Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C(Cl)OC(Cl)(Cl)Cl.[N-:25]=[C:26]=[O:27].Cl.[CH3:29][O:30][C:31](=[O:44])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)N.C(N(CC)CC)C>O1CCOCC1.ClCCl>[CH3:29][O:30][C:31](=[O:44])[C@@H:32]([NH:25][C:26]([NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])=[O:27])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1
Reactant: [N-]=C=O
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)Nc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
A mixture of 2-benzenesulfonylphenylamine (1.88 g, 8.04 mmol) and diphosgene (0.48 ml, 4.02 mmol) in dioxane (25 ml) was heated at 60° C. for 16 h. The solvent was removed under reduced pressure. A solution of the crude isocyanate (8.04 mmol) in dichloromethane (14 ml) was slowly added to a solution of (S)-4-nitrophenylalanine methyl ester hydrochloride (2.31 g, 8.84 mmol) and triethylamine (3.7 ml, 26.52 mmol) in dichloromethane (14 ml) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 ml) and washed with hydrochloric acid 1N (3×50 ml), saturated aqueous NaHCO3 (3×50 ml) and brine (1×50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to yield (S)-2-[3-(2-Benzenesulfonylphenyl)ureido]-3-(4-nitrophenyl) propionic acid methyl ester (3.64 g, 94%) that was used in the next step without further purification.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.[CH3:16]I.O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:6]1[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=1
Reactant: CI
Reactant: O=C([O-])C(=O)C=Cc1ccc(Br)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)C=Cc1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 30.6 %

Procedure:
A mixture of 4-(4-bromo-phenyl)-2-oxo-3-butenoic acid potassium salt (48.0 g, 164.0 mmol) prepared in Step 1 and methyl iodide (20.0 mL, 327.0 mmol) in N,N-dimethylformamide (250.0 mL) was stirred at 75° C. for 4 hours and then distilled water was added thereto. The reaction mixture was extracted with ethyl acetate. The extract was washed with a sodium hydrogen carbonate solution and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 13.5 g of the titled compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)(O)[O-].[Na+].O.Cl[CH2:17][C:18](Cl)=[O:19]>CC(=O)CC>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:17][C:18](=[O:19])[NH:1][C:2]=2[N:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(O)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of 2-amino-6-methyl-pyridin-3-ol (18.3 g, 148 mmol), sodium bicarbonate (30 g, 354 mmol), H2O (100 mL), and 2-butanone (100 mL) in an ice-water bath was added a solution of chloroacetyl chloride (13.3 mL. 167 mmol) in 2-butanone (30 mL) over 1.5 h, controlling the temperature below 10 ° C. After the addition was complete, the ice-water bath was removed and the mixture was stirred at ambient temperature for 30 minutes, followed by refluxing for 1.5 h. The solvents were evaporated, and the resulting solid was washed with H2O (3 times), and dried under high vacuum overnight, giving the title compound (19.2 g, 79% yield) as a pale yellow solid. 1H NMR (CDCl3) δ 10.45 (bs, 1H), 7.17 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.1 Hz), 4.62 (s, 2H), 2.52 (s, 3H). Mass spectrum (LCMS, ESI) calculated for C8H9N2O2 165.1 (M+1); found 165.1.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17].[F-].[K+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH:16]=[CH2:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)OC)c(Cl)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A solution of methyl 2-chloro-5-iodo-3-nitrobenzoate (3 g, 8.8 mmol) and vinyl tributyltin (3.6 g, 11.4 mmol) in DMF (50 mL) was degassed with argon. PdCl2/(PPh3)2 (308 mg, 0.44 mmol) was added, the reaction vessel was sealed under argon and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was cooled to RT and treated with aqueous KF (1.5 g in 20 mL water) for 2 h30. The mixture was diluted with water and EtOAc filtered on cellite. The organic layer was separated, washed with aq LiCl (×3), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (120 g silica gel, 0 to 20% EtOAc in hexane) to give methyl 2-chloro-3-nitro-5-vinylbenzoate as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=2 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 6.69 (dd, J=17.4 Hz, 10.8 Hz, 1H), 5.89 (d, J=17.4 Hz, 1H), 5.52 (d, J=10.8 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[F:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[F:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]2[N:15]=[CH:16][CH:17]=[C:18]3[C:3]([CH3:4])=[C:2]([CH3:1])[NH:20][C:19]=23)=[CH:10][CH:9]=1
