Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].O.CO.[Cl-].[Li+]>O1CCCC1>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][C:3]([OH:20])=[O:2])[CH2:12][CH2:11]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid methyl ester (35) (3.30 g; 11.5 mmol) is dissolved in 2:2:2 tetrahydrofuran: water: methanol. Lithium chloride (2.76 g; 115.3 mmol) is added and the mixture is stirred for 1 hour at ambient temperature. The solution is concentrated in vacuo to remove the tetrahydrofuran and methanol. The concentrate is poured onto citric acid solution (115 mL) and extracted with ethyl acetate (230 mL). The organic layer is washed with water (3×115 mL) and brine (1×115 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product as a solid. ESMS: MH+ 273.0
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1C1ON=C(C)N=1.N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C.[N:37]1[N:38](C2C=CC=CC=2C(O)=O)[N:39]=[CH:40][CH:41]=1>>[ClH:1].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:38]1[N:39]=[CH:40][CH:41]=[N:37]1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2N)n1
Agent: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Product: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-aminocyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide hydrochloride (Intermediate 2) from tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 1.58 g, 7.94 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 1.64 g, 8.68 mmol) to afford the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13](Br)[CH:14]=[N:15][CH:16]=2)[N:11]=1)=[O:9].OB(O)[C:23]1[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:23]3[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=3)[CH:14]=[N:15][CH:16]=2)[N:11]=1)=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: O=C(NCc1ccco1)c1ccc2cncc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: O=C(NCc1ccco1)c1ccc2cncc(-c3ccc(C(=O)O)s3)c2n1
Temperature: 25 °C

Procedure:
Compound 3 (above, 1 equiv.), 5-(dihydroxylboryl)-2-thiophene carboxylic acid (1 equiv.), dichloro(bistriphenylphosphine)palladium (II) (0.02 equiv.), and sodium carbonate (1.5 equiv.) are combined with 7:3:2; DME:water:methanol (4 mL) in a microwavable reaction tube. The reaction mixture is irradiated in the microwave at 140° C. for 300 seconds and then cooled to room temperature. The crude mixture is concentrated in vacuo, affording a green-brown solid. Purification via silica gel chromatography (EtOAc to 4:1; EtOAc:methanol containing 1% acetic acid) affords a bright yellow solid. LC/MS (M+H) 340.2.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OCC)OCC)C(=O)C)=[N-].O>CO>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1)#[CH:18]
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a mixture of 4-(phenylsulfonyl)benzaldehyde (8 g, 32.5 mmol) and potassium carbonate (8.97 g, 65 mmol) in methanol (400 mL) was added diethyl (1-diazo-2-oxopropyl)phosphonate (8.6 g, 39 mmol). The reaction was stirred at room temperature for 3 days then poured into water (600 mL) and extracted with ethyl acetate (×3). The combined organic layers were dried and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5% ethyl acetate/isohexane, to give 1-ethynyl-4-(phenylsulfonyl)benzene (3.3 g, 42%). δH (500 MHz, CDCl3): 7.94–7.88 (4H, m), 7.60–7.50 (5H, m), 3.23 (1H, s).
Reaction SMILES: [S:1](Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([OH:17])=O)([O-:7])=[O:6].[N+:18]([C:21]1C=CC=CC=1CC(Cl)=O)([O-])=O>C1(C)C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([N:18]=[C:21]=[S:1])=[O:17])([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)Cc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1[N+](=O)[O-])N=C=S
Temperature: 100 °C

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-nitrophenyl)acetic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-nitrophenyl)ethanoyl isothiocyanate was prepared using the resultant 2-(2-nitrophenyl)ethanoyl chloride as a starting compound according to the description of the literature. 2-(2-Nitrophenyl)ethanoyl isothiocyanate thus obtained was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (7 mg, yield 8%).
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[CH2:15][C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[O:28]=P(Cl)(Cl)Cl.C(N(CC)CC)C.CNC>C(#N)C>[CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[C:15](=[O:28])[C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCN(CC)c1nc(C)nc2c1CC(=O)N2c1c(C)cc(C)cc1C
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCN(CC)c1nc(C)nc2c1C(=O)C(=O)N2c1c(C)cc(C)cc1C

