Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:37])[C:11]=1[O:12][CH2:13][C:14]1[N:15]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)([CH3:21])[CH3:20])=[CH:17][N:18]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:37])[C:11]=1[O:12][CH2:13][C:14]1[N:15]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)([CH3:21])[CH3:20])=[CH:17][N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(F)c(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COc2c(F)cc(C(=O)O)cc2Cl)n1-c1ccc(F)cc1
Temperature: 65 °C
Yield: 38.8 %

Procedure:
A mixture of methyl 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)-5-fluorobenzoate (120 mg, 0.21 mmol) and 2N NaOH (0.31 mL, 0.63 mmol) in MeOH (3 mL) was heated 3 h at 65° C. After cooling, the reaction was neutralized to pH 3 with 3N HCl, concentrated under reduced pressure, diluted with water, and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by HPLC (MeCN/H2O, 10-99%) to give the title compound as an off-white solid (45 mg, 39%). MS (EI): 553.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[Li+:9].[Li+].[Li+].[NH2-:12].CN(C=O)C>COCCOC>[N-:12]([S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4].[Li+:9]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: [NH2-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
22 ml of trifluoromethanesulfonyl chloride were added to a suspension of 3.5 g of lithium nitride in 100 ml of a mixture of DMF and DME (50/50). The nitride dissolved in a few minutes with stirring at ambient temperature. The reaction took place according to the following reaction scheme:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][N:11]([CH3:15])[C:10](=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][N:11]([CH3:15])[C:10](=[O:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(=O)cc1-c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(C)c(=O)cc1-c1ccc(OCCCCl)cc1
Yield: 98 %

Procedure:
A solution of the product from step 2 (710 mg, 3.29 mmol), K2CO3 (1.36 g, 3.0 eq.) and 3-bromo-1-chloropropane (0.39 mL, 1.2 eq.) in CH3COCH3 (30 mL) was heated to 80° C. overnight. The mixture was then filtered, washed with acetone and concentrated to dryness to afford the product of step 3 (950 mg, 98%): MS m/z 293 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1
Yield: 88 %

Procedure:
Prepared according to the procedure described for Example 121 using 4-fluorobenzenesulfonyl chloride (2.14 g 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p. 209-211° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:18][O:17][C:11]1[CH:16]=[CH:15][C:14]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:7])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
To a solution of 4-methylbenzoyl chloride, 32-a, (10 g, 65 mmol) and anisole (8.8 g, 81 mmol) in DCM anhydrous was added aluminum(III) chloride (10.8 g, 81 mmol), the reaction mixture was then stirred for 10 h at ambient temperature. The resulting mixture was concentrated under reduce pressure, 100 ml of water was added, filtered, the residue was dried in vacuo. The product was obtained as a white solid, 32-b, (14 g, 95% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.71 (s, 3H), 6.85-6.89 (m, 2H), 7.11-7.19 (m, 6H). LC-MS 227 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30]N3CCN(C)CC3)=[CH:28][CH:29]=2)=[O:23])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[Cl:38]CC1C=CC(C(Cl)=O)=CC=1>>[Cl:38][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([NH:21][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:20]=[N:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH:6]=2)=[O:23])=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
Scheme 3 illustrates a third synthetic pathway for preparation of imatinib base, referred to herein as “Method C.” This method is described in WO 2004/108699 and in J. Med. Chem. 2005, 48(1), 249-255, and comprises the condensation of 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)benzene-1,3-diamine with 4-chloromethylbenzoyl chloride to yield 4-chloromethyl-N-(4-methyl-3-((4-pyridin-3-yl)-pyrimidin-2-ylamino)-phenyl)-benzamide, followed by the reaction of 4-chloromethyl-N-(4-methyl-3-((4-pyridin-3-yl)-pyrimidin-2-ylamino)-phenyl)-benzamide with N-methylpiperazine.
Reaction SMILES: [NH:1]1[C:62](=[O:63])[C@@H:61]2[CH2:64][CH2:65][CH2:66][N:60]2[C:58](=[O:59])[C@H:47]([CH2:48][C:49]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][CH:50]=2)[NH:46][C:44](=[O:45])[C@H:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])[NH:35][C:33](=[O:34])[C@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:27][C:25](=[O:26])[C@@H:14]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[NH:13][C:11](=[O:12])[C@@H:2]1[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:67]1[CH:68]=[CH:69][C:70]2[NH:75][CH:74]=C(C[C@@H](N)C(O)=O)[C:71]=2[CH:72]=1.N1CCC[C@H]1C(O)=O>>[NH:1]1[C:62](=[O:63])[C@H:61]([CH2:64][C:65]2[C:71]3[C:70](=[CH:69][CH:68]=[CH:67][CH:72]=3)[NH:75][CH:74]=2)[N:60]([CH3:66])[C:58](=[O:59])[C@H:47]([CH2:48][C:49]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][CH:50]=2)[NH:46][C:44](=[O:45])[C@H:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])[NH:35][C:33](=[O:34])[C@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:27][C:25](=[O:26])[C@@H:14]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[NH:13][C:11](=[O:12])[C@@H:2]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CCCNC(=N)N)NC1=O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](Cc2c[nH]c3ccccc23)N(C)C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CCCNC(=N)N)NC1=O

