Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>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.COCCOC>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3cccc(Cl)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (89 μL , 0.178 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 3-chlorophenylboronic acid (16 mg, 0.102 mmol) (Aldrich) in 3 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution) to provide pure (Z)-4-(3-chlorophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (26 mg, 90%) as a yellow solid (mp 165-167° C.).
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C[C@@H](Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
2(R)-Bromo-4-metylpentanoic acid (28.5 g, 146 mmol), benzyl alcohol (18.1 ml, 175 mmol) and 4-dimethylaminopyridine (1.90 g, 14.6 mmol) were dissolved in CH2Cl2 (140 ml), and added with EDC (35.6 g, 175 mmol) under ice-cooling and stirring The mixture was stirred under ice-cooling for 1 hour and further at room temperature overnight and washed for separation with water, a saturated aqueous solution of NaHCO3 and then a saturated aqueous solution of NaCl two times respectively. The organic layer was dried over an hydrous MgSO4, evaporated under reduced pressure and purified by column chromatography (silica gel; 700 g, elution with the mixed solvent; n-hexane:AcOEt=40:1), giving the title compound (32.0 g, 77%) of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[C:39]2[N:38]=[CH:37][N:36]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:35]=2[CH:34]=[CH:33][C:32]=1[CH3:48].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.O>CCO.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>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:31]3[C:39]4[N:38]=[CH:37][N:36]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:35]=4[CH:34]=[CH:33][C:32]=3[CH3:48])[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(ncn2COCC[Si](C)(C)C)c1I
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)ccc3c2ncn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester. (20 mg, 0.044 mmol, Example 140: step a), 4-Iodo-5-methyl-1-(2-methylsilanyl-ethoxymethyl)-1H-benzoimidazole (21 mg, 0.054 mmol, Example 287: step b) and Pd(PPh3)4 in 1.2 ml of 1:1:2 EtOH/2M Na2CO3/toluene was stirred at 90° C. for 5 h, the cooled to RT. Treated with 3 mL of H2O, the mixture was extracted with EtOAc (3×5 mL)/Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (30% EtOAc/hexane) gave 21 mg (71%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 8.42 (s, 1H). 8.08 (s, 1H), 8.05 (s, 1H), 8.01 (ddd, 1H, J=7.2, 1.8, 1.7 Hz), 7.71–7.67 (m, 2H), 7.57 (d, 1H, J=8.4 Hz), 7.39 (d, 1H, J=8.7 Hz), 5.64 (s, 2H), 3.57 (t, 2H, J=8.3 Hz), 2.61 (s, 3H), 2.33 (s, 3H), 1.51 (s, 9H), 0.95 (t, 2H, J=8.3), −0.03 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C31H40N4O5S3Si, 673.2, (M+H), found 672.9.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.N1C=CC=CC=1.Cl>>[C:11]([OH:13])(=[O:12])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Benzaldehyde (10 g, 94 mmol), malonic acid (2 eq.), and piperidine (0.1 eq.) were dissolved in pyridine (5 eq.) and stirred at 80° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled down to the room temperature and neutralized with 3M HCl. The white solid thus obtained was filtered out and dried in a vacuum oven to yield cinnamic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.O1CC[CH2:12][CH2:11]1>>[CH2:11]([C:6]1([OH:9])[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)[CH3:12]
Reactant: C1CCOC1
Reactant: O=C1CCC(CO)CC1
Product: CCC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (1.22 g) in tetrahydrofuran (20 mL) was treated with 1-Methylmagnesium bromide in tetrahydrofuran (28.6 mL) at 0° C. The reaction was warmed to room temperature over 4 hours and quenched with methanol (2 mL) and water (2 mL). The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated and purified by flash chromatography, eluted with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[C@H:6]([OH:12])[CH2:5]1.Cl[C:14]1[C:19]([CH3:20])=[N:18][CH:17]=[CH:16][N:15]=1.[O-2].[Ca+2]>C(Cl)Cl.CO>[CH3:20][C:19]1[C:14]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[C@H:6]([OH:12])[CH2:5]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: Cc1nccnc1Cl
Reactant: NCCN1CC[C@H](CO)[C@H](O)C1
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: Cc1nccnc1NCCN1CC[C@H](CO)[C@H](O)C1
Temperature: 120 °C
Reaction time: 5 h
Yield: 23.5 %