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethyphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (76 mg, 0.207 mmol), POCl3 (0.039 ml, 0.415 mmol), triethylamine (0.059 ml), and dimethylamine (1 ml) in 2 ml acetonitrile was heated at reflux for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown form (105 mg). After silica gel column chromatography, the title compound was isolated as a yellow glass (10 mg). 1H NMR (CDCl3) δ7.00 (s, 2H), 3.954-15 (m, 2H), 3.65-3.85 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 2.10 (s, 6H), 1.55-1.75 (m, 2H), 1.35-1.55 (m, 2H), 1.25 (t, 3H), 1.00 (t, 3H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C[Mg:14][Br:15]>C(OCC)C>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][Mg:14][Br:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: Cc1ccc(O[Mg]Br)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In an atmosphere of nitrogen, 16.42 g (100 mmol) of 2-tert-butyl-4-methylphenol was dissolved in 100 ml of diethyl ether and 33.3 ml of methylmagnesium bromide (100 mmol of diethyl ether solution) was added dropwise to this at 0° C. taking 5 minutes. After completion of the dropwise addition, the mixture was stirred at 25° C. for 10 minutes. After that, the diethyl ether was evaporated under vacuum, and 150 ml of toluene was added to obtain a toluene solution of 2-tert-butyl-4-methylphenoxymagnesium bromide. To the solution, 5.61 g (50 mmol) of 2-thiophenecarboxyaldehyde was added dropwise at 25° C. After stirring for 24 hours, 5% aqueous hydrochloric acid solution was added and aqueous layer was separated. After the organic layer was washed with a saturated aqueous sodium chloride solution, it was dried with anhydrous magnesium sulfate and the solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (a developing solvent: hexane/ethyl acetate=30/1) to obtain 2-bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methylthiophene in a yield of 63%.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]([O:20]CC)=O)[N:14]=3)[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33].C(O)(=O)/C=C\C(O)=O>CCO.CCOC(C)=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]([N:32]([CH3:33])[CH3:31])=[O:20])[N:14]=3)[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCOC(=O)c1noc(Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1noc(Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of ethyl 5-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazole-3-carboxylate (73 mg, 0.18 mmol) in EtOH (3 ml) was added dimethylamine (2 M in MeOH, 4 mL) and the mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography (2:98 MeOH/CH2Cl2) to give a clear oil. This was taken up in EtOAc (5 ml) and a solution of maleic acid (15 mg, 0.13 mmol) in EtOAc (2 mL) was added to the solution. The resulting salt suspension was stirred for 30 min , filtered and dried overnight to give the title compound (57 mg, 89 %) as an off white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.62 (d, 2 H), 7.82 (d, 2 H), 7.26-7.35 (m, 2 H), 7.12 (t, 2 H,) 6.82 (s, 1 H), 6.00 (s, 2 H), 4.18 (s, 2 H), 3.03 (s, 3 H), 2.95 (s, 3 H); m/z (APCI+) for C21H19N6O2F 407.1 (M+H)+.
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:25]([OH:27])=O)[NH:17]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[N+](C1C=CC=C[C:32]=1[S:37]([Cl:40])(=[O:39])=[O:38])([O-])=O.[S:41]1[CH2:45][CH2:44][NH:43][CH2:42]1>>[ClH:40].[NH2:17][C@H:16]([C:25]([N:43]1[CH2:44][CH2:45][S:41][CH2:42]1)=[O:27])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:9])[S:37]([CH3:32])(=[O:38])=[O:39]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: CN(CCCC[C@H](N)C(=O)N1CCSC1)S(C)(=O)=O
Product: Cl

