Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:18]([O-])=O)[CH:5]=[CH:6][CH:7]=1>C1COCC1.[Pd]>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccc(Nc2cccc(F)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1Nc1cccc(F)c1
Reaction time: 12 h

Procedure:
A solution of 4-(3-fluorophenylamino)-3-nitrobenzoic acid (5.57 g, 20.1 mmol) in THF (100 mL) was charged with 10% Pd/C (500 mg) and the reaction flask evacuated and subsequently charged with H2(g) three times. The mixture was stirred vigorously for 12 h after which it was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 3-amino-4-(3-fluorophenylamino)benzoic acid as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.19-7.13 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (d, J=11.6 Hz, 1H), 6.54 (t, J=8.4 Hz, 1H), 5.02 (b, 1H); MS (ES+): m/z 247 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][C:18]([O:33][CH3:34])=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ccc(-c2cccc3c2CCNC3C)c(OC)n1
Product: COc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N+:8]=2[O-])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16]C(OC)=O>C1COCC1>[Cl:16][C:7]1[N:8]=[C:9]2[C:4]([CH:3]=[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:1]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2ccc[n+]([O-])c2[nH]1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a stirred solution of ethyl 7-azaindole-2-carboxylate-7-oxide (1.32 g, 6.4 mmol) and hexamethyldisilazale (1.4 mL, 6.6 mmol) in THF (30 mL) at 0° C. was added dropwise over 30 min a solution of methyl chloroformate (1.2 mL, 15.5 mmol) in THF (5 mL). The mixture was warmed to room temperature, stirred for 2 h and partitioned between ether (50 mL) and water (50 mL). The aqueous layer was extracted with ether (30 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and purified by column chromatography [SiO2; heptane-ether (3:1)] to give ethyl 6-chloro-7-azaindole-2-carboxylate as a white solid (0.38 g, 26%). mp 144–145° C. Found: C, 53.69; H, 4.05; N, 12.39%. C10H9N2ClO2 requires: C, 53.47; H, 4.04; N, 12.46%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])=[N:7][C:6]=1[CH3:10]
Reactant: COCCc1scnc1C
Reactant: CCOC(=O)C(F)(F)F
Product: COCCc1sc(C(=O)C(F)(F)F)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and ethyl trifluoroacetate, following the procedure of Preparation 1.
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[C:13]([C:17]1[CH:24]=[C:23]([CH3:25])[C:20]([CH2:21]Cl)=[C:19]([CH3:26])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:1]([O:12][CH2:21][C:20]1[C:23]([CH3:25])=[CH:24][C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])=[C:18]([OH:27])[C:19]=1[CH3:26])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][C:20]2[C:23]([CH3:25])=[CH:24][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[C:18]([OH:27])[C:19]=2[CH3:26])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1COC(=O)c1ccc(C(=O)OCc2c(C)cc(C(C)(C)C)c(O)c2C)cc1

Procedure:
A mixture of disocium terephthalate, 16.5 g. (0.08 mole) and 4-tert.-butyl-3-hydroxy-2,6-dimethylbenzyl chloride, 35.7 g. (0.158 mole) in 200 ml. of dimethylformamide was heated at reflux for 18 hours. The salt was then filtered off, and the filtrate poured into 400 ml. of water. The resulting brown gum was dissolved in 50 ml. of methanol and reprecipitated by addition of water. This procedure was repeated to give 18.9 g. (44%) of product, m.p. 227°-230° C. Anal. calc'd. for C34H42O6 : C=74.67, H=7.75; found: C=74.03, H=7.75.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
A suspension of 31.4 g (178 mmol) 4-bromophenol, 30.6 g (178 mmol) (2-chloro-ethyl)-diethyl-amine (used as the hydrochloride) and 61.5 g (445 mmol) K2CO3 in 300 mL DMF is heated to 80° C. for 8 h. The solvent is evaporated down i.vac., the residue combined with water, the aqueous phase exhaustively extracted with EtOAc, the combined organic phases washed with water again and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M28) (282 mg, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (163 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20])([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of methyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinate (1.8 g, 5.28 mmol, 1.00 equiv) in methanol (15 mL), and a solution of NH4Cl (850 mg, 15.89 mmol, 3.00 equiv) in water (7.9 mL). This was followed by the addition of iron (2.9 g, 51.79 mmol, 9.99 equiv) in several batches at 70° C. The resulting solution was stirred for 4 h at 70° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water, extracted with 3×20 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 1.4 g (85%) of methyl 2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinate as a black semi-solid.
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 119 °C
Yield: 89 %

