Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C(Cl)Cl>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:31])([CH3:32])[C:28]([Cl:36])=[O:29])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (prepared according to the procedures described in U.S. Pat. No. 5,081,138 issued Jan. 14, 1992; 0.25 g, 0.53 mmol) suspended in CH2Cl2 (5 mL) was added oxalyl chloride (48 uL, 0.56 mmol) and catalytic DMF. The reaction was stirred at room temperature for 3 hours, and then concentrated to give I-1, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (10.0 g, 39.0 mmol), methylene chloride (500 mL), and a catalytic amount of DMF (0.2 mL) was stirred under argon, and oxalyl chloride (2M in methylene chloride, 50 mL, 100 mmol) was added dropwise into the mixture over 30 min. The mixture was stirred at room temperature for 1.0 hr and the reaction was concentrated to dryness. Benzene (100 mL) was added and the solution was evaporated to dryness again. The pale yellow solid was re-dissolved in methylene chloride (200 mL) and dripped, under argon, into a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (10.8 g, 39.0 mmol), and triethylamine (10.2 g, 100 mmol) in methylene chloride (250 mL) over 30 min. The reaction was stirred at room temperature for 1 hr then concentrated and the residue was taken up in EtOAc (500 mL) and washed with hydrochloric acid (0.1N, 200 mL), water (200 mL), saturated sodium bicarbonate solution (200 mL), and brine (200 mL). The organic layer was dried with anhydrous sodium sulfate and filtered. The solvent was removed and the residue was triturated with hexanes to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (19.24 g, 96% yield). ES-MS for C27H28F3N3O4 calcd. (m/e) 515, observed 516 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][CH2:10][CH2:9][C:7](=O)[C:5]=2[CH:6]=1>CC(O)=O.[Zn]>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][CH2:9][CH2:10]1
Reactant: O=C1CCOc2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCCO2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 mL) is added to a suspension of zinc dust (108 g, 1.65 mol) in AcOH (150 mL). The mixture is heated to 100° C. and is stirred mechanically overnight. The mixture is then filtered through Celite® (washed with EtOAc, 100 mL), diluted with PhMe (300 mL) and the solution is evaporated to give chroman intermediate 11b (8.45 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:31])=[C:4]2[O:13][C:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]4[S:30][C:28](=[O:29])[NH:27][C:25]4=[O:26])=[CH:21][CH:22]=3)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].C1(=O)OC(=O)CC1.C(Cl)CCl.O[N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:31])=[C:4]2[O:13][C:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]4[S:30][C:28](=[O:29])[NH:27][C:25]4=[O:26])=[CH:21][CH:22]=3)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].[C:45]1(=[O:50])[NH:44][C:48](=[O:49])[CH2:47][CH2:46]1
Reactant: O=C1CCC(=O)N1O
Agent: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: O=C1CCC(=O)O1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C1CCC(=O)N1

Procedure:
To make the succinyl CS-045 conjugate of β-phycoerythrin, first 44 mg of CS-045 was reacted for 5 hours at room temperature with 20 mg succinic anhydride in pyridine. Then 4 mg of the resulting succinyl CS-045 was reacted overnight at 4° C. with 2 mg EDC and 1.2 mg N-hydroxysuccinimide to produce CS-045 succinimide. Forty micrograms of this CS-045 succinimide was reacted for 4 hours at room temperature with 500 μg β-phycoerythrin. The final succinyl CS-045 conjugate of β-phycoerythrin was precipitated with 60% final (w/v) saturated ammonium sulfate and resuspended in phosphate buffered saline.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[N+:12]([CH3:15])([O-:14])=[O:13]>O>[OH:5][C:4]1([CH2:15][N+:12]([O-:14])=[O:13])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
Isatin (0.073 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 10 minutes. The formed solid product was filtered and recrystallized with MeOH to afford pure product.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([C:9]([OH:11])=[O:10])=[N:7][S:8][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([C:9]([O:11][CH3:18])=[O:10])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nsc2cc(Br)ccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nsc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
To a solution of 6-bromobenzo[d]isothiazole-3-carboxylic acid (1.0 g, 3.89 mmol) in methanol (15 mL), thionyl chloride (0.92 g, 7.74 mmol) is added slowly at room temperature and the solution is stirred at 80° C. for 14 h. Cool the mixture to room temperature and concentrate to give 1.0 g (95%) of the title compound as a light brown solid. 1H NMR (400 MHz, MeOD) δ 4.04 (s, 3H), 7.73 (dd, J=8.8, 1.6 Hz, 1H), 8.41 (s, 1H), 8.61 (d, J=8.8 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si](C(C)(C)C)(C)C)[CH2:14][C@H:13]2[CH2:25][CH:26](C(OC)=O)[C:27]([O:29]C)=[O:28])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O.O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:11])=[CH:35][CH:36]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2R,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-(2,2-dimethoxycarbonylethyl)-4-t-butyldimethylsilyloxypyrrolidine (1.04 g) was dissolved in 6 ml of methanol, 3 ml of 4N sodium hydroxide solution was added thereto, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was acidified with 6 ml of 6N hydrochloric acid, and 5 ml of tetrahydrofuran was added thereto. The resulting mixture was stirred at room temperature for 2 days, diluted with water, adjusted to alkaline with a saturated sodium bicarbonate solution and extracted with ether. The aqueous layer was acidified (pH 1) with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled to obtain (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-(2-carboxyethyl)-4-hydroxypyrrolidine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[C:22]([O:31][CH3:32])=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COc1c(B(O)O)ccc(F)c1F
Product: COc1c(-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)ccc(F)c1F