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(COc3ccc(F)cc3)nccc2c1C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5 M in tetrahydrofuran solution, 1.7 ml, 0.851 mmol) was added at −78° C. to a solution of 2-(4-fluorophenoxymethyl)-3-nitropyridine (71 mg, 0.284 mmol) prepared in Preparation 1 in anhydrous tetrahydrofuran (5 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate (15 ml). The organic layer was washed with water (5 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 15 mg of the titled compound as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=O)=[CH:8][C:7]=2[CH:16]=1.[ClH:19].Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.P(C#N)(=O)(OCC)OCC.Cl>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[ClH:19].[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:25]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:32][CH2:31]3)=[O:15])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)O)=C2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1)=C2
Yield: 27.9 %

Procedure:
Using 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (2 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (3.5 g), N,N-dimethylformamide (30 ml), triethylamine (3.3 g) and diethyl phosphorocyanidate (2.5 ml), a reaction as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1) to give an oily product which is converted to the hydrochloride in ethyl acetate to yield 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.2 g) as colorless crystals, m.p. 138°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[NH:15][CH:16]=[C:17]([CH3:18])[C:13]=3[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)C.N1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:19]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:21])=[C:13]3[C:17]([CH3:18])=[CH:16][NH:15][C:14]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCOCC1
Reactant: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCN1
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(3-chloro-phenylamino)-3-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (34 mg) in dimethylformamide (2 ml) was added 4-ethylmorpholine (57 μl), morpholine (19 μl), 1-hydroxybenzotriazole hydrate (24 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg) and the solution stirred at room temperature overnight. The dimethylformamide was evaporated and the residue triturated with 5% sodium bicarbonate to give an off white solid. The solid was filtered, washed thoroughly with water, and dried over sodium hydroxide at 50° C. to afford 1-[7-(3-chloro-phenylamino)-3-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (22 mg).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=O.CCN=C=NCCCN(C)C.[ClH:17].[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[N:27]([CH2:39][CH3:40])[C:28]3[C:33]([C:34]=2[C:35]#[N:36])=[CH:32][CH:31]=[C:30]([O:37][CH3:38])[CH:29]=3)[CH:22]=[CH:23][C:24]=1[OH:25]>C(#N)C>[Cl:17][CH2:2][C:3]([NH:18][C:19]1[CH:20]=[C:21]([C:26]2[N:27]([CH2:39][CH3:40])[C:28]3[C:33]([C:34]=2[C:35]#[N:36])=[CH:32][CH:31]=[C:30]([O:37][CH3:38])[CH:29]=3)[CH:22]=[CH:23][C:24]=1[OH:25])=[O:5]
Reactant: Cl
Reactant: O=C(O)CBr
Reactant: CCn1c(-c2ccc(O)c(N)c2)c(C#N)c2ccc(OC)cc21
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCn1c(-c2ccc(O)c(NC(=O)CCl)c2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Bromoacetic acid (52 mg, 0.37 mmol) is combined with EDCI hydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 μL) to form a homogeneous solution. 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in example 1BG, step B, is added to the solution. A thick paste soon forms. Another 1.1 mL of acetonitrile is added and the mixture is then stirred at room temperature for 2 hours. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields 2-chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxyphenyl]acetamide (82 mg, 60%), compound 333, as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[CH:6]=[CH:5]2.IC1C=C2C(=CC=1)N(C)C(=O)C=C2.C(I)C>CI>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cc(I)ccc21
Agent: Cn1c(=O)ccc2cc(I)ccc21
Solvent: CCI
Solvent: CI
Product: CCn1c(=O)ccc2ccccc21

Procedure:
