Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)[CH:20]=[CH:19][C:18]=2[CH3:29])=[N:13][C:12]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)[CH:20]=[CH:19][C:18]=2[CH3:29])=[N:13][C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([F:38])=[C:32]([CH3:31])[CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Nc1nc(Br)c(C(=O)NCc2ccccc2)s1
Reactant: Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(Nc3cc(C(=O)NC4CC4)ccc3C)sc2C(=O)NCc2ccccc2)ccc1F
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A microwave reaction flask was charged with 4-bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide (10 mg, 0.02 mmol, 1.0 eq), 3-methyl-4-fluorophenylboronic acid (32 mg, 0.21 mmol, 10 eq), tetrakistriphenylphosphine palladium (5 mg, 0.004 mmol, 0.2 eq), 200 μL of dioxane, and 200 μL of saturated aqueous K2CO3. The mixture was heated with stirring in the microwave at 120° C. for 10 minutes. The layers were separated and dioxane layer was concentrated and purified by preparative HPLC. Fractions containing product were concentrated to provide the title compound as a white solid (7.5 mg, 71%). HPLC (4 minutes gradient) tR 2.61 min; MS m/z 515.24 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 0.53 (m, 2H), 0.66 (m, 2H), 2.16 (s, 3H), 2.29 (s, 3H), 2.82 (m, 1H), 4.29 (d, J=4.3, 2H), 7.05 (t, J=8.9, 1H), 7.20-7.30 (m, 6H), 7.44-7.51 (m, 3H), 8.30-8.36 (m, 3H), 9.72 (s, 1H) ppm.
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].[CH2:9]([N:11]([CH2:22][CH3:23])[C:12]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH2:21])=[O:13])[CH3:10].[OH-].[Na+]>C1C=CC=CC=1>[CH2:22]([N:11]([CH2:9][CH3:10])[C:12]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH:21][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:13])[CH3:23]
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Reactant: CC(C)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCN(CC)C(=O)Oc1cnccc1NCC(C)C
Temperature: 85 °C
Yield: 33 %