Procedure:
Starting from (S)-N6-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-lysine, 2-nitrobenzenesulphonyl chloride and 1,3-thiazolidine, the expected product is obtained according to the procedure described in Steps A to C of Example 3.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:25]([CH3:29])[N:26]=[C:27]([CH3:28])[C:3]=12.C1C[O:33]CC1>C(N(CC)C(C)C)(C)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:8]([C:7]2[C:2]([OH:33])=[C:3]3[C:27]([CH3:28])=[N:26][N:25]([CH3:29])[C:4]3=[N:5][CH:6]=2)=[O:9])=[O:12])=[CH:15][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(F)c(C(F)(F)F)c3)c(Cl)c12
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(F)c(C(F)(F)F)c3)c(O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of (4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide (0.050 g) in THF (5 mL) was dissolved in a 1:3 mixture of N,N-diisopropylethylamine (DIPEA) and water (4 mL). The solution was stirred at room temperature for 24 h, concentrated, and the residue purified by column chromatography on silica-gel eluting with 3:1 EtOAc-MeOH to give the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[CH3:14][SH:15].O>CN(C)C(=O)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:15][CH3:14])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CSC(C)(C)C1(O)CC=C(C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 100 ml of N,N-dimethylacetamide was added 4.4 g of 60% sodium hydride. The mixture was cooled to 5°-10° C. and saturated with methyl mercaptan. Stirring was continued while heating the reaction mixture to 100° C. over a two and one-half hour period. After an additional hour at 100° C., the reaction mixture was poured into water and extracted twice with p-pentane. The combined extracts was washed with water, dried and Claisen-distilled to give 15.8 g of the desired product, b.p. 83°-85° C. (0.2 mm).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.O>CN1C(=O)N(C)CCC1.C1COCC1>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: OCCCOCc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1,3-Propanediol (6.0 mL, 85 mmol) is dissolved in 20% DMPU in THF (80 mL) and cooled to 0° C. Sodium hydride (60%, 3.6 mg, 90 mmol) is added portionwise, and the contents are allowed to stir for 15 min. at 0° C. 2-Chloromethylquinoline (7.64 g, 42.7 mmol) is added and the reaction is allowed to stir overnight. The reaction is poured into water (700 mL) and extracted with ethyl acetate (1×200 mL). Sodium chloride is added to the aqueous layer and extracted again with ethyl acetate (2×200 mL). The organic layers are pooled and washed with water (2×300 mL) and brine (2×300 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 2.5% methanol in dichloromethane) to give the title compound. MS (ESI) 218 (M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1C=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:9]=1[C:10]([OH:12])=[O:11].[CH:19]([Cl:22])(Cl)Cl>>[Cl:4][C:14]1[C:13]([O:17][CH3:18])=[C:9]([C:8]([O:7][CH3:6])=[C:19]([Cl:22])[CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: ClC(Cl)Cl
Reactant: COc1cccc(OC)c1C(=O)O
Product: COc1c(Cl)cc(Cl)c(OC)c1C(=O)O

Procedure:
A solution of 20 ml (0.25 mol) of sulphuryl chloride in 50 ml of chloroform is added dropwise to a solution of 15.0 g (0.08 mol) 2,6-dimethoxybenzoic acid in 100 ml of chloroform. The solution is left over night at room temperature and is then refluxed for 0.5 h. The solvent is evaporated and the residue recrystallized twice from light petroleum. Yield: 17.0 g, m.p. 98°-100° C. (first recrystallization). Yield: 12.0 g, m.p. 102°-103° C. (second recrystallization).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1C=C[C:11](Cl)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].ClCC(=O)CC1[S:22]C=CC=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[S:22][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1cccs1
Yield: 13 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-2-yl)propan-2-one (1.00 g, 5.73 mmol) with acetic acid (0.66 mL, 0.69 g, 12 mmol) and triethylamine (1.60 mL, 1.16 g, 11.5 mmol). Purification by flash chromatography over silica gel (1040% ethyl acetate in hexanes) gave an orange oil (0.144 g, 13% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.95 (s, 2H) 4.74 (s, 2H) 6.92-6.94 (m, 1H) 6.99 (dd, J=5.2, 3.4 Hz, 1H) 7.25 (dd, J=5.1, 1.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH2:23]>>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tryptophan methyl ester hydrochloride Sigma), the title compound was prepared as a solid (mp=191-193° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([NH2:11])=[C:5]([NH2:12])[C:4]=1[CH3:13].C(N(CC)CC)C.[C:21](Cl)(Cl)=[S:22].O>C(Cl)(Cl)Cl>[CH3:13][C:4]1[C:5]2[N:12]=[C:21]([SH:22])[NH:11][C:6]=2[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c(C)c(N)c(N)c1C
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(C)c(C)c2[nH]c(S)nc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 4-methoxy-3,5,6-trimethyl-1,2-phenylenediamine (1.8 g, 0.010 mol) and triethylamine (2.1 g, 0.021 mol) in CHCl3 (15 ml) was added dropwise to a stirred solution of thiophosgene (0.60 g, 0.0052 mol) in CHCl3 (5 ml). The mixture was then stirred at room temperature for 1 hour. Water (15 ml) and triethylamine (0.5 g) was added and the mixture was stirred for 1 hour. The precipitate was filtered off, washed with water and dried in the air giving the desired product (0.96 g, 43%), NMR: δ (CDCl3) 2.5 (s,3H), 2.65(s,6H), 3.65(s,3H), 12.0(br.s.,1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3 (3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): d 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): d 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.N1CCCCC1.N1C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])C=O>O>[F:20][C:21]1[CH:22]=[C:23]([CH2:3][CH2:2][C:1]([OH:7])=[O:6])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(CCC(=O)O)cc1F
Temperature: 120 °C
Yield: 65.8 %