The 1,2-dihydro-6-iodo-1-ethylquinolin-2-one used as a starting material was obtained using a similar procedure to that described in the portion of Example 1 which is concerned with the preparation of the starting material 1,2-dihydro-6-iodo-1-methylquinolin-2-one, except that ethyl iodide was used in place in methyl iodide. There were thus obtained in turn 1,2-dihydro-1-ethylquinolin-2-one, m.p. 52°-54° C., and the required starting material as an oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[C:35]([OH:41])[CH:34]=1>ClCCl>[Br:2][C:1]([Br:5])=[CH:37][C:36]1[CH:39]=[CH:40][C:33]([F:32])=[CH:34][C:35]=1[OH:41]
Reactant: O=Cc1ccc(F)cc1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1cc(F)ccc1C=C(Br)Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a solution of CBr4 (5.6 g, 17.1 mmoL) in dichloromethane (100 mL) was added PPh3 (7 g, 26.69 mmol) at 0° C., 30 min later, NEt3 (4.3 g, 42.6 mmol) and 4-fluoro-2-hydroxybenzaldehyde (1 g, 7.14 mmol) was added slowly. After stirring for 30 mins at room temperature, the resulting mixture was concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 2-(2,2-dibromoethenyl)-5-fluorophenol as a white solid (0.58 g, 27%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Br)[C:3]=1[O:10][CH2:11][CH2:12]Br.[Li]CCCC.[C:19](=[O:21])=[O:20].CC(C)=O.C(=O)=O>C1COCC1.CCCCCC>[CH3:8][C:6]1[CH:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]2[O:10][CH2:11][CH2:12][C:2]=2[CH:7]=1
Reactant: O=C=O
Reactant: Cc1cc(Br)c(OCCBr)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c(C(=O)O)c1)OCC2
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a stirred solution of 2-(2,6-dibromo-4-methylphenyloxy)ethyl bromide (19) (5.82 g, 15.6 mmol) in dry THF (90 ml) and hexane (30 ml) under argon there was added 7.8 ml of n-BuLi (2.5 M in hexane) at -78° C. (dry ice/acetone bath). After 30 minutes at -78° C., an additional 7.8 ml of n-BuLi was added. After an additional 1 hour stirring, the light yellow reaction solution was poured into a slurry of dry ice (prewashed with dry ether). After the mixture had come to room temperature, the precipitated white solid was collected on a filter, treated with lN HCl to adjust the pH of the supernatant liquid to 1. The mixture was cooled briefly in the freezer, and the solid collected on a filter to afford 2.52 g (90.7%) of acid 20. The crude product was recrystallized from CH3OH/H2O to yield 1.70 g (61.2%) of 20 as a white solid, mp 177-°- 79° C. IR(KBr) 3420 (OH) and 1680(C=0) cm-1NMR(CDCl3) δ 8.47 (br s, 1H, OH), 7.50 (s, 1H, aromatic proton), 7.15 (s, 1H, aromatic proton), 4.70 (t, 2H, J=9 Hz, OCH2), 3.20 (t, 2H, OCH2CH2), and 2.32 (s, 3H, CH3).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
2-Acetylthiomethyl-3-phenylpropionic acid (18.5 g) is mixed with 70% aqueous methanol (100 ml), and the mixture is stirred at room temperature for one hour under nitrogen while maintaining at pH 13.0 with 20% aqueous sodium hydroxide solution, and thereafter the mixture is adjusted to pH 2.0 with 20% hydrochloric acid, and methanol is distilled off under reduced pressure. The residue is purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give 2-mercaptomethyl-3-phenylpropionic acid (8 g) as a colorless oily substance. IR (film; cm-1): 1700
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].[CH3:14][C:15]([CH:18]=O)([CH3:17])[CH3:16].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:20]1([CH:18]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]([CH3:16])([CH3:17])[CH3:14])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: CC(C)(C)C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: COc1cc(OC)cc(C(N)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(OC)cc(C(=O)NC(n2nnc3ccccc32)C(C)(C)C)c1

Procedure:
A suspension of 3,5-dimethoxybenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(CN)OC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: COP(=O)(CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)OC

Procedure:
In a manner analogous to Example 13(a) starting from 64.0 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine and 35.1 g of dimethyl aminomethylphosphonate hydrochloride, there were obtained 73.3 g of dimethyl [(N-benzyloxycarbonyl-L-alanyl)amino] -methylphosphonate as an oil. This oil was refluxed in a mixture of 200 ml of trimethylchlorosilane and 100 ml of acetonitrile under exclusion of moisture for 100 hours. The mixture was then cooled, filtered and evaporated in vacuo on a rotary evaporator. The residue was re-evaporated several times with toluene. The final residue was dissolved in 250 ml of dioxane and treated with 25 ml of water. Crystallization began after several minutes and this was completed by storing overnight. The separated solid was filtered off, washed with ethyl acetate and dried in vacuo. There were obtained 29.0 g of solid of melting point 147°-148° C (decomposition). A further 28.0 g of solid of the same melting point were obtained by concentration of the mother liquors and treatment with ethyl acetate. The combined solids were recrystallized by dissolving in 1.5 parts by volume of tepid methanol, filtering and then adding 15 parts by volume of ethyl acetate to the filtrate. There were obtained 39.5 g of pure [(N-benzyloxycarbonyl-L-alanyl)amino] -methylphosphonic acid of melting point 153°-155° C (decomposition); [α]D20 = - 28.9° (c = 1% in water).