Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC1CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCC1CCN(Cc2ccccc2)C1
Yield: 99 %

Procedure:
14.7 g (0.0734 mole) (3RS)-1-benzyl-3-cyanomethyl pyrrolidine dissolved in 220 ml diethyl ether was slowly added to a slurry of 2.94 g of lithium aluminium hydride in 74 ml diethyl ether under an argon atmosphere. The mixture was stirred over night, and 6 ml water, 18 ml 3.75 M NaOH-solution and 6 ml water was added to the mixture. The slurry was dried from excess of water with Na2SO4 /cellite, filtered by suction and evaporated to yield 14.84 g (99%) of the product.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: CN(C)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formylbenzoic acid (24) (300 mg, 1.99 mmol) in DCM (4 mL) were added N,N-dimethylethane-1,2-diamine (193.8 mg, 2.19 mmol), HATU (911.8 mg, 2.4 mmol), NMM (505 mg, 5.0 mmol), and DMAP (24 mg, 0.199 mg) at RT. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. After 16 h, RM was washed with water and organic layer was concentrated after drying over Na2SO4. Column purification of crude material afforded pure product as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:14][N:15]1CCOC[CH2:16]1.CCN=C=NCCCN(C)C.Cl.OC1C2N=NNC=2C=CC=1.CNC>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:15]([CH3:16])[CH3:14])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1C(=O)N(C)C
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A solution of 2 g (10.7 mmol) 2-methyl-4-nitro-benzoic acid, 1.32 ml (11.8 mmol) N-methyl-morpholine, 2.36 g (12 mmol) EDC-HCl and 2.36 g (12 mmol) HOBt in 50 ml dichloromethane is stirred at RT for 45 min, then dimethylamine solution (5.9 ml, 33% in EtOH) is added and the reaction mixture is heated to 40° C. and stirred at this temperature for 20 h. Another 1.32 ml (11.8 mmol) N-methyl-morpholine, 2.36 g (12 mmol) EDC-HCl and 2.36 g (12 mmol) HOBt (hydroxyl-benzotriazole) are added and stirred for 45 min, the again dimethylamine solution (5.9 ml, 33% in EtOH) is added and the reaction mixture is stirred at 40° C. for 35 h. After that the reaction mixture is cooled to RT and poured onto EtOAc/water. The organic layer is washed with sat. NAHCO3 solution and with water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane:EtOAc=1:1=>EtOAc) to afford the title compound as a yellowish oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C([Sn](CCCC)(CCCC)CCCC)=NN2C)=CC=1.CN(C=[O:54])C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:54][CH2:17][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[CH:2][N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:15])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Product: CC(C)(CO)NC(=O)c1c[nH]c2nccnc12
Temperature: 90 °C
Yield: 37 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 0.203 mmol) and 6-chloro-1-methyl-3-(tributylstannyl)-1H-indazole (0.148 g, 0.228 mmol) were dissolved in DMF (3 mL). The reaction mixture was evacuated and filled with nitrogen then copper(I) iodide (9 mg, 0.081 mmol) and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.046 mmol) were added. The reaction mixture was heated at 90° C. for 2 h then partitioned between ethyl acetate and water. The organic phase was washed with brine then dried over magnesium sulfate. The crude material was purified by chromatography using 25% ethyl acetate/hexane to obtain 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-trimethyl-silanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (40 mg, 37%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:34][C:35]1[NH:39][N:38]=[C:37]([NH2:40])[CH:36]=1.[I-].[K+]>CN(C=O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:4]2[N:3]=[C:2]([NH:40][C:37]3[CH:36]=[C:35]([CH3:34])[NH:39][N:38]=3)[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=3)[N:5]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(C(F)(F)F)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To (4-chloro-7-(trifluoromethyl)quinazolin-2-yl)(4-fluorophenyl)methanone (1 g, 2.82 mmol) in DMF (10 mL) were added DIEA (0.49 mL, 2.82 mmol), 5-methyl-1H-pyrazol-3-amine (823 mg, 8.47 mmol), and potassium iodide (468 mg, 2.82 mmol) and the mixture was stirred at rt for 2 h. To the reaction mixture was added water followed by extraction with EtOAc. The organic phases were dried over sodium sulfate. The solvent was concentrated and the residue was dried under high vacuum overnight. The crude solid (240 mg) was purified on reverse-phase preparative HPLC (elution gradient of 40-90% acetonitrile in water with 0.05% acetic acid) to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(trifluoromethyl)quinazolin-2-yl)methanone as a yellow solid (40 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.2 (s, 3H) 6.55 (s, 1H) 7.35-7.5 (m, 3H) 7.9-8.0 (m, 1H) 8.05-8.3 (m, 4H) 11.1 (s, 1H) 12.25 (s, 1H) LC-MS (ESI) m/z 416 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15](Br)[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:20])[CH3:19])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:19])[CH3:20]
Reactant: [H][H]
Reactant: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CN=[N+]=[N-])C3
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)Nc2ccc3c(c21)OC(CN)C3
Yield: 80.1 %

Procedure:
2-Azidomethyl-5-bromo-9,9-dimethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (997 mg, 2.84 mmol) was dissolved in methanol (50 ml). To the solution, 10% palladium-on-carbon (1.0 g) was added, followed by stirring in a bath at 50° C. for 1 hour in the atmosphere of hydrogen. The catalyst was filtered off, and the filtrate was condensed under reduced pressure. Recrystallization from a solvent mixture of methanol-ether yielded 560 mg of the title compound as a yellow powder (80.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:19]1[CH2:29][CH2:28][CH2:27][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:19]2[CH2:29][CH2:28][CH2:27][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
4-Chlorobenzyl chloride (6.42 g, 39.9 mmol) and iPr2NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in CH3CN (15 mL). The reaction mixture was stirred at 70° C. for 1.5 h. The solvent was removed under reduced pressure. Saturated aqueous NaHCO (50 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to afford ethyl 1-(4-chlorobenzyl)nipecotate as a red yellow oil (11.025 g, 97.8%) used without further purification. The purity was determined by RPLC/MS (97%); ESI/MS m/e 382.2 (M++H, C15H23ClNO2).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31]>C(O)CCC>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCCCO
Product: CC(=O)[O-]
Temperature: 22.5 °C

Procedure:
Sunitinib base (4 g) was suspended in n-butanol (12 ml) with stirring at 20-25° C. Then 1.05 eq (0.45 ml) of acetic acid were added observing dissolution and after 1-2′ precipitation of an orange solid. Then methyl tert-butyl ether (80 ml) was added at 20-25° C. within 10 min with stirring, the mixture was cooled to −10° C. in 2 hours. After 16 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE and dried on the filter for 1 h yielding 4 g of Sunitinib Acetate.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[C:17]([CH2:23][CH3:24])[CH:16]=1)(C([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[C:17]([CH2:23][CH3:24])[CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)(NC(C)=O)C(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)NC(C)=O

Procedure:
A mixture of 35.2 g (104.9 mmol) monoethyl 2-acetylamino-2-(3,4-diethyl-benzyl)-malonate and 400 mL toluene was refluxed for 15 h. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in DCM and the organic phase washed with saturated NaHCO3 solution. The organic phase was then dried and evaporated down under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:13][C:14]([Cl:36])([Cl:35])[S:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=2[Cl:34])=[CH:21][CH:22]=1)[S:15][C:14]([Cl:36])([Cl:35])[Cl:13])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: FC(F)(F)c1ccc(Oc2ccc(NSC(Cl)(Cl)Cl)cc2)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(SC(Cl)(Cl)Cl)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)c1ccccc1Cl
Reaction time: 240 h

Procedure:
A solution of 3.6 g of 2-chlorobenzoyl isocyanate in 15 ml of dry toluene was added over five minutes to a stirred solution of 4.0 g of 1,1,1-trichloro-N-[4-[2-chloro-4-(trifluoromethyl)phenoxy]phenyl]methanesulphenamide in 25 ml of the same solvent at room temperature. After 10 days, the reaction mixture was diluted with 500 ml of light petroleum andd filtered. Evaporation of the filtrate gave a crude residue from which 7 was obtained, as a solid. m.p: 68°-71° C., by rapid chromatography on silica gel using methylene chloride as eluent.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH:21]([S:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH2:9])=[O:8])=[CH:10][CH:11]=1)(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCc1ccc(C(N)=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 299.6 %

Procedure:
A solution of 4-aminomethylbenzamide (0.58 g) and triethylamine (1.1 ml) in dimethylformamide (DMF; 6 ml) was added to a solution of 2-chloroethanesulphonyl chloride (0.63 g) in DMF (4 ml) at -60° under nitrogen over 30 mins. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was evaporated to give a semi-solid (2.78 g) which was purified by column chromatography (D) to give the title compound as a solid (0.54 g) m.p. 142°-4°.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:31])[N:4]=1.[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:5]6[N:4]=[C:3]([CH3:2])[O:7][N:6]=6)[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5noc(C)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B27), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (188 mg; compound C10) and HBTU (196 mg) in DCM (7.5 ml) is added DIPEA (0.33 ml). The reaction mixture is stirred at RT for 14 h. Additional DCM (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml) are added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] followed by preparative HPLC to yield the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:1]
Reactant: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(C=O)c1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a stirred solution of (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.250 g) in dichloromethane (5 ml) at room temperature was added pyridinium dichromate (0.414 g). After stirring for 3 hours, GC analysis of an aliquot indicated the absence of starting material. Water was added and stirring continued for 10 minutes. The reaction mixture was filtered (filter washed through with water (5 ml) and dichloromethane (5 ml)) and then further diluted with dichloromethane (5 ml). The organic layer was separated and the aqueous phase further extracted with dichloromethane (×3). The combined organic layers were dried, filtered and evaporated to give a dark yellow oil. Chromatography on silica gel (eluent ether-petroleum ether, 7:3) afforded (E)-methyl 2-[2-(3-formylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.136g, 55%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([OH:30])=O)([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:28]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:30])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.5 mmol) prepared in Example 20f and CDI (160 mg, 1 mmol) in DMF (2 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (285 mg, 3 mmol) and NaH (120 mg, 60%, 3 mmol) in DMF (1 mL), which had been mixed and stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to “pH” 1-2 by addition of concentrated HCl. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (70 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][C:24]=2[C:25]#[N:26])=[CH:18][CH:17]=1>CN(C=O)C>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:27][C:24]=2[C:25]#[N:26])=[CH:18][CH:17]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)nc3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (60 mg, 0.323 mmol), sodium hydride (25.9 mg, 0.647 mmol) and 2-((6-chloropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile (84 mg, 0.323 mmol) in DMF (2 mL).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]([CH3:45])[CH3:44])=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]([CH3:44])[CH3:45])=[CH:39][CH:38]=2)=[O:36])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C(=O)CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.3 g), 2-bromo-4'-dimethylaminoacetophenone (0.2 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using toluene-ethyl acetate (2:1) as an eluent. Fractions containing objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-dimethylaminophenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.26 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)[C:32]#[CH:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][N:34]6[CH:38]=[CH:37][N:36]=[CH:35]6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCn1ccnc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(C#CCn5ccnc5)cc34)ccc21
Temperature: 80 °C
Yield: 51 %

Procedure:
Quinazoline 14 (150 mg, 0.28 mmol), 1-N-2-propynylimidazole (200 mg, 1.89 mmol), Pd(OAc)2 (4 mg, 0.016 mmol) and PPh3 (9 mg, 0.033 mmol) were mixed in NEt3 (1.25 mL) and DMF (0.5 mL). The mixture was heated at 80° C under N2 for 16 hours. Upon cooling the black suspension was concentrated under reduced pressure and the residue dissolved in MeOH. Silica gel (1 g) was added and the methanol removed in vacuo. The resulting silica gel was placed atop a silica gel (40g) column which was then eluted with 200 mL 50:1 CH2Cl2:MeOH, the 300 mL 25:1 CH2Cl2 to provide alkyne 15 (72 mg, 51%) as a yellow foam. 1H NMR (CDCl3; 400 MHz): δ: 8.95 (br, 1H, NH), 8.63 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 7.96 (d, 1H, J=1.7 Hz), 7.84 (m, 3H), 7.71 (m, 2H), 7.51 (m, 3H), 7.41 (m, 2H), 7.14 (s, 1H), 7.10 (s, 1H), 6.55 (d, 1H, J=3.5 Hz), 5.01 (s, 2H).