Procedure:
Particularly preferred is cyclo[Tyr-D-Trp-Leu-Arg-Trp-Pro] where D-Trp is D-tryptophan and Pro is proline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([F:17])[CH2:12][N:11]([C@@H](C1C=CC=CC=1)C)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([F:17])[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(F)CCC[C@@]2(NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]12CCC[C@]1(F)CNC2
Yield: 91.3 %

Procedure:
(1R,5S)-1-(tert-Butoxycarbonylamino)-5-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (700 mg, 2.0 mmol) was dissolved in ethanol (30 mL). 10% palladium-carbon (50% wet) (1.01 g) was added, and the mixture was stirred in a hydrogen atmosphere at 50° C. for 15 hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=98:2→95:5) to give 446 mg of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>CN(C)C1C=CN=CC=1.C(#N)C.O>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([OH:18])([CH3:17])[C:2]([F:20])([F:19])[F:1])=[CH:8][CH:9]=1)(=[O:15])=[O:14])[CH2:22][CH3:23]
Reactant: CCCNCCC
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 22 °C
Yield: 34.8 %

Procedure:
A solution of 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide (0.2 g), di-n-propylamine (0.25 g), and 4-dimethylaminopyridine (13.0 mg) in dry acetonitrile (3 ml) was heated at reflux for 4 days. The reaction mixture was cooled to 22° C., diluted with water (30 ml) and extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with 1N HCl, brine, dried and evaporated to give an oil. The oil was purified by chromatography (12:1 CHCl3 : diethyl ether) to yield an oil which crystallized from hexane to produce the title compound as a colourless crystalline solid (87.5 mg); mp 132°-134° C.; MS: m/z=397(M+1); NMR (250M Hz): 0.77-0.83 (t,6), 1.41-1.49 (m,4), 1.58 (s,3), 2.96-3.02 (t,4), 7.54 (s,1), 7.72-7.75 (m,2), 7.96-7.98 (m,2), 10.36 (s,1). Analysis for C16H23 F3N2O4S: Calculated: C, 48.47; H, 5.85; N, 7.07; Found: C, 48.84; H, 5.90; N, 6.89.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:28]=[CH:27][C:21]4[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=4[CH:19]=3)[O:8][C:7]=2[CH:29]=1.[CH:30](N(C(C)C)CC)(C)[CH3:31].ICC>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C@H:9]([CH2:12][N:13]([CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:28]=[CH:27][C:21]4[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=4[CH:19]=3)[O:8][C:7]=2[CH:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1ccc2ccc(OCCCNC[C@H]3COc4ccc(O)cc4O3)cc2o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)C[C@H]1COc2ccc(O)cc2O1
Temperature: 60 °C

Procedure:
(S)-7-[3-[[(2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.89 g, 2.13 mmole), diisopropylethylamine (0.80 ml, 4.59 mmole) and iodoethane (0.24 ml, 3.0 mmole) were combined in DMF and heated at 60° C. for 15 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 75 ml ofdichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue (1.82 g) was column chromatographed on 75 g of silica gel using first 0.5% methanol/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the free base redissolved in methanol. 2.8 ml of 4N isopropanolic HCl was added, the mixture was brought to a boil on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.66 g of the title compound precipitated as a yellow solid, monohydrochloride, quarter hydrate, m.p. 204°-207° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([F:25])=[C:21]([CH:24]=1)[C:22]#[N:23]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:17]3[CH:18]=[CH:19][C:20]([F:25])=[C:21]([CH:24]=3)[C:22]#[N:23])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)ccc1F
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 8.32 (dd, J=6.3, 2.4 Hz, 1H), 8.11 (m, 1H), 7.62 (m, 1H), 7.58 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 4.26 (s, 2H), 1.62 (s, 6H); MS (ES) m/z 311 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH:21]([C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: NCCN1CCOCC1
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Solvent: c1ccncc1
Product: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Yield: 54 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine in pyridine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.15 g, 54%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=7.1 Hz, 6 H) 2.4 (m, 4 H) 2.6 (m, 2 H) 2.9 (dq, J=6.9 Hz, 1 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.6 (t, J=5.4 Hz, 1 H) 7.1 (m, 4 H) 7.3 (t, J=8.0 Hz, 1 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 9.6 (s, 1 H)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:28])[N:17]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)O1.ClCCl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[C:5]([CH3:15])[N:4]3[C:16](=[O:28])[N:17]([CH2:19][C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=4)[N:18]=[C:3]3[C:2]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C#N)cn3)c(=O)n12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)c(-c2ccncc2)c2nn(Cc3ccc(C#N)cn3)c(=O)n12
Temperature: 100 °C
Yield: 62.2 %

