Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C-:11]#[N:12].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[C:11]([CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:12]
Reactant: CCOC(=O)C[C@H](O)CCl
Reactant: [C-]#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CC#N

Procedure:
To a well stirred solution of ethyl (S)-4-chloro3-hydroxybutyrate (8.25 g, 50 mmoles) in 300 mM potassium phosphate buffer, 300 mM NaCN pH 8.0 (1 L) at 30° C. was added halohydrin dehalogenase SEQ ID NO: 14 (9 g) as a lyophilized powder. After fifty seven hours the mixture was washed with ethyl acetate (2 times 250 mL) and the combined organics dried over anhydrous sodium sulfate. The mixture was filtered and evaporated on a rotary evaporator to give essentially pure ethyl (R)-4-cyano-3-hydroxybutyrate, as determined using the gas chromatography method and elution time data described in Example 6, hereinbelow.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:30])[C:25]2([CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[CH2:28][CH2:29][C:25]4([C:23]([F:30])([F:22])[CH2:24]4)[CH2:26]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: FC1(F)CC12CCNC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(C1)CC2(F)F

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride (1215071-12-7) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=400.5 [MH+].
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3](O)=[O:4].S(Cl)([Cl:22])=O>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([Cl:22])=[O:4]
Reactant: CCCCCCCCCCCCCCC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCC(C)C(=O)Cl

Procedure:
2-Methylhexadecanoic acid (27.0 g 0.1 mol) was mixed with 100 ml of thionyl chloride and the resulting mixture was stirred and heated under reflux for eight hours and then stirred at room temperature overnight. The mixture was concentrated under vacuum, diethyl ether was added and the mixture again concentrated under vacuum. The residue was distilled to yield 25.8 g of 2-methylhexadecanoyl chloride, bp 120-125° C. at 0.25 mm Hg.
Reaction SMILES: C(OC([N:8]1[C@H:16]2[C@H:11]([CH2:12][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([C:33]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]6[C:34]=5[CH:35]=[CH:36][NH:37]6)=[N:21][C:20]=4[CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:42][C:40]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[C:33]([C:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:25]3[S:26][C:18]([CH2:17][N:13]4[CH2:14][CH2:15][C@H:16]5[NH:8][CH2:9][CH2:10][C@H:11]5[CH2:12]4)=[CH:19][C:20]=3[N:21]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN(Cc3cc4nc(-c5cc(F)cc6[nH]ccc56)nc(N5CCOCC5)c4s3)CC[C@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC[C@H]5NCC[C@H]5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared by BOC-deprotection of (3aS,7aR)-5-[2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester using TFA:DCM (1:6). The title compound was obtained as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=[C:16]([NH2:32])[N:15]=1)(=[O:12])=[O:11].[NH:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[NH2:32][C:16]1[N:15]=[C:14]([O:13][S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:11])=[O:12])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:33]3[CH2:37][CH2:36][CH2:35][C@@H:34]3[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Product: COc1cc(CN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 91.2 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (vii) from the product of example 1 step (v) (200 mg) and (R)-tert-butyl pyrrolidine-2-carboxylate (108 mg). The sub-title compound (234 mg) was obtained as a colourless amorphous solid; LC-MS: m/z 611.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.7 %

Procedure:
4-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). 1-Bromobutane (3.17 mL, 29.5 mmol) was added to this suspension, and stirred for 17 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.72 g).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([O:10][CH3:11])=[O:9].CCN(CC)CC.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:5]1[CH2:6][CH2:7][C@H:3]([OH:2])[C@H:4]1[C:8]([O:10][CH3:11])=[O:9])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)CCl
Reaction time: 24 h
Yield: 67 %

