Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)=[O:27])[CH:23]=3)[NH:18][N:17]=2)=[CH:12][CH:11]=1>ClCCl>[C:1]([N:30]1[CH2:31][CH2:32][CH2:33][CH:28]([C:26]([NH:25][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:13]2[CH:12]=[CH:11][N:10]=[CH:15][CH:14]=2)=[O:27])[CH2:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CCCNC1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
In a flask, dichloromethane (0.023mL) was added to benzoyl chloride. The reaction was cooled to 0° C., and a solution of N-(3-(pyridin-4-yl)-1H-indazol-5-yl)piperidine-3-carboxamide (0.014 g, 0.044 mmol) in dichloromethane (0.020 mL) was dropwise added to the benzoyl chloride solution. The reaction stirred for 6 hrs from 0° C. to room temperature. The reaction was quenched with water (1 mL) and extracted with dichloromethane (3×1 mL). The extracts were combined and dried with sodium sulfate. The crude product was purified using prep LC/MS. LC-MS: 426.1 [M+H]. LC/MS RT=2.998 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC
Reactant: N
Solvent: CO
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example A5, 1.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(2-ethylbenzyl)oxy]thiophene-2-carboxylate and 60 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ncc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Yield: 94.2 %

Procedure:
The title compound (0.51 g, 94%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.30 g, 1.45 mmol), 1,1-dimethylethyl 4-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-1-piperidinecarboxylate (0.45 g, 1.21 mmol), 2M Na2CO3 (7 mL) and Pd(PPh3)4 (15 mg, 0.013 mmol) in DME (7 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.92 (s, 2H), 8.06 (d, 2H, J=8.3 Hz), 7.92 (d, 2H, J=8.5 Hz), 4.33 (d, 2H, J=6.6 Hz), 4.20-4.10 (m, 2H), 3.15 (s, 3H), 2.90-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH:47]=O)=[CH:39]1>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:47][C:40]2[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:38][CH:39]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 75.7 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (200 mg, 0.399 mmol) was condensed over 24 hours with 1H-indole-3-carbaldehyde (70 mg, 0.479 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 20% acetone in CH2Cl2) provided 190 mg of N-benzyl-2-[8,9-difluoro-4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. MS 629.3 (M+1), 627.3 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:24]([O:26]CC)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:37](B1OC(C)(C)C(C)(C)O1)=[CH2:38].CC(O)=O>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:24]([OH:26])=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH:37]=[CH2:38])[CH:16]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1nc2cc(Br)c(F)cc2cc1NC(=O)OCc1ccccc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C=Cc1cc2nc(C(=O)O)c(NC(=O)OCc3ccccc3)cc2cc1F
Temperature: 90 °C
Yield: 74 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromo-6-fluoroquinoline-2-carboxylate (252.8 mg, 0.5652 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Aldrich, 22.8 mg, 0.0289 mmol) and K3PO4 (392.6 mg, 1.850 mmol) were added. The vial was sealed with a Teflon®-lined septum, and was then evacuated and backfilled with nitrogen three times. A solution of vinylboronic acid pinacol ester (146.9 mg, 0.9538 mmol) in 1,4-dioxane (4.0 mL) was added via a syringe, followed by deoxygenated water (2.0 mL). The resulting mixture was heated at 90° C. for 1 h, then allowed to cool to room temperature. Water (50 mL) was added followed by AcOH (379 mg, 6.32 mmol) to adjust the pH to 5. The mixture was extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the sub-title compound as a yellow solid (153.2 mg, 74%). LCMS calc. for C20H16FN2O4 (M+H)+: m/z=367.1. found 367.1.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[CH2:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O)[CH:10]=[CH2:11]>O.CO>[CH2:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=[N:7][OH:8])[CH:10]=[CH2:11]
Reactant: NO
Reactant: C=CCc1cccc(Cl)c1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCc1cccc(Cl)c1C=NO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.58 g of sodium bicarbonate were added to a solution of 4.62 g of hydroxylamine hydrochloride in 50 ml of water, and the mixture was cooled to 0° C. A solution of 9.7 g (44.32 mmol) of 2-allyl-6-chlorobenzaldehyde in 50 ml of methanol was then added dropwise, and the mixture was stirred at room temperature overnight. The methanol was subsequently removed under reduced pressure and the residue was stirred into 300 ml of water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with saturated ammonium chloride solution and dried, and the solvent was removed. This gave 8.7 g (quantitative) of 2-allyl-6-chlorobenzaldehyde oxime in the form of a viscous oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[CH2:10][CH2:11][CH2:12][C:13]#[N:14]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH2:3]1
Reactant: CC1CNCC(C)C1
Reactant: N#CCCCCl
Solvent: c1ccccc1
Product: CC1CC(C)CN(CCCC#N)C1

