Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.Br[CH2:19][C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:31][CH:30]=1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: COC(=O)COc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(OCC(=O)OC)cc1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (500 mg, 2.2 mmol) in anhydrous DMF (20 mL) was added the methyl 2-(4-(bromomethyl)phenoxy)acetate (565 mg, 2.2 mmol) followed by NaH (131 mg, 3.3 mmol). The resulting solution was allowed to stir overnight under argon atmosphere. The remaining NaH was hydrolyzed by the careful addition of a 0.5 N HCl solution. The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The crude residue was purified by chromatography on silica gel (Hexane/Ethyl acetate 5/5) to afford yellow oil (536 mg, 61%). ESI-MS (m/z): 408 [M+H]+
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:17])#[N:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)N2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1,2,3,4-tetrahydroquinoline (4.2 g, 31 mmol) was added dropwise to a solution of 3-cyanobenzoyl chloride (5.2 g, 31 mmol) and triethylamine (3.1 g, 31 mmol) in dichloromethane (125 ml) while cooling in an ice/water bath. The mixture was allowed to warm to RT and stirred for 18 h. It was washed with 0.3M potassium hydrogen sulphate solution, saturated sodium hydrogen carbonate solution and brine. The organic phase was filtered through phase separation paper and reduced to yield 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7.1 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1Cl)c1ccc(Br)cc1
Yield: 98 %

Procedure:
To a stirred solution of 2-chlorobenzylamine (2.42 mL, 20 mmol) in THF (80 mL, anhyd) at 0° C. added a solution of 4-bromobenzoyl chloride (4.39 g, 20 mmol) in THF (20 mL, anhyd.) and then triethylamine (2.93 mL, 21 mmol). After 12 h the resulting mixture was filtered and the solids rinsed with EtOAc. The combined filtrates were diluted with EtOAc (100 mL), washed with 1N HCl, satd NaHCO3 and brine, then dried (anhyd Na2SO4) and concentrated to afford the title compound (6.36 g, 98%) as a white solid, which was used in the next step without purification. GC-MS (EI): 322, 324.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[C:15]([S:29][CH2:30][CH2:31][CH3:32])[N:16]=[C:17]([N:18]([CH:20]4[CH2:22][CH:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[C:12]=3[N:11]=[N:10]2)[CH:6]([OH:33])[CH:5]1[OH:34].C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[OH:34][CH:5]1[CH:6]([OH:33])[CH:7]([N:9]2[C:13]3[N:14]=[C:15]([S:29][CH2:30][CH2:31][CH3:32])[N:16]=[C:17]([N:18]([CH:20]4[CH2:22][CH:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[C:12]=3[N:11]=[N:10]2)[CH2:8][CH:4]1[CH2:3][NH:2][C:44](=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCCSc1nc(N(C)C2CC2c2ccccc2)c2nnn(C3CC(CN)C(O)C3O)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCSc1nc(N(C)C2CC2c2ccccc2)c2nnn(C3CC(CNC(C)=O)C(O)C3O)c2n1
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A solution of the product from Example 7 (0.2 g) in dichloromethane (15 ml) was treated with N,N-diisopropylethylamine (0.11 g) followed by acetic anhydride (0.16 g) and the resultant mixture was stirred at room temperature for 4 hours. The mixture was washed with a saturated solution of aqueous sodium bicarbonate (15 ml) and the organic layer concentrated in vacuo. The residue was dissolved in a 0.1 molar solution of sodium methoxide in methanol (20 ml) and the solution allowed to stand for 2 hours at room temperature. Following concentration in vacuo the residue was acidified by careful addition of acetic acid, the mixture was again concentrated in vacuo and he residue azeotroped with toluene (3×100 ml). Purification by chromatography (SiO2 methanol:chloroform 1:24 as eluant) gave the title compound (0.12 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:29]2[CH:47]=[CH:46][C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]([C:42]([F:45])([F:44])[F:43])=[C:38]([CH:41]=3)[C:39]#[N:40])=[CH:31][CH:30]=2)O1>CN(C=O)C.O>[C:39]([C:38]1[CH:41]=[C:34]([CH:35]=[CH:36][C:37]=1[C:42]([F:43])([F:44])[F:45])[O:33][C:32]1[CH:46]=[CH:47][C:29]([C:2]2[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)#[N:40]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)c(C#N)c3)cc2)OC1(C)C
Reactant: CCOC(=O)/C=C/c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cccc(-c2ccc(Oc3ccc(C(F)(F)F)c(C#N)c3)cc2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