Procedure:
Malonic acid (7.5 g, 72.1 mmols) and piperidine (0.84 g, 9.83 mmols) were added to a pyridine (20 ml) solution of 3-fluoro-4-methoxybenzaldehyde (10.1 g, 65.5 mmols), and the mixture was stirred under heat at 120° C. for 7 hours. The reaction mixture was poured into water containing ice, and the powder that precipitated was taken out through filtration. The powder was dried and dissolved in acetic acid (300 ml) without being further purified. To this was added 5% palladium-carbon (3 g, containing 50% water), and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 8.54 g (yield: 66%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[N:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[NH3:6].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCCC2)nc1
Product: N
Reaction time: 18 h
Yield: 148.2 %
Yield: 1 %

Procedure:
To a solution of 6-formyl-nicotinic acid methyl ester (0.200 g, 1.21 mmol) and piperidine (0.14 mL, 1.33 mmol) in DCM (15 mL) was added NaB(OAc)3H (0.380 g, 1.80 mmol). After 18 h, the reaction was diluted with 1 N NaOH (10 mL) and extracted with DCM (2×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 1-3% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.210 g, 74%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A solution of 3-bromo-2-methylbenzoic acid (2.98 g, 13.9 mmol) in DMF (20 mL) was treated with cesium carbonate (4.56 g, 13.9 mmol) and iodomethane (0.900 mL, 14.4 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solution was poured into ethyl acetate and washed with water (3×) and brine. The ethyl acetate layer was concentrated under vacuum to give methyl 3-bromo-2-methylbenzoate (Cpd FF, 2.70 g, 85% yield) as a clear oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](=[O:21])[CH2:11][P:12]([CH2:17][CH2:18][CH2:19][CH3:20])(=[O:16])[O:13]CC)=O)(C)(C)C.C[Si](C)(C)[Br:24]>ClCCl.CO.O>[BrH:24].[NH2:8][CH2:9][C:10](=[O:21])[CH2:11][P:12]([CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])[OH:16]
Reactant: C[Si](C)(C)Br
Reactant: CCCCP(=O)(CC(=O)CNC(=O)OC(C)(C)C)OCC
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Br
Product: CCCCP(=O)(O)CC(=O)CN
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 0.642 g of ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(n-butyl)phosphinate in 10 ml of anhydrous dichloromethane under an inert atmosphere is treated with 1.53 g of trimethylbromosilane. After stirring for 7 hours at room temperature the volatile material is removed in vacuo to afford a pale yellow oil. This oil is dissolved in methanol containing 1% of water, and the clear pale yellow solution is stirred overnight at room temperature. The solvent is removed in vacuo to afford 3-amino-2-oxo-propyl(n-butyl)phosphinic acid hydrobromide, m.p. 135°-138°. Suspension in ethanol and treatment with propylene oxide affords 3-amino-2-oxo-propyl(n-butyl)phosphinic acid of m.p. 128°-130°.