Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.CN1C(=O)CCC1.C(N(C(C)C)CC)(C)C.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:48])[CH2:45][O:46][CH3:47])[CH2:39][CH2:38]1>C(Cl)Cl.CCOC(C)=O.CCCCCC.O>[N:11]1([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:36][C@H:37]3[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:48])[CH2:45][O:46][CH3:47])[CH2:39][CH2:38]3)[N:10]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: COCC(=O)NC1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(-n2nnc3ccccc32)n1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: COCC(=O)N[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a 10 mL sealable tube loaded with 1-(2-methanesulfonyl-pyrimidin-4-yl)-1H-benzotriazole (99.1 mg, 0.36 mmol) were added NMP (1 mL) and diisopropylethylamine (0.19 mL, 1.09 mmol). To a second 5 mL sealable tube loaded with N-(4-amino-cyclohexyl)-2-methoxy-acetamide (100 mg, 0.36 mmol) was added NMP (1 mL). Both tubes were heated at 120° C. and at complete dissolution of the solids the solution of 1-(2-methanesulfonyl-pyrimidin-4-yl)-1H-benzotriazole was transferred via cannula into the tube containing the solution of N-(4-amino-cyclohexyl)-2-methoxy-acetamide. The resulting mixture was stirred for 1.5 hours at 120° C., then cooled to RT and poured into water (15 mL). The resulting mixture was stirred overnight, then diluted with DCM and washed with water. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil which was dissolved in a small amount of EtOAc and hexane was added to precipitate the solids. The resulting mixture was allowed to settle for 1 h, after which the liquid supernatant was carefully decanted away. The remaining solid was dried under reduced pressure to yield 86 mg (63% yield) of trans-N-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-2-methoxy-acetamide. MS=381 [M+H]+; MP=233.5-235.4° C.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc(-c2cccc3ccc(O)nc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2cccc3ccc(Cl)nc23)cc1

Procedure:
A mixture of Example 336B (1.76 g, 6.3 mmol) in POCl3 (50 mL) was heated to reflux for 30 minutes and concentrated. The concentrate was purified through a silica gel pad with 4:1 hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 298 ( M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].[OH:37][C:38]1[CH:42]=[C:41]([CH2:43][CH2:44][C:45](O)=[O:46])[O:40][N:39]=1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[C:12]([C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:45](=[O:46])[CH2:44][CH2:43][C:41]4[O:40][N:39]=[C:38]([OH:37])[CH:42]=4)[CH2:32][CH2:31]3)=[N:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CCc1cc(O)no1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)CCc4cc(O)no4)CC3)nc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-6-{4-[3-(3-hydroxy-isoxazol-5-yl)-propionyl]-piperazin-1-yl}-nicotinamide was synthesized from the EDCI coupling of N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 3-(3-hydroxy-isoxazol-5-yl)-propionic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C26H31N5O4 (m/e) 477, obsd 478 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C1COCC1.[Cl-].[Na+].O>[CH:25]([S:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1)(=[O:29])=[O:28])([CH3:26])[CH3:24]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CC(C)S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cn(S(=O)(=O)C(C)C)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1H-indole-3-carboxylate (0.234 g, 1.336 mmol) in THF (6.68 ml) was added sodium bis(trimethylsilyl)amide (2.67 ml, 2.67 mmol) at RT. After 30 min, propane-2-sulfonyl chloride (0.3 ml, 2.67 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined extracts were filtered through MgSO4 and concentrated to give the title compound as a brown solid, which was used without further purification.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[F-:30].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>CN(C=O)C>[F:30][CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NC(F)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 0.400 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-oxoazetidine in 2 ml of DMF is added 0.590 g of tetra-n-butylammonium fluoride, and the mixture is stirred for 30 minutes at room temperature. To the reaction mixture are added ice-water and ethyl acetate. The ethyl acetate layer is separated and washed with water, followed by concentration. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.282 g of (3R)-4-fluoro-3-tritylamino-2-oxoazetidine.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=O)=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([N:14]2[C:7](=[O:6])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]2=[O:5])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC1=C(C)C(=O)N(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
In a manner analogous to that of Example 2, 26.2 g (0.2 mole) of dimethylmaleic acid anhydride and 32.6 g (0.2 mole) of 3,4-dichloroaniline are condensed to give N-(3,4-dichlorophenyl)dimethyl-maleimide, which is then dissolved in 300 ml of methanol. To this solution is slowly added in portions, with stirring, 10.8 g of sodium borohydride. After the addition is complete and the generation of gas has subsided, the reaction mixture is poured into ice water. The white precipitate is filtered off, washed with methanol and dried. There is obtained 49.3 g (84% of theory) of the above product in the form of colourless crystalline powder, m.p. 188°.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17](Cl)=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[Br:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)c(Br)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Reaction time: 0.67 h
Yield: 98.6 %