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].Br[CH2:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:23])=[CH:20][CH:19]=1>CO.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:23])[C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:34][CH:35]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(CBr)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C(=O)c2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 2-butyl-4-chloro-5-(hydroxymethyl)imidazole (11.12 g, 54 mmol, 1 eq) in 200 mL methanol was added dropwise a freshly prepared sodium methoxide solution (1.36 g Na, 59 mmol, 1.1 eq in 50 mL MeOH). After stirring for 0.5 hours, the methanol was removed in vacuo and the resultant glass was dissolved in 200 mL DMF. To this mixture was added a solution of methyl 2-[4-(bromomethyl)benzoyl]benzoate (18.00 g, 59 mmol, 1.1 eq) in DMF and the entire contents was stirred overnight under N2 at room temperature. The solvent was then removed in vacuo and the residue dissolved in 500 mL ethyl acetate and 500 mL H2O. The layers were separated and the aqueous layer was extracted twice with 500 mL portions of ethyl acetate. The organic layers were dried and concentrated and the crude product flash chromatographed to separate the two regioisomers in 60:40 hexane/ethyl acetate over silica gel. The faster moving isomer was isolated to yield 14.72 g of a glassy solid. NMR (200 MHz, CDCl3) δ8.03 (d, 1H, J=7 Hz); 7.67 (m, 4H); 7.36 (d, 1H, J=7 Hz); 7.05 (d, 2H, J=7 Hz); 5.28 (s, 2H); 4.43 (s, 2H); 3.63 (s, 3H); 2.53 (t, 2H, J=7 Hz); 1.60 (t of t, 2H, J=7,7 Hz); 1.30 (t of q, 2H, J=7,7 Hz); 0.87 (t, 3H, J=7 Hz). Mass Calcd. for C25H26ClF3N4O5S: 586.1264. Found: 586.1285.
Reaction SMILES: [H-].[Na+].C([C:11]([C:16]#[N:17])([CH3:15])[C:12]([O-:14])=[O:13])C[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:18]1([Se:24]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+].[CH3:31][CH2:32]OCC>C1COCC1>[C:18]1([Se:24][C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:16]([CH:11]([CH3:15])[C:12]([O:14][CH:31]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:18])[CH3:32])=[O:13])#[N:17]
Reactant: CCOCC
Reactant: Br[Se]c1ccccc1
Reactant: CCCCCCCCC(C)(C#N)C(=O)[O-]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(C)OC(=O)C(C)C#N
Product: c1ccc([Se]c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 4-neck 500 ml flask, equipped with a condenser, mechanical stirrer, thermometer, and nitrogen inlet, was added sodium hydride (3.9 g, 153 mmol) and THF (250 ml) under nitrogen. 2-octyl-2-cyanopropionate (20 g, 115 mmol) was added over 10 min. and the reaction mixture was stirred for 1 hour at room temperature. A solution of phenylselenium bromide, prepared by the above method, was added by syringe. The reaction mixture was stirred for 1 hour and added to 250 ml each of ether and sat. aq. NaHCO3. The organic layer was washed twice with 250 ml of H2O and once with 250 ml sat. aq. NaCl. The organic layer was separated, dried (MgSO4) and filtered. Solvent was removed under reduced pressure. Yield=43.2 g (quant.); NMR δ (CDCl3) 7.75 (d, 2H), 7.40 (m, 3H), 4.85 (m, 2H), 1.80 (s, 3H), 0.8-1.70 (m, 16H); IR (neat) 2333, 1734, 1251 cm-1.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:20]([C:23]1[S:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[C:26]([CH3:28])[N:27]=1)=[N+:21]=[N-:22]>>[CH2:32]([NH:31][C:29]([C:25]1[S:24][C:23]([N:20]2[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:22]=[N:21]2)=[N:27][C:26]=1[CH3:28])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 5-phenyl-1-pentyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 32% yield: mp 94-97° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.38-7.18 (m, 10H), 6.14 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.81 (t, J=9.0 Hz, 2H), 2.79-2.68 (m, 5H), 2.09-2.04 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.7, 153.3, 149.2, 141.5, 137.4, 128.9, 128.4, 128.3, 127.9, 127.8, 125.9, 123.9, 118.4, 44.3, 35.2, 30.6, 24.9, 17.4; MS (ES+) m/z 418.3 (M+1).