Procedure:
To a solution of the methyl (3S)-3-hydroxy-L-prolinate hydrochloride (D68, 1.8 g, 9.9 mmol) and Et3N (3 ml, 21.8 mmol) in 10 ml of dry benzene at the temperature of 7-8° C. was added dropwise a solution of chloroacetyl chloride (0.87 ml, 10.9 mmol) in 5 ml of dry benzene. After 24 h at rt, the precipitated was filtered off and washed with AcOEt. The filtrate was evaporated, and the crude oil was purified by flash chromatography column (Cy/AcOEt 1/4 as eluent). The title compound was isolated as a colourless oil (1.48 g). Yield 67%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH-].[NH4+:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: [OH-]
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 37.0 gm. (0.14 mole) of 2-chloro-3,5-dinitrobenzoyl chloride and 100 ml. of concentrated ammonium hydroxide is placed in a mortar, ground for ten minutes and allowed to stand for one hour. The yellow precipitate is removed by filtration and washed with water. There is obtained 32.3 gm (94%) of material melting at 181-3°.
Reaction SMILES: C(C1N(CC2COC(C)(C)O2)C2C(C=1)=CC([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=CC=2)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:28][C:25]1([F:27])[O:24][C:23]2[CH:29]=[CH:30][C:20]([C:17]3([C:15]([NH2:14])=[O:16])[CH2:19][CH2:18]3)=[CH:21][C:22]=2[O:26]1
Reactant: CC1(C)OCC(Cn2c(C(C)(C)C)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: NC(=O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 80 °C
Yield: 163.8 %

Procedure:
To a stirred solution of N-(2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.28 g, 2.43 mmol) in methanol (34 mL) and water (3.7 mL) was added para-toluenesulfonic acid-hydrate (1.87 g, 9.83 mmol). The reaction mixture was stirred and heated at 80° C. for 25 minutes. The solvent was evaporated under reduced pressure. The crude product was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane=13/7) to give N—((R)-2-tert-butyl-1-2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.96 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=2 Hz, 1H), 7.31 (dd, J=2, 8 Hz, 1H), 7.27 (dd, J=2, 8 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 7.02 (br s, 1H), 6.96 (dd, J=2, 8 Hz, 1H), 6.23 (s, 1H), 4.35 (dd, J=8, 15 Hz, 1H), 4.26 (dd, J=4, 15 Hz, 1H), 4.02-3.95 (m, 1H), 3.60 (dd, J=4, 11 Hz, 1H), 3.50 (dd, J=5, 11 Hz, 1H), 1.75 (q, J=8 Hz, 3H), 1.43 (s, 9H), 1.14 (q, J=8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a solution of ethyl 4-(1-tert-butoxycarbonylpiperidin4-yloxy)-phenoxyacetate (23.71 g) in a mire of tetrahydrofuran (34 ml) and ethanol (34 ml) was dropwise added 1N aqueous lithium hydroxide solution (68.7 ml) with ice-cooling, and the mixture was stirred at room temperature for 20 min. After completion of the reaction, the solvent was evaporated and to the obtained residue was added 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained solid was filtrated with hexane and dried under reduced pressure to give the title compound (19.09 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([Br:21])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2c(c(=O)n1Cc1ccccc1)CCC2
Solvent: CC(=O)O
Product: CCC(Br)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-benzyl-2-propyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-2, 0.52 g, 1.93 mmol) was dissolved in AcOH (3.0 mL) and treated with Br2 neat (0.11 mL, 2.13 mmol). The reaction was stirred overnight at 25° C. and then concentrated. The residue was purified by preparative thin layer chromatography (SiO2, 40% EtOAc/hexanes) to yield 3-benzyl-2-(1-bromopropyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-3). 1H NMR (300 MHz, CDCl3) δ 7.33 (m, 4H), 7.26 (d, 1H obscured), 6.15 (d, J=16.1 Hz, 1H), 4.80 (d, J=16.1 Hz, 1H), 4.58 (t, J=7.3 Hz, 1H), 2.92 (m, 4H), 2.36 (m, 1H), 2.12 (m, 3H), 0.69 (t, J=7.3 Hz, 3H). MS 347.0 found 347.3 required.
Reaction SMILES: O.S(O)(O)(=O)=O.[NH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:14]3[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]=1.[H][H]>[Pd].Cl.O>[NH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:14]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccc([N+](=O)[O-])cc1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccc2c(c1)CCc1nc(N)[nH]c(=O)c1-2