Procedure:
Magnesium turnings (0.22 g) and carbon tetrachloride (0.1 ml) was added to absolute ethanol (1.5 ml). To the stirring suspension was added dropwise a solution of diethyl malonate (1.4 g) and absolute ethanol (2 ml) in toluene (6 ml) during 25 minutes at 50°-60° C. The mixture was stirred for 40 minutes, and then cooled. A solution of 3-bromo-2,4,5-trifluorobenzoyl chloride (2.27 g) in anhydrous toluene (3 ml) was added dropwise to the solution at -8°~-4.5° C. during 28 minutes. The mixture was stirred for 2 hours and then mixed with ice-chilled diluted sulfuric acid. The resulting organic layer was collected and the water layer was extracted with toluene (6 ml×4). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (3.25 g) as pale yellow oil.
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]([F:53])([F:52])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[CH3:16][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[O:42][C:41]([F:53])([F:52])[F:40]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CNc1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-(trifluoromethoxy)phenylboronic acid after a reaction time of 7 hours at 90° C. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (91%). MS (ESI): m/z=269.090 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1>CN(C=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([I:1])=[N:3]2)=[N:24][CH:25]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (1.0 g, 3.46 mmol) in DMF (20 mL) was added potassium carbonate (0.956 g, 6.92 mmol) and 2-(chloromethyl)-5-fluoropyridine hydrochloride (0.630 g, 3.46 mmol). The mixture was stirred at ambient temperature for 18 hours under nitrogen. The mixture was concentrated under vacuum and then diluted water (300 mL). The precipitated solids were collected by filtration and washed with water. The material was dried under high vacuum for 16 hours to give 1-((5-fluoropyridin-2-yl)methyl)-3-iodo-4-nitro-1H-indazole (0.968 g).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[C:4]([CH3:30])[CH:3]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(O)(C)C>[N:31]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)(=[O:18])=[O:17])[CH2:12][C@@H:11]3[CH3:29])=[O:9])=[C:4]([CH3:30])[CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Solvent: CC(C)O
Product: Cc1cc(N2CCC2)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 120 °C
Yield: 92.6 %

Procedure:
(2S)-1-[(6-Fluoro-4-methyl-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 27) (67 mg, 0.15 mmol) was weighed into a microwave vial and dissolved in isopropanol (1.5 ml). Azetidine (0.203 ml, 3.01 mmol) was added and the mixture was heated in the microwave to 120° C. for 12 h with stirring. The reaction mixture was concentrated to give the crude material as a colourless gum (˜187 mg). This was purified by MDAP to give the title compound as a pale yellow gum (67 mg). The gum was redissolved in MeOH, water was added, and the mixture was concentrated under a flow of argon then dried in vacuo to give the title compound as a colourless solid.
Reaction SMILES: O[CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].C([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:2][C:3]1([CH3:10])[CH2:9][O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: CC(C)(CO)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CC1(C)CCC(=O)OC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.1 %

Procedure:
To a solution of 2,2-dimethyl-pentanedioic acid (3.0 g, 19 mmol) is added K2CO3 (6.49 g, 47 mmol) and iodomethane (2.5 ml, 39 mmol) at room temperature. The mixture is stirred at room temperature for 18 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, saturated aqueous NaHCO3 and brine, and dried over MgSO4. Solvent is removed under reduced pressure to give 2,2-dimethyl-pentanedioic acid dimethyl ester (2.49 g, 70%); TLC (hexane/AcOEt, 3:1) Rf 0.50, 1H NMR (400 MHz, chloroform-d) δ ppm 1.19 (s, 6H), 1.88 (m, 2H), 2.29 (m, 2H), 3.67 (s, 6H). To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g, 12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0 mmol). The mixture is stirred at room temperature for 16 hours and refluxed for 2 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 1M aqueous HCl (14 ml) is added and the solution is extracted with ether. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.97 g, 88%); 1H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H), 1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H). To a suspension of 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.00 g, 5.75 mmol) in THF (3 mL), 1M LiBHEt3 in THF (38.0 ml, 38.0 mmol) is added dropwise maintaining the temperature below 10° C. under nitrogen. The mixture is stirred at 10° C. for 1 hour. To the mixture, 50% AcOH (4.6 mL) and H2O are added. The solution is extracted with AcOEt, and the organic layer is washed with H2O, dried over MgSO4, and concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid (850 mg, quant.); 1H NMR (400 MHz, chloroform-d) ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.98 (s, 2H). To a solution of 5-hydroxy-4,4-dimethyl-pentanoic acid (300 mg, 2.05 mmol) in DMF (5 ml), K2CO3 (369 mg, 2.87 mmol) and iodomethane (154 ul, 2.47 mmol) are added at room temperature. The mixture is stirred at room temperature for 15 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, and brine, and dried over MgSO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 47%); TLC (hexane/AcOEt, 2:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) δ ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.97 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>CC(O)C>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-4-phenylquinazoline (9.6 g, 40 mmol) in 2-propanol (130 mL) was added 4-aminobenzoic acid (8.2 g, 60 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to rt and the precipitate was collected by filtration and washed with 2-propanol. The product, 4-(4-phenylquinazolin-2-ylamino)benzoic acid, was isolated as a yellow solid (12.9 g, 95%).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N-]>C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC.C(Cl)Cl>[O:23]=[C:4]1[CH2:3][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCCOC(=O)Cc1c(CCC(=O)C=[N+]=[N-])[nH]c2ccccc12
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: ClCCl
Product: CCCOC(=O)Cc1c2n(c3ccccc13)CC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Rhodium (II) octanoate dimmer (0.1 equiv.) was added to a CH2Cl2 solution (0.02 M) of propyl [2-(4-diazo-3-oxobutyl)-1H-indol-3-yl]acetate from Step 4. The reaction mixture was stirred overnight at rt and then concentrated. The residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hexane (2:98 to 10:90) to give the title compound (64%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[CH2:10][C:9](=O)[N:8]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]1=O)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:8]2[CH2:9][CH2:10][C@@H:11]([CH3:12])[C@H:6]([CH2:4][OH:3])[CH2:7]2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1C(=O)N(CCc2ccc(F)cc2)C(=O)CC1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.3 %