(E)-Ethyl 3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)acrylate (13) was prepared as follows: A mixture of compound 11 (0.6 g, 1.0 eq), K2CO3 (2 eq), 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile (12) (1.05 eq) and Pd[(o-toly)3P]2Cl2 (0.2 eq) in 10 mL of DMF and water (0.1 mL) was flushed with argon and then shaken at 90° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), and extracted with EtOAc. The organic layer was washed with brine, concentrated, and purified by column (EtOAc/hexanes 10/1) to afford compound 13 as a colorless oil (0.8 g): 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, 2H, 8.9 Hz), 7.74-7.84 (m, 4H), 7.39-7.43 (m, 2H), 7.3-7.33 (m, 1H), 7.21 (d, 2H, 8.8 Hz), 7.12 (d, 1H, 15.8 Hz), 4.32 (q, 2H, 7.2 Hz), 1.38 (t, 3H, 7.0 Hz).
Reaction SMILES: Br[C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Cl)[C:5]1=[O:11].[OH-:14].[Na+]>>[Br:13][C:2]([Br:12])=[CH:3][CH:4]1[C:7]([CH3:8])([CH3:9])[CH:6]1[C:5]([OH:11])=[O:14]
Reactant: [OH-]
Reactant: CC1(C)C(Cl)C(=O)C1CC(Br)(Br)Br
Agent: [Na+]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O
Temperature: 80 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 800 mg (0.02 mole) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-chlorocyclobutan-1-one and 5.6 ml of 5% by weight of aqueous sodium hydroxide solution is stirred for 18 hours at 0° C. and subsequently for one additional hour at 80° C. Then the reaction mixture is cooled to room temperature washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract is washed with water and dried over magnesium sulphate. After evaporation of the diethyl ether there is obtained 0.59 g (100% of theoriy) of 2-(2',2'-dibromovinyl)-3,3-dimethylcyclopropane-1-carboxylic acid consisting to 80% of the cis-isomer and to 20% of the trans-isomer.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 724. Product was isolated as a tan solid (0.023 g, 14%). Mp 77-82° C.; LCMS (m/e) 489 (M); 1H-NMR (DMSO, 400 MHz) δ 10.28 (s, 1H), 9.26 (s, 1H), 8.49-8.47 (d, 1H, J=8.34 Hz), 8.16 (s, 1H), 7.92 (s, 1H), 7.63-7.61 (d, 1H, J=7.89 Hz), 7.42-7.40 (t, 1H, J=7.83 Hz), 7.30-7.26 (t, 1H, J=7.58 Hz), 7.22-7.20 (d, 1H, J=8.33 Hz), 7.08 (s, 1H), 6.96-6.94 (d, 1H, J=7.85 Hz), 6.60 (s, 1H), 3.58-3.52 (s, 2H), 3.09-3.03 (q, 2H, J=6.57 Hz), 2.92-2.85 (s, 2H), 2.76-2.70 (s, 2H), 2.40-2.33 (m, 2H), 1.17-1.08 (t, 3H, J=6.57 Hz), 1.05-1.01 (t, 3H, J=6.82 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15].C(N)CCC.[I:21]I.[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([I:21])[C:5]2=[O:15]
Reactant: II
Reactant: COc1cc2[nH]c(C)cc(=O)c2cc1Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCN
Product: COc1cc2[nH]c(C)c(I)c(=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirred solution of 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (6.43 g, 28.7 mmol) and n-butylamine (28 ml, 287 mmol) in dimethylformamide (57 ml) cooled by a room temperature water bath was added iodine (7.30 g, 28.7 mmol) in a saturated solution of aqueous potassium iodide (29 ml). The reaction mixture was stirred 12 hours at room temperature. Residual iodine was quenched with 0.1 M aqueous sodium thiosulfate, and the resulting solution was concentrated in vacuo. The residue was resuspended in water and filtered to give 8.93 g (89% yield) of 6-chloro-3-iodo-7-methoxy-2-methylquinolin-4(1H)-one as a light brown powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[CH2:16][C:17]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:18]=2[C:19](N(CC)CC)=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)CC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:31][C:19](=[O:20])[C:18]3[C:17]([CH:16]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1c(Cl)cccc1CC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CCC(=O)O
Solvent: CCOC(C)=O
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc2cccc(Cl)c12
Temperature: 165 °C
Yield: 72.8 %

Procedure:
In a 10 mL round bottomed flask equipped with a magnetic stir bar 2-[2-(4-benzyloxyphenyl)-2-oxo-ethyl]-6-chloro-N,N-diethylbenzamide (340 mg, 0.78 mmol) was treated with propionic acid (1.5 mL). The resulting mixture was stirred and heated to reflux in a 165° C. oil bath. As the reaction heated, the 2-[2-(4-benzyloxyphenyl)-2-oxo-thyl]-6-chloro-N,N-diethylbenzamide was dissolved in the propionic acid to afford a pale brown solution. After stirring at reflux for 88 hours, the reaction was analyzed by TLC, which showed no starting material remaining. The reaction was allowed to cool to ambient temperature during which time a mass of pale brown crystals were deposited on the walls of the reaction flask. The reaction mixture was diluted with ethyl acetate to dissolve the solids, and the resulting solution was washed with saturated aqueous NaHCO3 solution. The basic aqueous solution was then extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford an off-white solid. This material was quite clean by 1H NMR analysis and was further purified by recrystallization from EtOAc to afford 3-(4-benzyloxyphenyl)-8-chloro-isochromen-1-one (206 mg, 73% yield) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)=[O:32]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccc(Cl)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 62.5 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 2,4-dichlorobenzoyl chloride (0.52 g), the title compound (0.66 g) was obtained as a crystalline solid, m.p. 180-182° C.; MS, m/z: 528 (M)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCc1ccccc1CBr
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 88.1 %

Procedure:
To a solution of the title compound of step (A) (10 g, 50 mmol) in CH2Cl2 (80 ml) cooled at 0° C. was added 2,6-lutidine (7.57 mL, 65 mmol), followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (14.92 mL, 65 mmol). The reaction mixture was stirred at 0° C. for 45 minutes, then quenched with H2O (20 mL) and partitioned between EtOAc (450 mL) and H2O (150 mL). The organic layer was separated and washed with 10% NaHCO3 solution, brine (2×), dried (MgSO4) and concentrated in vacuo to give a yellow syrup, which was chromatographed eluting with 10-50% EtOAc/hexane to afford 13.89 g (88%) of the title compound of this step as a light yellow oil.
Reaction SMILES: [P:1]([O-:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.[CH3:22][C:23]([CH3:25])=[O:24]>>[O:2]([P:1]([C:23]([OH:24])([CH3:25])[CH3:22])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)P(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 50 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 1 mole (234 g) diphenyl phosphite (DPP) and 500 ml THF were added. The mixture was heated to 50° C. and then stirred. The mixture was heated to a temperature of 90° C. and the stirring was continued until DPP was dissolved completely. To this solution was added slowly 1.0 mole (58 g) acetone within two hours, and the temperature thereof was increased to 70° C. and maintained at that temperature for four hours after the addition of acetone was completed. The mixture was then cooled to room temperature to obtain solid, which was then filtered, and purified with THF to yield 2-(diphenoxy phosphoryl) propan-2-ol [DPOP; (II)]. Yield, 96%; m.p. 70–72° C. Anal. Calcd. for C15H17PO4: C, 61.64; H, 5.82; O, 21.92; P, 10.62. Found: C, 61.52; H, 5.96; O, 21.78; P, 10.74. EIMS, m/z: 292 (92. M+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:15]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC[C@@H](CO)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
A solution of 13.2 g (113 mmol) of (5S)-dihydro-5-(hydroxymethyl)furan-2(3H)-one in 200 ml of dimethyiformamide was treated sequentially with 9.28 g (136 mmol) of imidazole and 18.84 g (125 mmol) of chloro-t-butyldimethylsilane, the latter in several portions. The resulting solution was stirred at ambient temperature for 6 h, poured into 10% aqueous citric acid, and extracted with ethyl acetate. The organic layer was washed sequentially with two portions of water, one portion of aqueous NaHCO3 and one portion of saturated brine. The organic layer was dried over MgSO4, and concentrated in vacuo to provide 22.04 g (90%) of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[CH:17]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:24][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=1
Reactant: Fc1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Reactant: NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Fc1cccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)c1

Procedure:
To 159a (1.0016 g, 3.9 mmol) dissolved in acetone (20 mL) was added a solution of cycloheptylamine (0.5 mL, 3.9 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.6 mL, 3.9 mmol) and water (4 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The filtered sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded an off-white solid (159b, 908 mg, 69%), mp 148° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.0M, pH 3.2): CH3CN], 264 nm, Rt 22.3 min, 79.2% purity; MS (TOF MS ES+): m/z 413 (60.4), 338 (44.0), 336 (M+H, 100).