Procedure:
Into a solution under reflux of 50 g (0.424 mole) of 3,5 dimethylpiperidine at 96% in 60 ml benzene are run in25 minutes 22 g (0.212 mole) of 4-chlorobutyronitrile and the reflux is continued for 2h.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[N+:17]([O-])=[O:18])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH:1]([C:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH:17][OH:18])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(Cl)cc2[N+](=O)[O-])c(=O)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1nn(-c2ccc(Cl)cc2NO)c(=O)o1
Yield: 47.3 %

Procedure:
A solution of 5-isopropyl-3-(2-nitro-4-chlorophenyl)-1,3,4-oxadiazolin-2-one (16 g.) in ethyl acetate (130 cc.) containing 3% w/w palladium on charcoal (1 g.) is hydrogenated at atmospheric pressure and at approximately 20°C. After the absorption of hydrogen (1.9 litres) (70% of the theoretical amount), the reaction is stopped and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure and the residue taken up in benzene (50 cc.); the crystals obtained are filtered off and washed with benzene (15 cc.). 5-Isopropyl-3-(2-hydroxylamino-4-chlorophenyl)-1,3,4-oxadiazolin-2-one (7.2 g.), which melts at 138°-140°C., is obtained. The benzene filtrate is recycled and is subjected to an operation identical to that described above. 5 -Isopropyl-3-(2-hydroxylamino-4-chlorophenyl)-1,3,4-oxadiazolin-2-one (2.9 g.), which melts at 138°-140°C., is obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH:13]=[O:14].O>C(O)C>[Cl:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH2:13][OH:14]
Reactant: O=Cc1sc2ccccc2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium borohydride (231 mg, 6.1 mmol) in absolute ethanol (10 mL) was added a solution of 3-chloro-1-benzothiophen-2-carbaldehyde (1.0 g, 5.1 mmol) in absolute ethanol (5 mL) at 0° C. The mixture was stirred for 2 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3-chloro-1-benzothiophen-2-yl)methanol was obtained as an orange pale solid (944 mg, 94% yield) and used for next step without further purification; 1H NMR (400 MHz, CDCl3): δ 2.17 (bs, 1H), 4.99 (s, 2H), 7.37-7.47 (m, 2H), 7.78-7.82 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[F:28].C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][C:11]=2[CH:12]=1)[CH:24]=[O:25]
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)c(F)c1
Yield: 25.2 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (14 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1C#N.OS(O)(=O)=O.[C:18](=[O:21])([O-])[O-:19].[Na+].[Na+]>O>[Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:18]([OH:19])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
2-Bromo-4-nitro-benzonitrile (0.5 gm, 2.34 mmol) was hydrolysed using H2SO4 (2.2 ml) in 2.7 ml water at 80° C. for 8 hrs. After completion of reaction solution was poured over crushed ice, basified with sodium carbonate and extracted with ethyl acetate. Aqueous layer was separated, acidified with 1:1 HCl and extracted with ethyl acetate. Combined organic layer was then concentrated to obtained compound(51).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH:2]=[CH2:3].Cl[C:15]1[C:20]([C:21](OCC)=[O:22])=[CH:19][N:18]=[C:17]([S:26][CH3:27])[N:16]=1>C(#N)C>[CH3:27][S:26][C:17]1[N:18]=[C:19]2[N:8]=[C:7]([C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:1][CH:2]=[CH2:3])[NH:9][C:21](=[O:22])[C:20]2=[CH:15][N:16]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: C=CCOc1ccccc1C(=N)N
Solvent: CC#N
Product: C=CCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 8 h
Yield: 235.6 %

Procedure:
2-Allyloxybenzamidine (from sodium, 0.22 g, in ethanol, 100 ml, and 2-allyloxybenzamidine hydrochloride, 2.00 g) was dissolved in acetonitrile (50 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) solution of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (2.19 g) in acetonitrile (50 ml). The temperature was allowed to rise and the reaction mixture was stirred overnight at ambient temperature. The volume of the reaction mixture was reduced by evaporation under reduced pressure to yield a solid (0.96 g) which was collected. More product (0.45 g) precipitated from the filtrate. The combined products were recrystallized twice from ethanol to yield the title compound, 340 mg, m.p. 205-206° C.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1)=[O:6])[CH3:3].[CH3:35][C:36]([CH3:55])([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]>C1COCC1>[CH3:37][C:36]([CH3:55])([O:38][C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:48]=[CH:49][C:50]([CH:51]=[CH:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:34][CH:33]=3)=[CH:53][CH:54]=2)[CH2:45][CH2:46]1)=[O:40])[CH3:35]
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 0 °C
Yield: 103.5 %