Procedure:
First, 4.29 g (51.1 mmol) of tiglic aldehyde and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.15 g (5.00 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 6 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 10.5 g of 2-benzenesulfonyl-5-methylpyridine as colorless crystals (purity of 99%, yield of 89% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([CH2:20][N:21]4[CH2:28][CH2:27][CH2:26][C@H:22]4[C:23](O)=[O:24])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=4)[O:2]1.N>>[CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([CH2:20][N:21]4[CH2:28][CH2:27][CH2:26][C@H:22]4[CH2:23][OH:24])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=4)[O:2]1
Reactant: COc1ccc2c(CN3CCC[C@H]3C(=O)O)cc3cc4c(cc3c2c1)OCO4
Agent: N
Product: COc1ccc2c(CN3CCC[C@H]3CO)cc3cc4c(cc3c2c1)OCO4

Procedure:
General procedure f from 31 (95%); white powder; mp 138-139° C.; 1H NMR (400.13 MHz) δ 8.16 (d, J=4 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=2 Hz, 1H), 7.46 (s, 1H), 7.23 (dd, J=4 Hz, 2 Hz, 1H), 7.14 (s, 1H), 6.07 (s, 2H), 4.03 (s, 2H), 3.94 (s, 3H), 3.70 (d, J=17 Hz, 2H), 3.16 (m, 1H), 2.38 (m, 2H), 2.23 (m, 2H), 1.95 (m, 2H); MS (DCI/NH3) m/e: 366 (M+H)+. Anal. (C22H23O4N) C, H, N.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3Br)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:38]1([C:44]#[CH:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[C:45]#[C:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(C#Cc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of (2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (1.26 g, 2.67 mmol), CuI (0.102 g, 0.534 mmol), and Pd(PPh3)2Cl2 (0.187 g, 0.267 mmol) in DMF was added DIPEA (0.930 mL, 5.34 mmol) and phenylacetylene (1.17 mL, 10.69 mmol). The mixture was stirred at 75° C. for 1 hour then concentrated. The residue was dissolved in CH2Cl2 (70 mL) and washed with saturated aq EDTA.Na2 (3×50 mL). The combined organics were dried (Na2SO4) and concentrated. The dark crude oil was purified by flash chromatography (40% EtOAc/hexanes) to afford the title compound (1.2 g, 91%).
Reaction SMILES: B.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]#[N:13])=[C:6]2[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21].N>O1CCCC1>[NH2:13][CH2:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=2
Reactant: N#Cc1[nH]c2ccc(Cl)cc2c1-c1c(F)cccc1F
Agent: B
Agent: N
Solvent: C1CCOC1
Product: NCc1[nH]c2ccc(Cl)cc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane in tetrahydrofuran (7 ml of a 1M solution) is added to a solution of 1 g (3.46 mmol) of 5-chloro-3-(2,6-difluorophenyl) indole-2-carbonitrile in 15 ml of dry tetrahydrofuran. The solution is stirred at room temperature for 2 hours and then refluxed for 1/2 and cooled to room temperature. 5 ml of 5N aqueous NCl is added dropwise and the mixture is refluxed for 20 minutes. The mixture is then poured onto a mixture of ice and aqueous 10 percent ammonia, and the precipitate is extracted with chloroform. The chloroform layer is washed with water and dried over magnesium sulfate, filtered and evaporated to dryness. Recrystallization from chloroform (charcoal) affords colorless crystals; m.p. 212°-214°.
Reaction SMILES: CC(C)=O.[SH:5][N:6]1[NH:10][N:9]=[CH:8][N:7]1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>C(Cl)Cl>[Cl:21][CH2:20][CH2:19][S:5][N:6]1[NH:10][N:9]=[CH:8][N:7]1[CH3:11]
Reactant: CN1C=NNN1S
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN1C=NNN1SCCCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an acetone (50 ml) solution containing 2-mercapto-1-methyltetrazole (4.0 g) and anhydrous potassium carbonate (20 g) was added 1-bromo-2-chloroethane (5.0 ml) under ice-cooling. The mixture was stirred for 90 minutes at room temperature, to which was added methylene chloride (50 ml). The mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure to afford 2-(chloroethylthio)-1-methyltetrazole (6.0 g) as a pale yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCc1ccc(Br)cc1
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a 0° C. solution of of 4-bromophenethylamine (10.0 g, 50.0 mmol) and triethylamine (7.7 mL, 55.0 mmol) in 150 mL of dichloromethane was added dropwise methanesulfonyl chloride (4.3 mL 55.0 mmol) in 20 mL of dichloromethane. After two hours, the reaction mixture was washed once with 100 mL of 10% aqueous sodium bisulfate. The organic portion was separated and the aqueous portion was extracted three times with 50 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford 14.0 g (100%) of the intermediate title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:23][CH:24]([O:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:23][CH:24]([O:30][CH:31]([CH3:32])[CH3:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)CP(=O)(OCC)OCC)c1)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