Procedure:
A suspension of 3-amino-5,6-dihydro-8-nitrobenzo[f]quinazolin-1(2H)-one sulfate monohydrate (2.0 g, 5.3 mmoles) and 5% palladium on carbon (10 mg) in 1 N HCl (20 ml) was reacted with hydrogen using a Parr hydrogenation apparatus. When uptake of hydrogen ceased, the mixture was filtered and the filtrate was evaporated, leaving a white residue which was resuspended in water (20 ml) with stirring, and filtered. The crude product was recrystallized from 2M H2SO4 to give, after drying, 3,8-diamino-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as a white solid. (1.1 g, 61%) 1H NMR (DMSO-d6, 80 MHz) δ: 2.60-2.65(m, 4H, CH2CH2); 4.99-5.69(br s, 2H, NH2); 6.75-6.79(m, 4H, NH2 +Ar); 8.24-8.35(d, J=9 Hz, 1H, Ar). Anal. Calculated for C12H12N4O.H2SO4.1 /2H2O: C, 42.98; H, 4.51; N, 16.71; S, 9.56. Found: C, 42.95; H, 4.54; N, 16.66; S, 9.57.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8].[Br:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][N:23]=1)[C:15](N(OC)C)=[O:16].[NH4+].[Cl-]>C1COCC1.O>[Br:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:21]=[CH:22][N:23]=1
Reactant: COC(CCBr)OC
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CCC(=O)c1ccnc(Br)c1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a suspension of Mg (3.67 g, 153.01 mmol) in THF (40 mL) is added cat. Iodine, followed by a solution of 3-bromo-1,1-dimethoxy-propane (21.47 g, 117.30 mmol) in THF (40 mL). The mixture is stirred at room temperature for 2 h. Then the fresh prepared Grignard reagent is cooled down in an ice bath, and added to a solution of 2-bromo-N-methoxy-N-methyl-isonicotinamide (12.50 g, 51.00 mmol) in THF (50 mL) at 0° C. The mixture is warmed up to room temperature and stirred at this temperature for 2 h. Then the reaction mixture is cooled in an ice bath, sat. NH4Cl and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 10%) to give 1-(2-Bromo-pyridin-4-yl)-4,4-dimethyoxy-butane-1-one (12.1 g, 82%) as a pale yellow oil. M/Z=288.14
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1.N>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3ccc(Cl)nc3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 2H), 8.17 (m, 1H), 8.4 (m, 1H), 8.43 (d, J=1.7 Hz, 1H), 8.6 (m, 1H), 9.25 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:15][C:16]([OH:18])=[O:17])[O:3]1.[C:19](OC(=N)N(C(C)C)C(C)C)([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.Cl[Cu]>[CH3:1][N:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:3]1
Reactant: CN1O[C@@H](CC(=O)O)C[C@H]1c1ccc(C#N)cc1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Agent: Cl[Cu]
Solvent: ClCCl
Product: CN1O[C@@H](CC(=O)OC(C)(C)C)C[C@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a solution of [2-methyl-3(S)-(4-cyanophenyl)-isoxazolidin-5(R)-yl]acetic acid (480 mg, 1.95 mmol) in CH2Cl2 (30 ml) cooled in an ice-water bath was added a 1.6M solution of O-tert-butyl-N, N-diisopropylisourea, cat. CuCl (3.7 ml). The resulting mixture was stirred at rt for 48 hrs. After filtration, the fitrate was concentrated in EtOAc and the residue dissolved in EtOAc. The EtOAc solution was washed with brine and then dried over Na2SO4. After contration, the residue was chromatographed with a mixture of EtOAc and hexane to afford 550 mg of the product as a white solid (93%). 1H NMR (300 MHz, CDCl3) δ1.44(s, 9H), 1.98(m, 1H), 2.50(dd, 1H), 2.60(s, 3H), 2.80(dd, 1H), 2.98(dt, 1H), 3.70(t, 1H), 4.64(m, 1H), 7.50(d, 2H0, 7.66(d, 2H); MS(ESI) Calc. for (M+1)+: 303. Found: 303.
Reaction SMILES: [CH3:1][P:2]([CH:7]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[CH3:8])(=[O:6])[O:3]CC.[OH-].[K+]>C(O)C.O>[CH3:1][P:2]([CH:7]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[CH3:8])(=[O:3])[OH:6]
Reactant: CCOP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate (1.1 g) in ethanol (10 ml) is added potassium hydroxide (0.5 g) in water (15 ml). The mixture is stirred at RT for 4 hours. The ethanol is removed, and the aqueous solution is acidified and extracted with ether. The combined extracts are dried and evaporated to dryness to give P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-ethylphosphinic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)CC1