Procedure:
In a pressure tube, to a stirring solution of 6-((8-bromo-7-(4-chlorophenyl)-5-methyl-3-oxo-[1,2,4]triazolo[4,3-a]pyridine-2(3H)-yl)methyl)nicotinonitrile (54 mg, 0.11 mmol) in THF (2 mL) at room temperature under argon was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (45 mg, 0.22 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (9 mg, 0.011 mmol) and powdered K3PO4 (60 mg, 0.28 mmol). The resulting suspension was stirred and heated at 100° C. under argon for 7 h. The reaction mixture was filtered through filter paper and the filtrate was concentrated under vacuum to a dark brown solid. The crude product thus obtained was purified by reverse phase preparative HPLC (without TFA) to obtain 31 mg of the title compound as a yellow solid. HPLC/MS: retention time=2.482 min, [M+H]+=453.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([N:24]([CH3:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>C(OCC)(=O)C.C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([N:24]([CH3:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(C(=O)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C(=O)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)c1ccccc1
Yield: 59 %

Procedure:
In a manner similar to that of Example 1(g), starting with 1.1 g (2.6 mmol) of 2-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide in 20 ml of ethyl acetate and 20 ml of ethanol, 660 mg (60%) of the desired product, with a melting point of 158° C., are obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 71 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-yl)-vinyl ester (0.52 g, 0.97 mmol), 4-(methanesulfonyl)phenylboronic acid (0.48 g, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (68 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.2 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 57%) as a white solid: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([Br:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncccc1N
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)ccc1N
Yield: 37.5 %

Procedure:
A solution of 2.00 g (12.04 mmol) 3-Amino-pyridine-2-carboxylic acid ethyl ester and 2.57 g (14.44 mmol, 1.2 equiv.) of N-Bromosuccinimide in 80 ml of acetonitrile was stirred for 2 h at room temperature. Silicagel (5 g) was added to the reaction mixture Which was evaporated to dryness. The residue was loaded onto a Flash chromatography column (SiO2, 50 g) and eluted with heptane/ethyl acetate 3:1. One obtains 1.11 g (4.51 mmol, 37%) of the title compound as a white cristalline solid, MS (ISP): m/e=245.1, 247.1 (M+H+).
Reaction SMILES: C([O:3][C:4]1[CH2:5][C@@H:6]([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=O)[CH2:14][CH2:13]2)[CH2:7][C:8](=[O:10])[CH:9]=1)C.C1(CN2CCCC2=[O:37])C=CC=CC=1.Cl>O1CCCC1>[O:37]=[C:13]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:12]1[CH2:11][CH:6]1[CH2:5][C:4](=[O:3])[CH2:9][C:8](=[O:10])[CH2:7]1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: CCOC1=CC(=O)C[C@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CC(=O)CC(C[C@H]2C(=O)CCN2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone and (5S,1S)-5-[(3ethoxy-5-oxo-3-cyclohexen-1-yl)methyl[-1-(phenylmethyl)-2-pyrrolidinone (150 mg, 0.46 mmol) in 10 mL of tetrahydrofuran was treated with 2 mL of 2N HCl and stirred at room temperature for 2 h, then refluxed for 1 h. The solvent was removed on a rotary evaporator and the residue was extracted with methylene chloride. The combined extracts were dried over Na2SO4 and evaporated to give 130 mg of (S)-5-[[oxo-1-(phenylmethyl)-2-pyrrolidinyl]methyl]-1,3-cyclohexanedione, mp 159°-161° C. (ethyl acetate), which was identical in all respects to that obtained in the synthesis from (E)-4-[2(S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-2-butenoic acid, ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][N:9]([CH3:12])[C:5]2=[C:6](Cl)[N:7]=1.[CH3:13][O-:14].[Na+].CO>>[Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][N:9]([CH3:12])[C:5]2=[C:6]([O:14][CH3:13])[N:7]=1
Reactant: Cn1ccc2cc(Br)nc(Cl)c21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Br)cc2ccn(C)c12
Temperature: 130 °C
Yield: 97 %

Procedure:
The product from Example 91A (0.43 g, 1.752 mmol) and 0.5 M sodium methoxide in methanol (15 mL, 7.50 mmol) were combined in a sealed microwave tube, heated by microwave at 130° C. for 45 minutes, cooled and concentrated. The residue was partitioned between ethyl acetate and water adjusting the pH to 7 with 1 M HCl. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.41 g, 97%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>ClCCl>[CH2:1]([N:4]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCNc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCN(C(=O)OCc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
Under nitrogen, to a solution of allylphenylamine (3 ml) in dichloromethane (30 ml) were added pyridine (2.1 ml) and benzyl chloroformate (3.5 ml) at 5° C., and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into aqueous 1N hydrogen chloride and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1 to 10:1) to give N-allyl-N-phenylbenzyloxycarbonylamine (5.5 g).