Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.O=P(Cl)(Cl)Cl.[NH2:13][C:14](=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:15].[O-]CC.[Na+].Cl>ClCCCl>[OH:23][C:22]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:15])[N:13]=[C:3]2[N:2]([CH3:1])[CH2:6][CH2:5][C:4]=12
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)N
Reactant: CN1CCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc2c(c1O)CCN2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 1-methylpyrrolidin-2-one (14.81 ml, 154 mmol) in anhydrous 1,2-dichloroethane (DCE) (250 ml) under a nitrogen atmosphere was added drop wise POCl3 (28.5 ml, 307 mmol) over a 10 min period and the mixture was stirred at ambient temperature. After 1 h, a solution of diethyl 2-(1-aminoethylidene)malonate (30.9 g, 154 mmol) in DCE (10 mL) was added and the mixture was heated to 40° C. After 18 h, the reaction mixture was partitioned between sat. aq. NaHCO3 and DCM. The organic later was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo, The residue was dissolved in N,N-dimethylformamide (DMF) (150 ml) and treated dropwise with sodium ethoxide (172 ml, 461 mmol) and heated to 100° C. After 3 h, the reaction mixture was cooled to ambient temperature and the pH was adjusted to pH 7 with 1M HCl. The mixture was partitioned between water and EtOAc and the organics washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 0-25%) to afford ethyl 4-hydroxy-1,6-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (11.0 g, 30.3% yield) as a white solid. 1H NMR (CHLOROFORM-d) δ: 11.89 (s, 1H), 4.37 (q, J=7.0 Hz, 2H), 3.54 (t, J=8.7 Hz, 2H), 2.87-3.05 (m, 5H), 2.64 (s, 3H), 1.41 (t, J=7.1 Hz, 3H); LC/MS (m/z) ES+=237.1 (M+1)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:24]([N:23]([CH3:22])[C:8]([C:5]1[C:4]([C:11]#[N:12])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1cc(Br)cnc1C(=O)O
Reactant: CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Br)cc1C#N)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid (100 mg, 0.44 mmol) in dichloromethane (5 ml) at 0° C. were added DIPEA (0.226 ml, 1.32 mmol, 3 equiv.), methyl tert-butyl amine (0.079 ml, 0.661 mmol, 1.5 equiv.) and HBTU (250 mg, 0.661 mmol, 1.5 equiv.). The reaction mixture was stirred at 25° C. for 14 hours. The solvent was removed in vacuum and the resulting crude material was purified by column chromatography over normal silica gel (10-20% EtOAc in hexane) to afford 5-bromo-3-cyano-pyridine-2-carboxylic acid tert-butyl-methyl-amide (85 mg, 65%) as colorless oil.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].C[O-].[Na+].[C:12]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH2:13][CH3:14].Cl>CO>[OH:2][N:1]=[C:13]([CH3:14])[C:12]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CCC(=O)c1ccncc1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of isoamyl nitrite (2.6 ml) and sodium methoxide (28% in methanol, 3.4 ml) in methanol (40 ml) was added dropwise a solution of 4-propionylpyridine (2.0 g) in methanol (10 ml) under ice-cooling. The reaction mixture was stirred at ambient temperature for 3 hours, and then neutralized with 1N hydrochloric acid. After evaporation to remove methanol, the organic layer was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, evaporated and triturated with diisopropyl ether to give 4-(2-hydroxyiminopropionyl)pyridine (0.95 g).