Procedure:
Intermediate 1 was coupled with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].B.CSC>C1COCC1>[Br:1][CH2:2][CH:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[OH:4]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)CBr)cc1
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
Following the procedure of Corey et al. (Angew. Chem. Int. Ed., 37:1986-2012 (1998)), a solution of 4-(2-bromoacetyl)benzonitrile (10.00 g, 44.6 mmol) in THF (50 mL) was cooled to 0° C. and treated with (S)-methyl oxazaborolidine (1.0 M in toluene) (8.93 mL, 8.93 mmol) followed by borane-methyl sulfide complex (2.0 M in THF) (13.01 mL, 26.0 mmol) over 10 minutes. The reaction was stirred for 1.5 hours and then quenched by adding MeOH. The reaction was concentrated on a rotary evaporator and then extracted from 1 M HCl using DCM×3 followed by drying over MgSO4, and filtering. The crude material was concentrated in vacuo and purified on a 220 g SiO2 cartridge using 20-80% EtOAc/hexanes gradient over 10 column volumes. The product eluted in fractions 46-60 to afford 9.8 g of 4-(2-bromo-1-hydroxyethyl)-benzonitrile as a clear oil. Chiral HPLC conditions showed 80% e.e. favoring the (S) stereoisomer based on the Corey precedent. The minor (R) stereoisomer was removed by chiral HPLC using multiple runs on a Thar 350 Preparative SFC instrument equipped with a CHIRALPAK® AD-H (25×5 cm, 5 μM). Temp: 35° C.; Flow rate: 280 mL/min; Mobile phase: CO2/iPrOH in 88:12 ratio; Runtime 7.7 min; Retention time=5.1 min to give (S)-4-(2-bromo-1-hydroxyethyl)-benzonitrile in 99.8% d.e. 1H NMR (400 MHz, CDCl3) δ ppm 7.76 (2H, d), 7.56 (2H, d), 5.02 (1H, dd), 3.68 (1H, dd), 3.55 (1H, dd), 3.53 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[CH2:19]([N:21]([CH2:34][CH3:35])[CH2:22][CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH3:20].C(Cl)Cl>O>[CH2:34]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:30])=[CH:32][CH:33]=1)[CH3:35]
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.2 g. (0.05 mol.) of 2-(4-methoxyphenyl)benzofuran and 14.6 g. (0.05 mol.) of 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride in 100 ml. of methylene chloride is added 39.1 g. (0.15 mol.) of stannic chloride. The reaction mixture is stirred for 1.5 hours at ambient temperature then poured into water. The layers are separated and the organic phase is washed with aqueous sodium carbonate until basic and water, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[N:15]=[C:14]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[Cl:25]N1C(=O)CCC1=O>CN(C)C=O>[Cl:25][C:13]1[C:14]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:15][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of methyl 2,6-bis[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 26, Step 1, 186 g, 555 mmol) in anhydrous N,N-dimethylformamide (930 mL) was added a solution of N-chlorosuccinimide (81.5 g, 610 mmol) in anhydrous N,N-dimethylformamide (560 mL) dropwise from a dropping funnel (1 L) during the period of 2.5 h at 70° C. (internal temperature) under nitrogen atmosphere. The resulting pale yellow solution was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction solution was quenched with a solution of 250 g of ammonium chloride and 100 g of sodium hydrogen sulfite in 3 L of water and extracted with a mixture of ethyl acetate and hexane (3 L, 3: 1). After the layers were separated, the organic layer was washed with water (2 L), dried over sodium sulfite (300 g) and evaporated. The residual pale yellow solid was added isopropylether (1.4 L) and the resulting mixture was stirred at 60° C. for 2 h. After the mixture was cooled to room temperature, the mixture was filtered through paper filter, and the cake was washed with isopropylether (200 mL), dried under reduced pressure at room temperature to give (153.9 g, 416 mmol) of the title compound as a white solid.