Procedure:
A mixture of (±)-cis-1-(2-aminoethyl)-3-hydroxy-4-piperidinemethanol (0.064 mol), 2-chloro-3-methylpyrazine (0.068 mol) and calcium oxide (0.145 mol) was stirred for 5 hours at 120° C. The reaction mixture was cooled. The mixture was dissolved in CH2Cl2 /CH3OH and filtered over dicalite. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 90/10). The desired fractions were collected and the solvent was evaporated. The oily residue was triturated in CH3CN. The precipitate was filtered off and dried, yielding 4 g (23.5%) of (±)-cis-1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-3-hydroxy-4-piperidinemethanol (interm. 5a).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26](C(OCC2C=CC=CC=2)=O)[CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-propionic acid ethyl ester (0.11 mmol) in EtOH (12 mL) was added 10% palladium on carbon (0.050 g), and the reaction was stirred under a balloon of H2 at room temperature for 1 hour. The mixture was filtered through a pad of Celite and rinsed with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: [F:1][B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([N+]#N)=[CH:11]2.C(OCC)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=2
Reactant: COc1ccc2ncc([N+]#N)cc2c1
Reactant: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(F)cc2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A suspension of 1007 g of 6-methoxy-3-quinolinediazonium fluoroborate taken in 9 l of toluene is heated to 60° C. in 85 minutes. A release of gas is observed at 60° C. The reaction medium is then gradually heated further for 90 minutes to 70-72° C. After having been kept at 72° C. for 90 minutes, the medium is then gradually heated again to 85° C. After cooling and stirring overnight, 4 l of ice-cold water are added to the suspension. After having stirred for 15 minutes, 2.5 l of ethyl acetate are added. After having stirred for 45 minutes, the pH is adjusted to pH=7-7.5 by adding 47% sodium hydroxide (250 ml). The medium is stirred for 30 minutes and then separated by settling out for 1 hour. The lower aqueous phase is re-extracted with ethyl acetate. The organic phases are combined together and washed with water. The solution is filtered and then concentrated under reduced pressure so as to give 655 g of crude 3-fluoro-6-methoxyquinoline. The crude product is distilled under reduced pressure. The distillation fractions (bp 103-110° C. under 1 mbar) containing the expected product are combined together. 498.9 g of 3-fluoro-6-methoxyquinoline (76%) are thus obtained in the form of a white solid which melts at 51-53° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.CN([CH:28]=[O:29])C>C1COCC1>[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[C:21]([CH2:28][OH:29])[S:20][CH:19]=1
Reactant: FC(F)(F)c1ccsc1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (7.79 g) in THF (150 ml) was added n-butyllithium (1.6 M in hexane, 34.5 ml) at −78° C., and the mixture was stirred at 0° C. for 10 min. The solution was cooled to −78° C., and stirred for 30 min. To the solution was added 3-(trifluoromethyl)thiophene (6.99 g) in THF over 30 min, and the mixture was stirred for 1 h at same temperature. Then DMF (10.1 g) was added to the mixture, and the mixture was stirred overnight at room temperature. The mixture was quenched with 1 M HCl and extracted with EtOAc. The organic layer was separated, washed with 1 M HCl and brine successively, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc). The resulting residue was dissolved in MeOH (100 ml), and NaBH4 (0.865 g) was added to the mixture at 0° C. After stirred at room temperature for 30 min, the mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was separated, washed with saturated NH4Cl solution and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (1.79 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].IC.[C:26](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:26])[CH:17]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccccc1Cl)C1CCCC1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccccc2Cl)C2CCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(2-chloro-phenyl)-3-cyclopentyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=344.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([NH:26]C(=O)OC(C)(C)C)[CH:22]=[CH:23][C:24]=2[F:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[ClH:35]>O1CCCC1>[ClH:35].[NH2:26][C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:34])[CH:20]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(NC(=O)OC(C)(C)C)ccc1F
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(N)ccc1F
Yield: 75 %

Procedure:
The product of Step 1, (2.9 g, 5.3 mmol) was dissolved in tetrahydrofuran (75 mL) and 6N HCl (10 mL). The reaction mixture was heated at 60 C for 18 h and was concentrated in vacuo to give the final product (1.89 g, 75%). 1H NMR (400 MHz, CD3OD) δ 7.64 (q, J=8.4 and 15.2 Hz, 1H), 7.56 (m, 2H), 7.46 (m, 1H), 7.05 (m, 2H), 6.69 (s, 1H), 5.37 (s, 2H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.37 (1F), −115.86 (1F), −123.16 ppm. ES-HRMS m/z 440.0334 (M+H calcd for C19H15BrF3N2O2 requires 440.0295).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:15]3=[N:14][C:13]=2[CH3:29])=[O:11])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1.[Cl-].[NH4+].C(OCC)(=O)C>CN1CCCC1=O>[CH:23]1([CH2:22][O:21][C:20]2[C:15]3[N:16]([C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([N:30]5[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]5)=[N:7][CH:6]=4)=[O:11])=[C:13]([CH3:29])[N:14]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCc1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(c2ccc(CNC(=O)c3c(C)nc4c(OCC5CCCCC5)cccn34)cn2)C1