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21](=S)=[S:22].C(O)C.[OH-].[K+]>O>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:21]([SH:22])=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A mixture of 5.28 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 2.3 parts of carbon disulfide, 80 parts of ethanol, 1.68 parts of potassium hydroxide and 11 parts of water was stirred for 3 hours at reflux temperature. After evaporation, 100 parts of water were added to the residue and the mixture was neutralized with 1.8 parts of a 0.03M acetic acid solution. After stirring, the precipitated product was filtered off, washed with 2-propanone and dried, yielding 4.3 parts (70.1%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzimidazole-2-thiol; mp. 260.1° C. (compound 225).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:12]([O-:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A suspension of 100g (463 mmol, 1.0 equiv.) of 4-nitrobenzyl bromide and 64.2 g (509 mmol, 1.1 equiv.) of sodium sulfite in 500 mL of methanol and 500 mL of water was heated to reflux. The progress of the reaction was monitored by TLC. When the bromide was consumed, the reaction mixture was allowed to cool to room temperature. The product precipitated and was collected by filtration. It was thoroughly dried for sixteen hours at 65° C. at 0.05 mm Hg to give 100 g (90%) of sodium 4-nitrobenzyl sulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][C:19]([C:27]([F:30])([F:29])[F:28])=[N:18]2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1>C(O)C>[C:1]([O:5][C:6]([N:8]([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([C:27]([F:28])([F:30])[F:29])=[N:18]2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCN1CCC(n2nc(C(F)(F)F)cc2C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 95 (1.09 g, 2.43 mmol) in ethanol (8.1 ml) was added a solution of NaOH (2.43 ml, 2N, 4.86 mmol) followed by THF (1.6 ml). After stirring at room temperature for 1 h, the mixture was taken to dryness and crude 96 was used as is for the next step. LRMS (ESI): calc. 420.4; found 421.3 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cnc2ccccc2c1
Yield: 99 %

Procedure:
Using general procedure C, 3-bromoquinoline was coupled with 2-pyrrolidinone with the reaction time of 15 h. Chromatography gave 210 mg (99%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 9.24 (d, 1H, J=2.7 Hz), 8.45 (d, 1H, J=2.4 Hz), 8.08 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.66 (t, 1H, J=7.7 Hz), 7.55 (t, 1H, J=7.5 Hz), 4.04 (t, 2H, J=7.2 Hz), 2.69 (t, 2H, J-8.1 Hz), 2.28 (p, 2H, J=7.8 Hz).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=1[O:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=3[O:29][CH3:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122.8 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone (4.3 g, 20.0 mmol), K2CO3 (3.0 g 21.8 mmol), acetonitrile (125 ml) and a catalytic amount of KI was heated to reflux and stirred under nitrogen for 24 hours. At this point, an additional amount of K2CO3 (1.0 g, 7.2 mmol) and alkylating agent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating at reflux was resumed for 24 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed with acetonitrile and the filtrate was concentrated to afford a dark oil. The oil was extracted with methylene chloride, and the organic extract was washed with water, dried with MgSO4 and concentrated to yield 9.2 g of an oil. Purification by preparative HPLC (Waters Associates Prep LC/System 500 utilizing 2 silica gel columns and 3% methanol/methylene chloride as eluent) provided 3.8 g of a soft, beige gum, which readily solidified. The compound was recrystallized twice from ethanol to give 2.1 g (28%) of 1-]4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxyl]-3-methoxyphenyl]ethanone as a beige solid, m.p.=98°-100° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1.O>[Zn].CCOCC>[Br:3][C:4]1[CH:5]=[C:6]([NH:10][NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Product: Brc1cccc(NNc2cccc(Br)c2)c1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a stirred solution of 50% NaOH (3.6 mL, 45 mM) was added 3-bromonitrobenzene (15 g, 74 mM) and the resulting solution was heated to 60° C. Zinc dust (11 g, 170 mM) was added in portions in such a manner as to keep the reaction temperature below 80° C. After the addition was complete, 20% NaOH (22 mL, 113 mM) was added followed by water (37 mL). An additional portion of zinc dust (14 g, 220 mM) was then added in one portion. The resulting mixture was heated at 70° C. for 1 hour, cooled to room temperature, and poured into ether (200 mL). The liquid was decanted away from the solids and the solids were resuspended in ether and this procedure was repeated an additional three times. The organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography afforded the titled compound as a white solid (10.1 g, 79%). NMR (CDCl3): 6.99 (m, 6H), 6.76 (dd, J1 =1 Hz, J2 =8 Hz), 5.66 (br s, 2H). MS(CI): 341/343(M+1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[C:12]([O:16][C:17](=[O:37])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35][Cl:36])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:39].