Procedure:
To an oven dried 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(ethoxycarbonylmethoxy)benzyltriphenyl-phosphonium bromide (1.106 g, 2.07 mmol) and dry THF (50 mL). To this well stirred mixture was added a solution of lithium hexamethyldisilylazide (2.20 mL of a 1M solution in THF). The deep red solution was stirred 1 h at ambient temperature then cooled in an ice bath to 0° C. To this mixture was added a solution of 4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)benzaldehyde (0.60 g, 2.07 mmol) in 10 mL of THF. The ice bath was removed and the solution was stirred at ambient temperature for 3 h. The reaction mixture was diluted with EtOAc and washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 1 g of an oil. This material was chromatographed on 80 g of silica gel using 25% EtOAc-hexane as eluant. There was obtained (E)-ethyl 4-(2-(4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)phenyl)ethenyl)phenoxyacetate 35-7 as an oil. 1H NMR (CDCl3): δ 1.26 (t, j=7 Hz, 3H), 1.49 (s, 9H), 3.16 (m, 4H), 3.57 (m, 4H), 4.27 (q, j=7 Hz, 2H), 4.60 (s, 2H), 6.90 (m, 6H), 7.40 (m, 4H), and 175 mg of a mixture of E,Z isomers.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.N=C=N.C(N(CC)CC)C.Cl.[CH2:40]([O:47][P:48]([CH2:57][C@H:58]([OH:61])[CH2:59][NH2:60])([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:40]([O:47][P:48]([CH2:57][C@H:58]([OH:61])[CH2:59][NH:60][C:16](=[O:18])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:13]([CH3:14])[CH3:15])([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:49])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Agent: N=C=N
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
To a solution of N-Cbz-L-valine (1.0 g, 3.98 mmol) dissolved in CH2Cl2 (80 mL) under nitrogen was added hydroxybenzotriazole (0.538 g, 3.98 mmol) and PS-Carbodiimide (2.25 g, 5.17 mmol). After stirring for 10 min, triethylamine (0.665 mL, 4.78 mmol) and ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (1.44 g, 3.98 mmol) were added. The reaction was stirred for 2 h, then filtered and concentrated in vacuo. The residue was purified by flash chromatography with methanol/dichloromethane on a 35 g RediSep disposable column to give [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester (0.60 g, 1.07 mmol) as a white foam. NMR and MS spectra were substantially similar to the product obtained via Method A set forth above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH3:31])[N:23]=3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 21 mg (19%). MS (m/e) 377.2 (M+1)
Reaction SMILES: [CH:1]([C@@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH:10]=1)[C:5](O)=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+].II.CO>O1CCCC1>[CH:1]([C@@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH:10]=1)[CH2:5][OH:6])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C[C@@H](C(=O)O)C(C)C)ccc1OC
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](CO)C(C)C)ccc1OC
Reaction time: 96 h

Procedure:
186 g of 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionic acid in 0.5 liter of tetrahydrofuran are added dropwise at room temperature to a stirred mixture of 27.2 g of sodium borohydride in 1.5 liters of tetrahydrofuran. After 45 minutes a solution of 76.2 g of iodine in 1 liter of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 4 days and then 1 liter of methanol is carefully added dropwise. After evaporation of the solvent the residue is taken up in 2 liters of 2N hydrochloric acid and extracted repeatedly with ethyl acetate. The organic extracts are washed in succession with water, saturated sodium thiosulfate solution, water/saturated sodium chloride solution (1:1), 0.1N sodium hydroxide solution and saturated sodium chloride solution. The organic extracts are concentrated by evaporation and purified by FC (2.4 kg of silica gel, ethyl acetate/hexane=1:4). The title compound is obtained: Rf (ethyl acetate/hexane=1:1)=0.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([OH:13])[CH:9]=[CH:8]2
Reactant: COc1ccc2cccc(OC)c2c1
Agent: Cl
Solvent: CC(Cl)Cl
Product: COc1cccc2ccc(O)cc12

Procedure:
Bromocatecholborane (4.18 g, 21 mmol) is added to a solution of 1,7-dimethoxynaphthalene (1.97 g, 10.5 mmol) in dichloroethane (20 mL). The resulting solution is heated to reflux for 72 hours, allowed to cool and then poured into 1N HCl. The resulting mixture is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4), filtered and concentrated to dryness. The product is purified by three columns (step gradient of 50–60–70% CH2Cl2 in hexanes) to give 8-methoxy-2-hydroxy naphthalene as a gummy solid (92% pure, 633 mg, 35%). 1H NMR (300 MHz, CDCl3) δ 7.72, 7.55, 7.36, 7.20, 7.11, 6.79, 5.02, 3.97.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2C=CC=C[CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.C(O)(C)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:19][CH3:20])[CH2:9][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CCC(CC(=NO)c1ccncc1)c1cccc(Br)c1

Procedure:
As a byproduct from the crude reaction mixture of example 12, step 2, HPLC separation (Chiralpak AD column, 10% isopropanol in n-heptane) provided 3-(3-bromo-phenyl)-1-pyridin-4-yl-pentan-1-one oxime as a mixture of E and Z isomers (4:1) as a colorless oil, MS (ESI+): m/z=333.0 ([M+H]+, 1Br).