Procedure:
Example 2 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (3,4-difluoro-2-methoxyphenyl)boronic acid (AOBChem USA). The batch was purified by preparative HPLC:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:16]([CH2:19][CH2:20][CH3:21])([O-:18])=[O:17].[OH-].[Na+].CO>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH:14]([OH:15])[CH:19]([N+:16]([O-:18])=[O:17])[CH2:20][CH3:21])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=CC1CCN(c2ccc(Cl)cc2)CC1
Reactant: CCC[N+](=O)[O-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C(O)C1CCN(c2ccc(Cl)cc2)CC1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.3 %

Procedure:
A mixture of 1-(4-chlorophenyl)piperidine-4-carbaldehyde (157 mg, 0.7 mmol), 1-nitropropane (0.125 mL, 1.400 mmol), 0.025 M NaOH (2 mL) and MeOH (1 mL) was treated with 25% aqueous cetyltrimethylammonium chloride (0.139 mL, 0.105 mmol). The reaction mixture was sonicated at RT for 4 h, and then stirred at RT for 14 h. After this time, the mixture was treated with brine and extracted with diethyl ether. The extract was dried over MgSO4 and concentrated to yield a residue. The residue was purified by flash chromatography on silica gel, eluting with 15-25% EtOAc/hexanes to give the diastereomeric mixture (2:1 more polar/less polar on reverse-phase HPLC) of the title compound (75 mg, 0.240 mmol, 34.3% yield) as a clear oil. LC-MS: (Waters Sunfire C18 4.6 mm×50 mm) 313.20, [M+H]; tR=1.95 min, 2.21 min; 10%-90%-0.1% MeOH/H2O/TFA to 90%-10%-0.15 MeOH/H2O/TFA at 1n 4 min 4 mL/min flow rate. 1H-NMR (400 MHz, CD3OD) δ ppm 7.05-7.11 (2H, m), 6.81-6.87 (2H, m), 4.42-4.51 (1H, m), 3.67 (2H, dd, J=7.36, 3.84 Hz), 3.61 (3H, d, J=11.42 Hz), 2.51-2.62 (3H, m), 1.81-1.91 (2H, m), 1.58-1.64 (3H, m), 1.51-1.56 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[C:19]#[N:20])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.CN1C2C(=[O:39])C3C=C(CC4C=C(C=CC=4)C#N)C=CC=3NC=2C=N1>>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[C:19]([NH2:20])=[O:39])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Reactant: Cn1ncc2[nH]c3ccc(Cc4ccccc4C#N)cc3c(=O)c21
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4C(N)=O)cc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of EXAMPLE 29 using 2-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile (EXAMPLE 32, step 2), instead of 3-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(N(CC)CC)C.[C:32](Cl)(=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>ClCCl>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1[CH:6]=[C:7]([NH:8][C:32](=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(Cc1cccc(N)c1)OC
Agent: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)Nc1cccc(CC(OC)OC)c1
Reaction time: 0.17 h

Procedure:
By the method outlined in example 9 above, 3-(2,2-dimethoxyethyl)aniline is prepared from 3-nitrobenzaldehyde. To a solution of this material (2.13 g) in dichloromethane (25 ml) is added triethylamine (1.7 ml). The solution is cooled in an ice bath, and octanoyl chloride (2.0 ml) is added dropwise with stirring. After 10 min, the solvent is removed in vacuo and the residue is taken up in ether, filtered, and washed with aqueous sodium bicarbonate. The solution is dried, filtered, and concentrated to leave N-(3-(2,2-dimethoxyethyl)phenyl)octanamide (3.4 g) as a light brown oil. By the method of example 2 above, this is converted into the title compound, mp 128°-130° after recrystallization from dichloromethane.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C(O)(=O)C.[CH:17]([NH2:19])=[NH:18].NN.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(#N)C>[N:18]1[CH:17]=[N:19][N:10]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([NH2:3])=[CH:5][CH:6]=2)[N:9]=1
Reactant: N=CN
Reactant: N=C(N)c1ccc(N)cc1
Agent: Cl
Agent: NN
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1ccc(-c2nncnn2)cc1
Yield: 19.1 %