Procedure:
To a solution of 70 mg of N-[(6-chloropyridin-3-yl)methyl]-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 1 mL of N-methyl-2-pyrrolidone was added 0.12 mL of ethyl piperidine-3-carboxylate to carry out a reaction at 240° C. for 50 minutes under microwave irradiation. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 43 mg of ethyl 1-{5-[({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]pyridin-2-yl}piperidine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1N)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.Cl.CCCCCC.[OH-:32].[Na+]>CCOCC>[CH3:1][C:2]1[C:3](=[O:32])[C:4](=[O:5])[C:6]2[C@@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C@@:14]3([O:21][CH3:22])[C@H:13]4[NH:23][C@H:12]4[CH2:11][N:10]3[C:7]=2[C:8]=1[OH:9]
Reactant: [OH-]
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Temperature: 25 °C
Reaction time: 30 h
Yield: 63 %

Procedure:
Mitomycin C (2.2 g, 6.6 mmoles) was dissolved in 140 ml 0.1N methanolic NaOH (50%) and the reaction mixture was stirred at room temperature for 30 hours. The solution was then adjusted to ca. pH 4.0 with 1N HCl and extracted with ethyl acetate (4×500 ml). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated under reduced pressure at about 30° to 35° C. to obtain a solid residue, which upon dissolving in ether and treating with excess hexane afforded a purple precipitate. The precipitate was collected and air dried to afford the title compound as a fine purple powder (1.4 g, 63%).
Reaction SMILES: O=C1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([N:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[CH2:13][CH2:14][N:3]1[C:4]=23.[OH-].[Na+]>CO>[CH3:19][N:15]([CH:12]1[C:11]2[C:4](=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][CH:10]=2)[NH:3][CH2:14][CH2:13]1)[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCN(C)C1CCN2C(=O)OCc3cccc1c32
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCN(C)C1CCNc2c(CO)cccc21
Yield: 91.2 %

Procedure:
To a solution of 6,7-dihydro-3-oxo-7-(N-methyl-N-allylamino)-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.89 g) in methanol (80 ml) was added 15% aqueous solution of sodium hydroxide (20 ml) and the mixture was refluxed for 6 hours. After distilling off methanol and extracting with dichloromethane, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4-(N-methyl-N-allylamino)-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (4.83 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>O1CCCC1.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([C:41]3[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=3)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1c[nH]c2c(-c3ccc(C(F)(F)F)cc3)cccc12)NC(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (305 mg, 0.699 mmol) in tetrahydrofuran (4.5 mL) is added sodium carbonate (1 mL, 2M, 2 mmol), tetrakis(triphenylphosphine)-palladium (32 mg, 0.0280 mmol) and 4-trifluoromethylbenzeneboronic acid (0.199 g, 1.05 mmol). The mixture is refluxed for 22 hours, then cooled, diluted with brine and extracted three times with ethyl acetate. The combined organics are dried over anhydrous sodium sulfate, filtered and then evaporated in vacuo. The residue is purified using silica gel chromatography (hexane/20% ethyl acetate, hexane gradient elution) to give 282 mg of {1,1-dimethyl-2-[7-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (93%). FDMS m/e=433 (M++1).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH3:41][CH:42]([C:44]1[N:45]=[CH:46][S:47][C:48]=1[CH:49]=O)[CH3:43]>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:49]/[C:48]1[S:47][CH:46]=[N:45][C:44]=1[CH:42]([CH3:43])[CH3:41]
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: CC(C)c1ncsc1C=O
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1scnc1C(C)C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
1,1,3,3-Tetramethylguanidine (41 μL, 0.33 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 75 mg, 0.15 mmol) in tetrahydrofuran (2 mL) at about −25° C. After 5 min, a solution of 4-(1-methylethyl)thiazole-5-carboxaldehyde (Example 56; 26 mg, 0.168 mmol) in tetrahydrofuran (1 mL) was added. The cooling bath was removed and the solution was stirred at room temperature for 17 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (10 mL) and 10% aqueous acetic acid (5 mL). The ethyl acetate layer was washed with brine and each of the aqueous layers was extracted with ethyl acetate (10 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to give a colorless foam which was triturated with diethyl ether (5 mL). The resulting solids were recovered by filtration to furnish (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid methyl ester (76 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1
Reactant: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}phenyl)carbonyl]amino}propanoate (320 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (213 mg, 71%) as a pale-brown solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Br:49]C1C=CC(N)=CC=1>C(O)(=O)C>[Br:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(Br)cc1
Yield: 4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 4-bromoaniline (280 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 13 mg (0.034 mmol, 4% yield) of the title compound.