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[C:12]([O:16][C:17](=[O:37])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:39])[C:25]=2[N:24]=[C:23]1[CH2:35][Cl:36])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (13.3 g of 77% max, 59.4 eq.) was added in portions over a period of 5 minutes to a solution of tert-butyl[3-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (8.9 g, 23.7 mmol) in chloroform (200 mL). The reaction mixture was allowed to stir at ambient temperature overnight. Ammonium hydroxide (50 mL) was added and the reaction mixture was stirred vigorously. Para-toluensulfonyl chloride (5.43 g, 28.5 mmol) was added over a period of 5 minutes. The reaction mixture was stirred at ambient temperature for 2 hours; an additional 1 g of para-toluensulfonyl chloride was added and the reaction mixture was stirred for another hour. The reaction mixture was filtered to remove solids. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with 1:1 water:saturated aqueous sodium bicarbonate (2×150 mL). The combined aqueous was extracted with dichloromethane (2×150 mL) and ethyl acetate (1×100 mL). The combined organic extracts were concentrated under reduced pressure to provide 13.6 g of crude product as a brown foam. The foam was dissolved in dichloromethane (20 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The first cartridge was eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 5% methanol in 1:1 ethyl acetate:hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes. The second cartridge was eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 7% methanol in 1:1 ethyl acetate:hexanes, and 7% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 4.3 g of tert-butyl[3-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light yellow foam.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][OH:7])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:7][CH2:6][CH:5]([NH:8][C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[CH2:4][O:3][CH2:1][CH3:2])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCC(CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOCC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (1-ethoxy-3-hydroxypropan-2-yl)carbamate (2.2 g, 9.4 mmol) in DCM (40 mL) was added methanesulfonylchloride (2.10 g, 18.8 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford 2-[(tert-butoxycarbonyl)amino]-3-ethoxypropyl methanesulfonate. MS ESI calc'd. for C11H24NO6S [M+H]+ 298. found 298. 1H NMR (400 MHz, CDCl3) δ 4.95 (s, 1H), 4.28 (d, J=8.0 Hz, 1H), 4.13-4.11 (m, 1H), 3.58-3.48 (m, 5H), 3.03 (s, 3H), 1.45 (s, 9H), 1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH2:36]([N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:42](Cl)=[O:43])[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:42](=[O:43])[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
To a suspension of 1.05 g (2.3 mmole) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]piperazine-2carboxylic acid hydrobromide (from Step C) in 20 ml of methylene chloride was added 1.23 g (9.5 mmole) of N,N-diisopropylethylamine followed by the dropwise addition of a solution of 523 mg (2.38 mmole) of dipentylcarbamoyl chloride (from Example 1, Step C-2) in 5 ml of methylene chloride. After stirring 24 hours at 25° C., the solution was extracted with 2N HCl, then H2O and dried over MgSO4. The dried methylene chloride solution was concentrated in vacuo and the residue was dissolved in isopropyl ether and was diluted with petroleum ether (bp. 30°-60° C.) until cloudy. The oil which precipitated was then decanted, redissolved in isopropanol and concentrated in vacuo to yield 464 mg (36%) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]-4-(dipentylcarbamoyl)piperazine-2-carboxylic acid as a glassy solid; TLC showed a single spot, Rf 0.75 (Analtech SGF plates developed with isoamyl alcohol:acetone:water [5:2:1]).
