

Procedure:
To a solution of 0.181 g (1.0 immol) of 5,6-dihydrophenanthridine in 2 ml of warm pyridine is added 0.273 g (1.0 mmol) of 4-[(2-methylbenzoyl)amino]-benzoyl chloride. The mixture is stirred overnight at 30 room temperature, 1.2 ml of 2N HCl added. The solid which separates is filtered and washed with water. The solid is dissolved in dichloromethane and the solution washed with 2M sodium carbonate. The organic layer is concentrated and the residue chromatographed twice on silica gel with ethyl acetate-hexane as solvent to give 79 mg of crystals, m.p. 190°-194 ° C. Mass Spec-FAB 419 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOC(C)=O.O.C(=O)([O-])O.[Na+]>[CH2:21]([S:28][C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(Oc2c(F)cc(Br)cc2C#N)cc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2c(F)cc(SCc3ccccc3)cc2C#N)cc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
The title compound was prepared according to the method described for Preparation at reflux using 5-bromo-2-(4-cyano-3-chlorophenoxy)-3-fluorobenzonitrile (Preparation 41) and benzyl mercaptan. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL), water (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The organic was separated and the aqueous was re-extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was absorbed onto silica and purified by silica gel column chromatography eluting with 10% EtOAc in heptanes to afford the title compound as a yellow solid (115 mg, 28%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(-c2nc(N)sc2-c2ccnc(NCc3ccccc3)c2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
A mixture of [5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.29 g, 1.0 mmol) and benzylamine (1.2 mL, 11 mmol) was stirred at 150° C. for 3 hrs. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to give the title compound (0.16 g, yield 41%).