600 mg diethylphosphonoacetic acid and 969 mg of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropionate were dissolved in 10 ml N,N-dimethylformamide, followed by the successive addition of 470 μl diethyl cyanophosphonate and 1.07 ml triethylamine. The mixture was stirred overnight at room temperature, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. Thus, 1.387 g of ethyl 3-[3-([2-(diethoxyphosphoryl)acetyl]aminomethyl)-4-methoxyphenyl]-2-isopropoxypropionate was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH2:53]([O:60][C:61]([N:63]1[C:68]2[CH:69]=[C:70]([Cl:74])[CH:71]=[C:72](Br)[C:67]=2[O:66][CH2:65][CH2:64]1)=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[C:75]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]1)=[O:81])([CH3:78])([CH3:77])[CH3:76]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:53]([O:60][C:61]([N:63]1[C:68]2[CH:69]=[C:70]([Cl:74])[CH:71]=[C:72]([N:85]3[CH2:84][CH2:83][N:82]([C:80]([O:79][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:81])[CH2:87][CH2:86]3)[C:67]=2[O:66][CH2:65][CH2:64]1)=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(OCc1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3C(=O)OCc2ccccc2)CC1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
A three neck flask was charge with tris(dibenzylideneacetone) dipalladium(0) (21.5 mg, 0.024 mmol, 2 mol % Pd), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (36.4 mg, 0.059 mmol, 5 mol %) and sodium-tert-butoxide (159 mg, 1.65 mmol) and flushed with nitrogen. A solution of 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester (450 mmg, 1.18 mmol) and piperazine-1-carboxylic acid tert-butyl ester (263 mg, 1.41 mmol) in toluene (2 mL) was added. The mixture was heated to 95° C. and was stirred for 12 hours. The mixture was cooled to room temperature, taken up in ethyl acetate, filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3, v/v) to give 8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester a colorless oil (275 mg, 48%). MS: MH+=488.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[O:12][C:11]([NH2:13])=[N:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16](OCC)(=[O:19])[C:17]#[CH:18]>C(O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[O:12][C:11]2=[N:13][C:16](=[O:19])[CH:17]=[CH:18][N:10]2[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CN=C(N)O1
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1Cn2ccc(=O)nc2O1
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-4,5-dihydro-oxazol-2-ylamine (6.65 g, 28.9 mmol) in ethanol (150 mL) was added ethyl propiolate (2.92 mL, 28.9 mmol). The reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature, concentrated under vacuum and purified by column chromatography on silica gel (0-10% methanol in dichloromethane). This afforded 2.45 g (30%) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17]C(=O)OC(C)(C)C)[C:12]1=[O:25])(C(C)(C)C)(C)C.O1CCOCC1.[ClH:32]>>[ClH:32].[NH2:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[C:12]1=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
(S)-tert-Butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxopiperidin-3-ylcarbamate (Example 13; 100 mg, 0.268 mmol) was dissolved in 4M hydrogen chloride in dioxane (2 mL, 8.0 mmol) and the reaction mixture was allowed to stir at ambient temperature for 72 hours. The reaction mixture was concentrated to yield (S)-3-amino-1-(2-hydroxyethyl)piperidin-2-one hydrochloride (52 mg, 100%) which was taken on to the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:1]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2]1)=[O:31]
Reactant: O=C(O)CCCCCCNc1ccccn1
Reactant: COC(=O)CC1CNCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(C(=O)CCCCCCNc2ccccn2)CCc2ccccc21
Reaction time: 4 h

Procedure:
To a stirring solution of methyl 2-(1H,2H,3H,4H,5H-benzo[d]azepin-1-yl)acetate in dichloromethane (0.2 M) was added 7-(2-pyridylamino)heptanoic acid (1.2 eq), triethylamine (1.5 eq), and EDAC (2 eq). After 4 hrs, the reaction was washed with water, 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica; EtOAc) afforded a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[CH:8]2[CH2:17][CH2:18][OH:19].[CH3:20][S:21]SC.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[C:8]2([S:21][CH3:20])[CH2:17][CH2:18][OH:19]
Reactant: COc1cc2c(cc1OC)C(CCO)C(=O)N2
Reactant: CSSC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(CCO)(SC)C(=O)N2
Yield: 57.6 %

Procedure:
To 50 ml of dimethylformamide was added 360 mg of sodium hydride, and 1.76 g of 5,6-dimethoxy-3-hydroxyethyl-1,3-dihydro-2(2H)-indolone and 706 mg of dimethyl disulfide were added thereto. To the reaction mixture was added a sodium hydrogencarbonate aqueous solution, and the solvent was evaporated. The residue was extracted three times with methylene chloride, and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate) to yield 1.21 g of the title compound.