Procedure:
To a mixture of 4-Aminobenzamidine dihydrochloride (1 mmol, 208 mg) and formamidine acetate (4 mmol, 416 mg) in acetonitrile (25 mL) was added anhydrous hydrazine (10 mmol, 315 uL). The solution was heated to reflux for 1 hour, cooled, and the solvent was removed by rotary evaporation. The residue was resuspended with water (25 mL) and was stirred with solid tetrachloro-1,4-benzoquinone (2 mmol, 492 mg) for 1 hour. After removal of the solids from the pink solution by filtration, the reaction was concentrated by rotary evaporation and purified by preparative HPLC using a gradient from 0-40% buffer B (buffer A is water with 0.1% TFA, and buffer B is acetonitrile with 10% water and 0.1% TFA) to afford pure 4-(1,2,4,5-tetrazin-3-yl)aniline (33 mg, 19%), as a pink solid. LRMS-ESI [M+H]+ calcd. for C8H8N5+: 174.08, found: 173.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1COCC1>[Pd].C(O)C>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of 4-(2,6-difluoro-4-nitrophenyl)morpholine (4.71 g, 19.3 mmol), THF (30 mL), ethanol (30 mL) and Pd/C (2.0 g, 10%) was stirred at rt under H2 overnight. The mixture was filtered and concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (3.62 g, 88%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:40])[CH3:41])=[CH:35][CH:34]=1)[C@H:16]([OH:17])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Product: CC(C)c1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(O)cc2)cc1
Yield: 90.9 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-3-hydroxy-2-(4-isopropylphenoxy)propionyl]oxazolidine-2-one (25.0 g), which is the product of Reference example 29(b) and palladium on carbon (5%, 2.50 g) and the reaction mixture was treated to afford the desired compound (19.1 g) as a mass of foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:3]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 89 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using 2,2,2-trifluoroethylamine instead of aminomethylcyclopropane, to the title compound (91 mg, 89%) which was obtained as an off white solid. MS: m/e=410.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15](F)=[N:14][CH:13]=[CH:12][N:11]=2)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][N:11]=3)[NH:18][N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc(Cl)n1)c1nccnc1F
Reactant: NN
Solvent: C1CCOC1
Product: Clc1cccc(-c2n[nH]c3nccnc23)n1
Yield: 63.5 %

Procedure:
To a solution of (6-chloro-2-pyridyl)-(3-fluoropyrazin-2-yl)methanone (1.12 g, 4.713 mmol) in THF (10 mL) was added hydrazine (1M in THF) (9.897 mL of 1 M, 9.897 mmol). Mixture turned orange and an exothermic reaction occurred, cream precipitate rapidly formed and mixture became difficult to stir. Stirred for 45 mins. Added sat. NaHCO3 solution and collected solid by filtration, washing solid with water then petrol. Solid then dried in vacuum oven overnight at 80° C. to leave title compound as an off-white solid (693 mg, 64%). 1H NMR (DMSO-d6) δ 7.58 (d, 1H), 8.07 (t, 1H), 8.52 (d, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 14.55 (br s, 1H). ES+232.13.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[C:57]([O:61][C:62]([N:64]1[CH2:68][CH2:67][CH:66]([CH2:69][NH2:70])[CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58].[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[C:57]([O:61][C:62]([N:64]1[CH2:68][CH2:67][CH:66]([CH2:69][NH:70][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a mixture of 0.097 g (0.15 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0634 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 3 mL of dichloromethane, 0.13 mL of triethylamine was added followed by 0.0317 g (0.17 mmole) of 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. After 1 hour, 4 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 100:0-0:100) to give 0.0748 g of 3-{[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (I-92).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=[N+]([O-])c1ccccc1
Product: CN(C)c1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cc1
Yield: 14.6 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (77 mg, 0.26 mmol) and 4-(dimethylamino)benzaldehyde (54 mg, 0.36 mmol) were combined and heated in 8 mL nitrobenzene at 140° C. for six hours. The reaction was concentrated and purified by reverse phase chromatography on a Gilson chromatograph to afford 16 mg (14%) of the title compound. 1H NMR (d-chloroform): 13.55 (br s, 1H), 7.99 (m, 3H), 6.84 (m, 2H), 6.62 (br s, 1H), 6.36 (m, 2H), 5.45 (d, J=9 Hz, 1H), 5.37 (s, 1H), 5.21 (t, J=9 Hz, 1H), 3.19 (s, 1H), 3.11 (s, 6H), 2.92 (m, 2H), 2.35 (d, J=9 Hz, 1H), 1.76 (d, J=9 Hz, 1H). MS: 424.05 (M+H). HPLC retention time: 2.39 minutes (G Method).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[C:25]([OH:26])=[C:24]([CH3:27])[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:26][C:25]1[C:24]([CH3:27])=[CH:23][CH:22]=[CH:21][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cccc(N)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Yield: 83.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 680 mg of 6-amino-2-methylphenol and 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 6 ml of pyridine and 8 ml of N,N-dimethylformamide. 1.1 g of N-(2-hydroxy-3-methyl phenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following: