Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClCC(OC(=O)CCl)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>ClC(Cl)C>[C:1]1([C:7]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[C:22]([O:27][CH3:28])[CH:23]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)C1=CCCCC1
Reactant: COc1ccccc1OC
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)C2=CCCCC2)cc1OC
Temperature: 75 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
In 50 ml of dichloroethane were dissolved 6.31 g (0.05 mole) of 1-cyclohexene-1-carboxylic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 8.98 g (0.065 mole) of 1,2-dimethoxybenzene and 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 75° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over, anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 7.27 g of 4-(1-cyclohexenoyl)-1,2-dimethoxybenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][C:20]=3[S:21][C:22]=2[N:23]([CH3:25])[CH3:24])=[O:17])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([O-])=O.[BH4-].[Na+].O.[OH-].[Na+]>CCO.CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:26][C:20]=3[S:21][C:22]=2[N:23]([CH3:25])[CH3:24])=[O:17])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(CN2CCCC2)c(N)c1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
The 492 mg (0.955 mmol) of 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-nitro-4-(1-pyrrolidinylmethyl)phenyl ketone (Part D, above) was dissolved in 21 mL of an EtOH/MeOH mixture (5:2 ratio). To the reaction mixture was added 1.07 g (4.77 mmol) of stannous chloride dihydrate. The reaction mixture was heated to 75° C. and to the solution was added 18.1 mg of sodium borohydride dissolved in 10 mL of EtOH/MeOH mixture (7:3 ratio). The solution was added dropwise via syringe over 25 min. The reaction mixture was stirred at 75° C. for 1.5 h. The reaction was then allowed to cool to room temperature. and was then poured into 20 mL of chilled (0° C.) water. The mixture was neutralized by adding 4 mL of 2 N NaOH solution and then concentrated under reduced pressure to a volume of 30 mL. This mixture was extracted with EtOAc (4×100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford 451 mg (97% crude yield) as a orange foam.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][CH:6]1[C:12](=[O:13])[N:11]2[CH:7]1[S:8][C:9]([CH3:31])([CH3:30])[CH:10]2[C:14]([O:16][CH:17]([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)=[O:15].C([O-])(=O)C.[NH4+:36].[OH-].[NH4+]>C(OCC)(=O)C.O>[NH2:36][C:1]([NH:5][CH:6]1[C:12](=[O:13])[N:11]2[CH:7]1[S:8][C:9]([CH3:31])([CH3:30])[CH:10]2[C:14]([O:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])=[S:2]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: S=C(Cl)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)SC2C(NC(N)=S)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A 0.9 ml portion of thiophosgene was added to a stirred mixture of 5.55 g of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, diphenylmethyl ester in 100 ml of ethyl acetate and 5.0 g of ammonium acetate in 50 ml of water. After stirring for 10-15 minutes concentrated ammonium hydroxide was added in increments over 5 hours. The layers were separated and the organic layer washed twice with brine, dried, evaporated to about 20 ml and chilled. The solid was collected, giving 2.385 g of the desired compound.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][C:24]3([C:30]([O:32]C)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=O.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:18]1[C:19]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH2:15][CH2:16][N:17]1[S:20]([CH2:23][C:24]1([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)(=[O:21])=[O:22]
Reactant: COC(=O)C1(CS(=O)(=O)N2CCc3c(n(C(=O)OCC(Cl)(Cl)Cl)c4ccccc34)C2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(CS(=O)(=O)N2CCc3c([nH]c4ccccc34)C2)CCOCC1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-(4-Methoxycarbonyl-tetrahydro-pyran-4-ylmethanesulfonyl)-1,2,3,4-tetrahydro-β-carboline-9-carboxylic acid 2,2,2-trichloro-ethyl ester (556 mg) and lithium hydroxide monohydrate (206 mg) in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml) was heated to reflux for 8 h. The reaction was left to stand at room temperature overnight and then refluxed for a further 4 h. The mixture was evaporated under reduced pressure and the residue dissolved in water (25 ml) and washed with ethyl acetate (2×30 ml). The aqueous was acidified to pH=4 with 5% citric acid solution and extracted with dichloromethane (2×40 ml) followed by ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound (299 mg, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[CH3:16][N:17]([CH3:19])[CH:18]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ccc(F)cc1
Yield: 34.3 %

Procedure:
Combined ethyl 2-(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100° C. for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2% yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 3 H) 2.64 (s, 6 H) 3.98 (q, J=7.1 Hz, 2 H) 7.06-7.15 (m, 4 H) 7.49 (s, 1 H).
Reaction SMILES: CO[C:3]([C:5]1(C(OC)=O)CC=[CH:7][CH2:6]1)=O.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O:23][C:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26]C)C>C(O)C.O>[CH2:19]1[C:14]2([CH2:15][O:23][C:24]3([O:25][CH2:26][C:30]4([CH2:7][CH:6]=[CH:5][CH2:3]4)[CH2:29][O:28]3)[O:31][CH2:20]2)[CH2:16][CH:17]=[CH:18]1
Reactant: Cc1ccccc1
Reactant: COC(=O)C1(C(=O)OC)CC=CC1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CCO
Solvent: O
Product: C1=CCC2(C1)COC1(OC2)OCC2(CC=CC2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser, a thermometer and a magnetic stir bar, was placed diol 1 (14.8 g, 115.5 mmol) and 370 mL of toluene under an atmosphere of N2. The mixture was brought to reflux and maintained at reflux temperature for 2 hours to azeotropically remove any moisture. About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap. The mixture was then allowed to slowly cool to room temperature and 0.2 g of anhydrous para-toluenesulfonic acid (PTSA) was added, followed by dropwise addition of tetraethylorthocarbonate (TEOC, 4563-91-2, 99.1%, 12.2 mL, 57.8 mmol). The resulting mixture was brought to reflux to azeotropically remove ethanol generated during this reaction. The azeotropic mixture was shaken with sale water to determine the amount (volume) of ethanol collected. After a total of 140 mL of azeotropic mixture (12.5 mL of ethanol) was collected, the reaction mixture was allowed to reflux for an additional 2 hours and then allowed to stir at 102° C. overnight. The reaction mixture was allowed to slowly cool to room temperature and then neutralized by the addition of 1 mL of triethylamine. The resulting mixture was allowed to stir at room temperature for an additional 30 min, and was stripped off solvents to give an off white solid. The crude material was then purified by flash chromatography (silica gel, CH2Cl2/hexanes 2/1 v/v) or by recrystallization from refluxing toluene. The desired product 7,9,17,18-tetraoxatrispiro[4.2.2.4.2.2]nonadeca-2,13-diene (DCP 3) was obtained as white crystals in 62% yield. Mp (DSC) 174.53° C.; 1H-NMR (CDCl3, 300 MHz) δ5.61 (s, 2H), 3.82 (s, 4H), 2.29 (s, 4H); 13C-NMR (CDCl3, 300 MHz) δ128.53, 114.14, 71.07, 39.79; FT-IR (CH2Cl2) (cm−1) 3052, 2947, 2928, 2880, 2842, 1614, 1481, 1267, 1210, 1171, 1014, 990, 738, 671; Anal. Calcd for C15H20O4: C, 68.16; H, 763; Found: C, 68.18; H, 7.81.
Reaction SMILES: [N:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].[Cl:18][CH2:19][C@H:20]([OH:22])[CH3:21].B(F)(F)F.CCOCC>ClCCl>[CH2:11]([O:10][C:8]([NH:1][C@H:2]([CH2:3][O:22][CH:20]([CH3:21])[CH2:19][Cl:18])[C:4]([O:6][CH3:7])=[O:5])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Reactant: C[C@@H](O)CCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](COC(C)CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
To a 100 mL flask was added 1-benzyl 2-methyl aziridine-1,2-dicarboxylate (1 g, 4.25 mmol), dichloromethane (12 mL), (R)-1-Chloro-2-propanol (0.76 mL, 8.50 mmol), and boron trifluoride diethyl etherate (0.05 mL, 0.398 mmol). The mixture was stirred at room temperature for 15 minutes Solvent was removed in vacuo and the residue purified on silica gel eluting with Hexanes-EtOAc (0-50%) to give (R)-methyl 2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg, 41%). MS [M+H] found 330.2.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C(O)C.O1CCCC1>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:10]2[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:27])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1)=[O:24]
Reactant: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2cccc(C(C)(C)C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 2-[3-(4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionic acid ethyl ester (Intermediate 133, 0.12 g, 0.33 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as an oil (0.11 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>>[CH2:17]([O:16][C:10](=[O:15])[C:11](=[C:4]([NH2:5])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])[C:12](=[O:13])[CH3:14])[CH3:18]
Reactant: N#Cc1ccccc1F
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccccc1F

Procedure:
The title compound was synthesized in analogy to Example 1 from 2-fluoro-benzonitrile and ethyl acetoacetate: MS (m/z) 252.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][C@@H:8]([NH2:33])[C:9]([NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[O:44]=[C:45](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@@H:8]1[C:9](=[O:10])[N:11]([C@H:12]([C:21]2[NH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=3)=[CH:24][N:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:45](=[O:44])[NH:33]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)CC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2)[nH]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CC(=O)OC(C)(C)C)C1=O
Temperature: 10 °C
Yield: 40.8 %

Procedure:
A solution of ((R)-3-amino-N-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-succinamic acid tert-butyl ester (400 mg, 0.7 mmol) in tetrahydrofuran (3 mL) containing N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) was added via an addition funnel to diphosgene (0.059 mL, 0.49 mmol) in a 1:1 v/v mixture of toluene/tetrahydrofuran (6 mL) at −40° C. under an atmosphere of nitrogen with stirring. The reaction was stirred at this temperature for 20 minutes and then allowed to warm to 10° C. before quenching with ice/water (5 mL). After stirring for 2 minutes the mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with water (2×10 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 0 to 50% v/v ethyl acetate/hexanes to give ((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-acetic acid tert-butyl ester (120 mg, 29%). LC-MS: calcd for C27H29IN4O4 [M+H+] 601. Found 601
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:9]([CH3:10])=[C:8]([NH2:11])[CH:7]=[CH:6][C:5]=1[NH2:12].Br.[CH2:14]([N:16]1[C:21]2[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1)[CH3:15].[OH:27]O>O.N.CC(C)=O>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([NH:12][C:24]2[C:23](=[O:26])[CH:22]=[C:21]([N:16]([CH2:17][CH2:18][OH:27])[CH2:14][CH3:15])[C:20](=[O:19])[CH:25]=2)=[C:4]([CH3:3])[C:9]=1[CH3:10]
Reactant: OO
Reactant: CCN1CCOc2ccc(O)cc21
Reactant: Cc1c(N)ccc(N)c1C
Agent: Br
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: O
Product: CCN(CCO)C1=CC(=O)C(Nc2ccc(N)c(C)c2C)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.05 g (0.005 mol) of 2,3-dimethylbenzene-1,4-diamine dihydrochloride in 5 ml of water and 3 ml of 20% aqueous ammonia is added a solution of 1.31 g (0.005 mol) of 4-ethyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 3 ml of water, 1 ml of 20% aqueous ammonia and 15 ml of acetone. 17 ml of 6% aqueous hydrogen peroxide solution are added and the mixture is stirred at room temperature for 6 hours 30 minutes. After 12 hours at 6° C., the reaction medium is concentrated and left for a further 12 hours at 6° C. A precipitate forms, which is filtered off. It is purified by chromatography, eluting with dichloromethane/methanol. 0.01 g of 2-(4-amino-2,3-dimethylphenylamino)-5-[(2-hydroxyethyl)ethylamino][1,4]benzoquinone (compound 10) is obtained in the form of a brown powder.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[CH:8]1[CH2:14][N:13]([CH2:15][CH3:16])[CH2:12][CH2:11][N:10]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][C:38]=1[CH3:45]>CO>[CH2:15]([N:13]1[CH2:14][CH:8]([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[C:9]2=[N:20][C:19]([C:21]([NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[C:38]([CH3:45])[CH:39]=3)=[O:23])=[C:18]([OH:25])[C:17](=[O:26])[N:10]2[CH2:11][CH2:12]1)[CH3:16]
Reactant: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Reactant: Cc1cc(CN)ccc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1CCn2c(nc(C(=O)NCc3ccc(F)c(C)c3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Crude methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-8-ethyl-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluoro-3-methylbenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 9.74 (bs, 1H), 7.26-7.16 (m, 2H), 6.96 (t, J=8.62 Hz, 1H), 5.40-5.22 (m, 2H), 4.51 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.42 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.18-3.92 (m, 3H), 3.78-3.73 (ms, 1H), 3.28-3.18 (m, 3H), 3.01 (s, 3H), 2.95 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H), 1.30 (t, J=5.97 Hz, 3H). MS (ES) C24H31FN6O5 requires 502. Found: 503 (M+H+).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[CH:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccco1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 252A (0.058 g, 0.134 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.010 mL, 0.268 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.105 mL, 0.210 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.03 (s, 2 H) 6.20 (t, J=6.07 Hz, 1 H) 6.35 (m, 1 H) 7.05 (t, J=7.72 Hz, 1 H) 7.29 (t, J=7.72 Hz, 3 H) 7.46 (t, J=7.72 Hz, 1 H) 7.56 (m, 2 H) 7.67 (d, J=7.72 Hz, 2 H) 8.06 (d, J=8.09 Hz, 1 H) 16.24 (s, 1 H). MS (ESI−) m/z 435 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[C:26]([C:28]1[CH:29]=[C:30]([O:34][C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42](OC)=[O:43])[CH:36]=2)[CH:31]=[N:32][CH:33]=1)#[N:27].Cl>C1COCC1.CCOC(C)=O>[C:26]([C:28]1[CH:29]=[C:30]([O:34][C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=3)=[O:43])[CH:36]=2)[CH:31]=[N:32][CH:33]=1)#[N:27]
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)c1cc(Oc2cncc(C#N)c2)cc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Oc2cncc(C#N)c2)cc(C(=O)Nc2ccc(F)cn2)n1
Reaction time: 0.08 h
Yield: 46 %

Procedure:
2-Amino-5-fluoropyridine (34.3 mg, 0.306 mmol, 1.10 eq) was dissolved in THF (0.7 mL) in a flame-dried round bottom flask. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (0.613 mL, 0.306 mmol, 1.10 eq) was added dropwise and the reaction was stirred for 5 minutes. Methyl 4-(5-cyanopyridin-3-yloxy)-6-methylpicolinate (75 mg, 0.28 mmol, 1.0 eq) was added as a solution in THF (0.7 mL) and the reaction was stirred for 30 minutes. The reaction was diluted with EtOAc, neutralized with 1N HCl, and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 45 mg (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.99 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.41-8.39 (m, 2H), 8.27 (dd, J=9.1, 4.1 Hz, 1H), 7.86 (td, J=8.7, 2.8 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 2.58 (s, 3H); [M+1]+: 350.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetate (351.7 mg, 0.732 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (173.0 mg, 0.732 mmol), Et3 N (122.4 μl, 0.878 mmol) in DMF (5.2 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:5, v/v) as eluent to afford methyl 2-[[1-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred solution of this compound in THF (5.6 mL) and H2O (1.4 mL) was added LiOH (45.7 mg, 1.91 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3, and treated with sat. NH4Cl, washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et2O—CHCl3-MeOH to afford 193.8 mg (59%) 40 as a white crystalline powder. mp 125–128; IR (KBr) 1716, 1600, 1533, 1255 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.67–2.03 (m, 4H), 2.50 (s, 3H), 3.33–3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27–4.31 (m, 2H), 4.42–4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87–6.95 (m, 3H), 7.11–7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 519 (M++1); Anal. Calcd for C28H30N4O6.1/2H2O: C, 63.75; H, 5.92; N, 10.62. Found: C, 63.61; H, 5.94; N, 10.27.