Reaction SMILES: [C:1]([CH2:3][C@H:4]([NH:34]C(=O)OC(C)(C)C)[C:5]([NH:7][C@@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH2:24][CH2:23][CH2:22][CH:21]=1)[C:13]([C@@:15]1([CH3:18])[CH2:17][O:16]1)=[O:14])=[O:10])=[O:6])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@@H:4]([CH2:3][C:1]#[N:2])[C:5]([NH:7][C@@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH2:24][CH2:23][CH2:22][CH:21]=1)[C:13]([C@@:15]1([CH3:18])[CH2:17][O:16]1)=[O:14])=[O:10])=[O:6]
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](CC#N)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)[C@@H](N)CC#N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 138.7 %

Procedure:
To a solution of tert-butyl ((S)-3-cyano-1-(((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyl oxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (0.59 g, 1.0 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred for 15 min at ambient temperature then concentrated to dryness to afford (S)-2-amino-3-cyano-N-((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)propanamide (650 mg, quant.) as its TFA salt, which was used directly without further purification.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:22](=[O:24])[CH3:23])[CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][CH:20]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH:1]=[O:2])[C:22](=[O:24])[CH3:23]
Reactant: O=CNc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)C(C)N(C=O)c1cccc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 99.9 %

Procedure:
To a suspension of N-formyl-3-nitroaniline (831 mg) and potassium carbonate (830 mg) in N,N-dimethylformamide (5 ml) was added 2-bromo-3-butanone (906 mg), and the mixture was stirred for 72 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated to give N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide (1.18 g, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[N:35]O)[NH2:34])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:30]4[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccc(Cl)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(Cl)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 4-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 61 mg (64% of theory)
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[C:19]2[N:20]=[CH:21][CH:22]=[N:23][C:24]=2[CH:25]=[CH:26][CH:27]=1)(=[O:17])=[O:16].C1COCC1.Cl>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[C:8]([NH:14][S:15]([C:18]2[C:19]3[N:20]=[CH:21][CH:22]=[N:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH:9]=1
Reactant: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
A solution of LiOH.H2O (0.32 g, 7.7 mmol) in water (5 mL) was added to a solution of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester (0.58 g, 1.5 mmol) and THF (10 mL). The biphasic mixture was stirred rapidly at rt for 16 h, then adjusted to pH 5 with 1 M HCl. The resulting precipitate was collected by filtration to afford the acid as a white solid (0.51 g, 92%). MS (ESI+): calcd. for C15H10ClN3O4S, 363.0; m/z found, 364 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.20 (br s, 1H), 11.73 (s, 1H), 9.12 (d, J=1.6, 1H), 9.00 (d, J=1.5, 1H), 8.65 (d, J=7.3, 1H), 8.42 (d, J=8.3, 1H), 8.06 (t, J=7.8, 1H), 7.80 (d, J=8.5, 1H), 7.63 (d, J=2.0, 1H), 7.07 (dd, J=8.4, 1.9, 1H).