Procedure:
A solution of isobutyric acid (49.85 g) in 100 ml of benzene was treated with NaBH4 (6.91 g added portionwise). After the frothing subsided, 4-amino-3-pyridinol N,N-diethylcarbamate (4.90 g) was added and the mixture was heated at 85° C. for 3 hours. The reaction mixture was poured into a dilute NaOH solution and the aqueous phase was extracted with ethyl acetate (3×). The combined organics were washed with water and dried (saturated NaCl, MgSO4). The desired amine was purified via flash chromatography to give 2.05 g of solid. This product was recrystallized from hexane to give analytically pure material, m.p. 71°-75° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][C:3]=1[N+]([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(OCC)(=O)C>O1CCOCC1.O.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:2]1([C:21]2[CH:20]=[CH:19][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCC
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4,4,5,5-Tetramethyl-2-[4-(2-methylisoindolin-1-one)-yl]-[1,3,2]-dioxoborolane (0.97 g, 3.6 mmol) and 4-chloro-3-nitroanisole (0.67 g, 3.6 mmol) were dissolved in a mixture of dioxane (10 mL) and water (2 mL). K2CO3 (0.98 g, 7.2 mmol) and Pd(PPh3)4 (0.21 g, 0.2 mmol) were added. The reaction mixture was heated in a flow of argon to 80° C., kept at this temperature over a period of 24 h (TLC monitoring: hexane/ethyl acetate, 4:1), cooled, and filtered through Celite. The filtrate was evaporated. The residue was dissolved in CH2Cl2. An undissolved precipitate was filtered off. The filtrate was partially evaporated, and the product was purified in a short silica gel column (hexane/ethyl acetate) to give 0.76 g of a product containing PPh3O. The product was cyclized without additional purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[BrH:8].[C:9]([OH:12])(=O)[CH3:10]>C(Cl)Cl>[C:9]([O:1][C@H:2]([CH2:7][Br:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH3:10]
Reactant: O=C1C[C@H](O)CO1
Reactant: Br
Reactant: CC(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@H](CBr)CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A solution of (S)-3-hydroxybutyrolactone (10 g) in 85% purity and hydrogen bromide/acetic acid (40 ml) in 30% purity was charged to a 250 ml flask equipped with a thermometer, reflux condensor and agitator, and stirred at 40˜60° C. for 5 hours. After the reaction was completed, the reaction solution was cooled at room temperature. With the addition of methylene chloride (200 ml), the mixture washed with 1M sodium acetate solution and then an organic layer was separated, dried over anhydrous magnesium sulfate, filtered off and concentrated. Toluene (100 ml) was added to (S)-3-acetoxy-4-bromobutyric acid, so concentrated, to remove the remaining acetic acid. The concentration under reduced pressure gave 18.74 g of (S)-3-acetoxy-4-bromobutyric acid (yield: 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([CH:39]=1)[C:36](O)=[O:37]>CN(C)C=O>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([CH:39]=1)[C:36]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:37]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1F
Reactant: Nc1cccnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Pyridinamine (0.21 g, 2.19 mmol), EDC (0.34 g, 1.75 mmol), HOBT (0.36 g, 2.33 mmol) and N-ethylmorpholine (0.37 ml, 2.91 mmol) were added to a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}benzoic acid (may be prepared by Description 103; 0.5 g, 1.46 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hours. The N,N-dimethylformamide was removed on a buchi and the residue was diluted with ethyl acetate (50 ml) washed with saturated aqueous sodium hydrogencarbonate (1×25 ml) and water (1×25 ml) and dried (MgSO4), filtered and evaporated to yield the title compound as a white solid. 0.6 g.
Reaction SMILES: C1(CO[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:25][OH:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])C=CC=CC=1.C(N(CC)CC)C.[N:34]1(C(Cl)=O)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CO.C(Cl)Cl.[C].[Pd]>[N:34]1([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:25][OH:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCC[C@@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCC[C@@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
70 mg of 10% palladium-carbon was added to a solution of 700 mg (2 mmol) of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol obtained in Reference Example 185 in 10 ml of methanol, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. 20 ml of methylene chloride and 404 mg (4 mmol) of triethylamine were added to the residue. A solution of 299 mg (2 mmol) of 4-morpholinecarbonyl chloride in 3 ml of methylene chloride was added to the mixture solution under ice-cooling. The reaction solution was returned to room temperature and stirred overnight. After the reaction solution was washed with water and then saturated brine, it was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ether was added to the residue to wash it to obtain 488 mg (71%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:28]2[C:29]([C:30]#[N:31])=[C:32]([F:35])[CH:33]=[CH:34][C:27]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (820 mg, 4.4 mmol) in DCM (7 mL) was added triethyloxonium tetrafluoroborate (877 mg, 4.6 mmol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (7 mL). 3-Amino-6-fluoro-2-(pyridin-2-ylamino)benzonitrile (620 mg, 2.7 mmol) was added and the reaction heated at 75° C. for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (563 mg, 54%). LCMS (Method C): RT=3.20 min, [M+H]+=382.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[O:11][N:10]=1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[O:11][N:10]=1
Reactant: CC(O)c1cc(-c2c(F)cccc2Cl)no1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(-c2c(F)cccc2Cl)no1
Temperature: 5 °C