Procedure:
A solution of 1-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carboxylic acid ethyl ester (2.0 g, 6.22 mmol) in tetrahydrofuran (10 mL) was added over 5 minutes to an ice-cold solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 28 mL, 28 mmol). The resulting solution was stirred at room temperature for 17 hours, then was quenched by the slow dropwise addition of water (1.06 mL), 15% aqueous sodium hydroxide (1.06 mL), and water (3.18 mL). The resulting suspension was stirred for 20 minutes, then filtered and the solid washed with ethyl acetate. The combined filtrates were concentrated under vacuum to provide an oil which slowly crystallized. This material was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide a pale yellow solid (724 mg, 46%) as a mixture of cis- and trans isomers. Pure trans isomer was isolated by further chromatography. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.83 (dd, J=11, 3 Hz, 1H), 3.54 (dd, J=11, 7 Hz, 1H), 3.18 (dm, J=10 Hz, 1H), 2.95 (dm, J=12 Hz, 1H), 2.85 (m, 2H), 2.61 (m, 2H), 2.12 (dt, J=11, 3 Hz, 1H), 2.01 (t, J=11 Hz, 1H), 1.77 (m, 1H), 1.6-1.3 (m, 3H), 1.00 (d, J=6 Hz, 3H). Mass spec (ES+) m/z 252.1 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:7][NH2:8])=[O:6].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([C:20](=O)[CH3:21])[CH:19]=1>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:7]/[N:8]=[C:20](/[C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[OH:23])\[CH3:21])=[O:6]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccc(Cl)c(Br)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccc(Cl)c(Br)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.1 %

Procedure:
3-Bromo-4-chlorobenzohydrazide (30 mg, 0.120 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (20.51 mg, 0.120 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (15 mg). 1H NMR (400 MHz, acetone-d5): δ 8.30 (s, 1H), 7.98 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.61 (d, 1H, J=2.4 Hz), 7.29 (dd, 1H, J=2.4 & 8.4 Hz), 6.93 (d, 1H, J=8.8 Hz), 2.55 (s, 3H). ESI-MS: 402.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].O1CCCC1.[CH3:13][C:14](=O)[CH2:15][C:16](=[O:18])[CH3:17]>O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:14]([CH3:13])=[CH:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: COC(CN)OC
Solvent: C1CCOC1
Solvent: O
Product: COC(CNC(C)=CC(C)=O)OC
Reaction time: 8 h

Procedure:
21.0 g of aminoacetaldehyde dimethylacetal (0.2 moles) were dissolved into 100 ml of tetrahydrofuran to which 20.0 g of 2,4-pentanedione (0.2 moles) were added dropwise over 5 minutes. The resulting mixture was then stirred overnight after which time the solvent and water of condensation formed during the reaction was removed by vacuum distillation. The final product was then vacuum distilled as a clear liquid. Yield of MeC(O)CH2C(NCH2CH(OMe)2)Me=25.0 g (72% of theoretical).
Reaction SMILES: C(N(CC)CC)C.[I-].[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20](N2C=C[N+](C)=C2)=[O:21])[CH2:16][C@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10].[CH2:28]([N:34]([CH3:43])[C:35]([C@@H:37]1[CH2:41][C@@H:40]([OH:42])[CH2:39][NH:38]1)=[O:36])[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:38]2[CH2:39][C@H:40]([OH:42])[CH2:41][C@H:37]2[C:35](=[O:36])[N:34]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:43])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Triethylamine (1.3 mL, 3 eq.) was added at room temperature under nitrogen to a mixture of compound 34 (0.7 g, 1 eq.) and compound 49 (1.2 g, 1 eq.) in DCM (15 mL). The reaction mixture was stirred overnight at room temperature and then quenched with 1M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 50 as a white solid in 70% yield.