Reaction SMILES: [CH:1]1([N:7]([CH3:30])[C:8]2[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:10]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:7]([CH3:30])[C:8]2[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:10]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N(C)C2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N(C)C2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 67.4 %

Procedure:
To a solution of methyl 2-(2-(cyclohexyl(methyl)amino)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (61 mg; 0.15 mmol) in methanol (1.5 mL) was added a 10 N sodium hydroxide solution (149 μL; 1.489 mmol) and the mixture was heated at 100° C. for 18 h. The volatiles were removed under reduced pressure and the mixture was acidified by adding 6N hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The compound was precipitated from a mixture of ethyl acetate and heptane and the formed solid was triturated with heptane to give 40 mg (68%) of the title compound as a white solid. ESI/APCI(+): 396 (M+H). ESI/APCI(−): 350 (M−CO2H); 394 (M−H).
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:28][C@@H:27]([P:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([P:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:25]1)=O)(O)=O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:28]1[N:24]([CH2:22][C:21]2[CH:2]=[CH:1][CH:16]=[CH:19][CH:20]=2)[CH2:25][C@@H:26]([P:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:27]1[P:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCCC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)[C@H](P(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: c1ccc(CN2C[C@@H](P(c3ccccc3)c3ccccc3)[C@H](P(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 369.9 %

Procedure:
Preparation of polyester-supported DUGPHOS ligand. DCC (40 mg, 0.194 mmol) was added to a mixture of the above OH-terminating polyester (Mw=4200, 0.390 g, ~0.186 mmol OH), (3R, 4R)-N-(4-carboxybutanoyl)-3,4-bis(diphenylphosphanyl)pyrrolidine (120 mg, 0.223 mmol), and DMAP (5 mg, 0.041 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 12 h at ambient temperature and the urea precipitate was removed by filtration. Methanol was then slowly added to the resulting filtrate under stirring, and the precipitated polyester-supported DEGPHOS ligand was then isolated by filtration, and washed with cold methanol and dried in vacuo to give 380 mg polymeric DEGPHOS ligand (96% theoretical yield): ##STR16## The analytical data for this new material are as follows:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[F:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][N:23]=1.[I:29][CH3:30]>C1COCC1>[F:21][C:22]1[C:27]([CH3:26])=[C:30]([I:29])[CH:25]=[CH:24][N:23]=1
Reactant: Fc1ncccc1I
Reactant: CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c(I)ccnc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78° C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78° C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78° C. The mixture is quenched with saturated sodium bicarbonate solution at -78° C. and then extracted with ether. Combined ether extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72%) of product as an off-white solid having amp of 90-91 ° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2].[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)c(C(C)=O)c2ccccc21
Reaction time: 8 h
Yield: 84.5 %

Procedure:
1 g of (75) was dissolved in 25 ml THF. 250 mg NaH was added, and then 1.87 g of (2-methyloxyethyl)oxymethylchlorid. The reaction was left with stirring overnight, another 100 mg NaH was added, and the reaciton continued another 4 hours. The reaction mixture was added to a 2N K2 CO3 solution and extracted with toluene. The organic phase was washed with water and brine, dried and evaporated. The resulting oil was extracted twice with boiling heptane, cooled, filtered, and evaporated giving 1.23 g of (80) as a yellow oil. 1H-NMR (ppm): 8.35(m, 1H); 7.44(m, 1H); 7.27(m, 2H); 5.62(s, 2H); 3.58(m, 2H); 3.47(m, 2H); 3.32(s, 3H); 2.65(s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (11.5 g, 38.4 mmol), imidazole (7.84 g, 115.2 mmol) and DMAP (234 mg, 1.92 mmol) in CH2Cl2 (200 mL) was added a solution of TBSCl (8.68 g, 57.6 mmol) in CH2Cl2 (100 mL) dropwise. The reaction mixture was stirred at rt for overnight. The reaction was washed with water (100 mL) and the aqueous layer was extracted with CH2Cl2 (3×100 mL), the combined organic layers was washed with brine (70 mL), then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (9 g, 57%).