Procedure:
To a solution of 30 g (124 mmol) of 1-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-ethanol in 187 ml of acetic acid maintained under stirring at 5° C. were added dropwise 9.07 (90.7 mmol) of CrO3 in 9.34 of water and 132 ml of acetic acid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].[Li]CCCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[C:22]1([CH2:25][C:26](=[O:40])[C:27]([NH:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:35](=[O:36])[O:34][CH2:33]3)=[O:28])[CH2:24][CH2:23]1.[Cl-].[NH4+]>C1COCC1>[OH:40][C:26]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])([CH2:25][C:22]1([C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[F:11])[CH2:24][CH2:23]1)[C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:35](=[O:36])[O:34][CH2:33]2)=[O:28]
Reactant: O=C(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Reactant: C#CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC#CC(O)(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution that consists of 1-pentyne (0.94 ml) in THF (9 ml) was mixed at −78° C. with nBuLi (0.6 ml, 1.6 M in hexane). It was allowed to stir for 30 minutes at −78° C., and then a solution of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide (200 mg) in 3 ml of tetrahydrofuran was added. Then, it was allowed to come to 23° C. over about 3 hours, and it was stirred for 10 more hours at this temperature. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product was chromatographed on silica gel. 130 mg of product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)=[O:14])[CH:7]=[CH:6]2.[F:39][C:40]([Si](C)(C)C)([F:42])[F:41].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(O)(C)C>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([OH:14])[C:40]([F:42])([F:41])[F:39])[N:16]=[CH:17]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(F)(F)F)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was dissolved in THF (10 ml) and to the solution was added trifluoromethyltrimethylsilane (1.40 g). The reaction mixture was cooled to 0° C., and tetrabutylammonium fluoride (0.4 ml) was added. The mixture was stirred at room temperature for 2 h. To the mixture were added 1 N-hydrochloric acid (10 ml) and isopropanol (5 ml), and the mixture was stirred at room temperature for 24 h. The reaction mixture was neutralized, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform methanol=20:1→10:1). Recrystallization from ethyl acetate gave the titled compound (0.40 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10](=[O:18])(=[O:17])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26].[OH:32]OS([O-])=O.[K+].Cl>O1CCCC1.O>[OH:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10](=[O:18])(=[O:17])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28]1)=[O:26]
Reactant: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCSC1
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
3-[4-hydroxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (67 mg) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and oxone (45 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (46 mg) as a colorless crystal.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[C:19]([NH:21][CH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2)=[O:20]>CO.ClCCl>[ClH:2].[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH:5]=1)[C:19]([NH:21][CH2:22][C:23]12[CH2:30][CH:29]3[CH2:31][CH:25]([CH2:26][CH:27]([CH2:28]3)[CH2:32]1)[CH2:24]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 196.1 %

Procedure:
Hydrochloric acid (4M in 1,4-dioxane, 3.0 ml) was added to a solution of [2-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]ethyl]carbamic acid, 1,1-dimethylethyl ester (2.2 g, Example 30b) in methanol/dichloromethane (1:1) (50 ml). After 24 h the solvent was evaporated to leave the title compound as a foam (1.85 g).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].N[C:14]1[CH:22]=[CH:21]C(CN(C=O)C)=C[C:15]=1[C:16]([OH:18])=[O:17]>CN(C)C=O>[C:15]12[C:12](=[CH:11][CH:21]=[CH:22][CH:14]=1)[NH:8][C:1](=[O:2])[O:18][C:16]2=[O:17]
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c(=O)o1

Procedure:
There was suspended, in 7.6 mL of N,N-dimethylformamide, 1.67 g of 1,1′-carbonyl-diimidazole (CDI) and the suspension was cooled to 5° C. To this slurry, there was added 2.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)-benzoic acid to thus carry out a reaction for forming an isatoic anhydride derivative at 5° C. After the confirmation of the completion of the reaction by HPLC, 3.80 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine isopropyl ester was added to the reaction system to thus carry out amidation at 60° C. overnight. After the confirmation of the completion of the reaction by HPLC, the reaction system was cooled to a temperature ranging from 25 to 50° C. followed by the addition of 3 mL of water. This solution was slowly dropwise added to another egg plant-shaped flask to which 29 mL of water had previously been added to thus form a solid material and then the separated solid was isolated through filtration under reduced pressure. After washing the solid with 20 mL of water, it was dried under reduced pressure to thus give 5.50 g of a crude product of the intended compound. To this crude product, there was added 5.5 mL of acetonitrile to obtain a uniform dispersion, 137.5 mL of 2-propanol and seed crystals were added thereto to precipitate a solid material and the slurry was stirred at 20° C. for 2 hours. The solid thus separated was isolated through filtration under reduced pressure, washed with 20 mL of 2-propanol and then dried under reduced pressure to thus give 2.60 g of the intended product as a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(Cl)Cl.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: Brc1ncccn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: OC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.48 h
Yield: 53.5 %

Procedure:
To a solution of 2-bromopyrimidine (0.20 g, 1.258 mmol) in dry methylene chloride (3.0 mL) was dropwise added 1.6 M of n-butyllithium in hexane (0.86 mL) at −78° C. The reaction mixture was stirred for 29 min at −78° C. and 1,4-dioxa-spiro[4.5]decan-8-one (0.196 g, 1.26 mmol) in CH2Cl2(3 mL) was added dropwise. The reaction was stirred at −78° C. for 50 min and quenched with an aqueous solution of NH4Cl. After being warmed to room temperature, the mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to provide 0.50 g of crude product. Purification by column chromatography on silica gel eluting with 0->50% EtOAc in hexanes provided 0.159 g (54%) of desired product as a light brown-yellow solid. MS (M+H)+237.2.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].CCO.[ClH:17].[NH3:18]>C(Cl)Cl.CO>[ClH:17].[NH2:18][N:2]=[CH:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: N
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(CC=NN)c1
Temperature: 0 °C
Reaction time: 144 h

Procedure:
A sample of methyl 3-(cyanomethyl)benzoate (1.87 g, 0.011 mol) was dissolved in anhydrous CH2Cl2 (100 mL) containing absolute EtOH (15 mL). The mixture was cooled to 0° C. and a stream of HCl gas passed through the solution for 10 min. The mixture was then refrigerated for 6 days. The mixture was transferred to a 500-mL flask and concentrated in vacuo (0.05 mm Hg) at 0° C. to give a white solid. The solid material was dissolved in anhydrous methanol (200 mL) and anhydrous ammonia passed through the solution for 20 min. The mixture was warmed to 50° C. for 18 h. The solution was cooled and filtered to remove solids. The filtrate was concentrated at room temperature in vacuo to give a white foam (2.5 g, quantitative). A portion (ca. 1 g) of the material was dried over toluene to give methyl 3-[(aminoiminomethyl)methyl]benzoate hydrochloride, mp 139°-140° C.
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:17]1[NH:16][C:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:11](=[O:22])[C:12]=2[C:18]=1[CH3:19]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 48.05 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (39 mg, 48.05%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)C(O)=O)([O-:3])=[O:2].C1C=C2N=NN([OH:23])C2=CC=1.O.Cl.C(N=C=NC1[C:36]([N:37]([CH3:39])[CH3:38])=CC=CN=1)C.Cl.CNC>CN(C=O)C.O.C(N(CC)CC)C>[Cl:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:12]([CH:8]=1)[C:36]([N:37]([CH3:39])[CH3:38])=[O:23]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN=C=Nc1ncccc1N(C)C
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Yield: 99.6 %

Procedure:
To a solution of 5-nitro-2-chlorobenzoic acid (1 g), 1-hydroxybenzotriazolemonohydrate (1.14 g) and 1-ethyl-3-(3-dimethylaminopyridyl)carbodiimide hydrochloride (1.42 g) in N,N′-dimethylformamide (10 mL) were added dimethylamine hydrochloride (0.61 g) and triethylamine (1 mL). The mixture was stirred for all day and night, and then water was added. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated to give the title compound (1.13 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3].[CH:10]1[C:16]([NH2:17])=[N:15][C:13](=[O:14])[N:12]([C@@H:18]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C:19]2([F:27])[F:26])[CH:11]=1.Cl>>[F:27][C:19]1([F:26])[C@H:20]([OH:25])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:18]1[N:12]1[CH:11]=[CH:10][C:16]([NH:17][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3])=[N:15][C:13]1=[O:14]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Product: CCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 95 %

Procedure:
Using Method A and pentyl chloroformate, gemcitabine hydrochloride was converted to 29 (white solid, 95% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.23-8.27 (d, 1H), 7.11-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.16-6.24 (t, 1H), 5.34 (s, 1H), 4.11-4.18 (t, 3H), 3.82-3.94 (m, 2H), 3.57-3.72 (m, 1H), 1.61-1.68 (t, 2H), 1.34-1.38 (t, 4H), 0.88-0.95 (t, 3H).