Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][SH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:32])[C:23]([CH3:31])([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH3:24])=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[SH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][S:8][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[O:32])[C:23]([CH3:24])([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH3:31])=[CH:20][CH:21]=1
Reactant: SCCCCCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)c1ccc(SCCCCCCS)cc1)N1CCOCC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
10.0 g (0.066 mol) of 1,6-hexanedithiol are added to a suspension of 3.6 g (0.026 mol) of potassium carbonate in 15 ml of dimethylacetamide. The suspension is heated to 85° C., and a solution of 3.6 g (0.013 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 20 ml of dimethylacetamide is added dropwise over 20 min. After stirring for 18 h, the reaction mixture is cooled, diluted with ethyl acetate (60 ml), and filtered. The filtrate is washed with water (3×50 ml), dried over MgSO4, and concentrated i.v. (85° C./5 mm Hg). The resulting oil is purified by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to a pale yellow oil which crystallizes to a colorless solid upon standing. m.p. 61-64° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.35 (t, SH), 1.4-1.8 (m, 8H), 2.53 (q, 2H), 2.57 (t, 4H), 3.00 (t, 2H), 3.69 (t, 4H), 7.24 (d, 2H), 8.50 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (8.6 g) was dissolved in DMF (60 ml) and triethylamine (12 ml) was added. 1,1-Dimethylethyl (2-bromoethyl)-carbamate (7.8 g) was added and the solution was stirred at room temperature for 12 hours. Diethyl ether/water (1:1500 ml) was added and the organic phase was separated, dried (MgSO4) and evaporated. Purification by chromatography (dichloromethane: methanol: NH3 (aq) 98.5:1:0.5) gave the subtitle compound (10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][CH:9]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[N:31][CH:32]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncc(Cl)c1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 16 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with 5-chloropyridin-3-ylboronic acid yielded the title compound (16% yield) as a grey solid. MS (ISP): m/z=442.3 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]1.[N+:31](/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]>C1COCC1>[N+:31]([CH2:34][CH:35]([C:16]1([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18][CH2:19][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][CH2:15]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C[N+](=O)[O-])c2ccccc2)CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of diisopropylamine (667 ul, 4.68 mmol) in THF (dry) (4 ml) was treated with n-BuLi (1.6M in hexanes) (2.93 ml, 4.68 mmol). After 5 minutes, the mixture was allowed to warm to RT and then re-cooled to −78° C. This mixture was added dropwise to a cooled (−78° C.) solution of 1-tert-butyl 4-methyl azepane-1,4-dicarboxylate (step 1) (927 mg, 3.6 mmol) in THF (4 ml). The reaction mixture was stirred at −78° C. for 40 minutes. To this mixture was added (E)-(2-nitrovinyl)benzene (537 mg; 3.6 mmol) in THF (4 ml) and the resulting mixture was allowed to warm slowly to RT. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc followed by 10-100% TBME in iso-hexane afforded the title compound as a diastereomeric mixture.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[N:3]1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=2)[N:13]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([N:6]1[CH2:5][C@H:4]([CH3:8])[N:3]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)[C@@H:2]([CH3:1])[CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CNC[C@@H]3C)nc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C(C)=O)C[C@@H]3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To an ice-cold solution of methyl 2-((2S,6S)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate (273 mg, 0.943 mmol) in CH2Cl2 (5 mL) was added pyridine (0.114 mL, 1.41 mmol) followed by acetyl chloride (0.100 mL, 1.41 mmol) under an atmosphere of nitrogen. The mixture stirred for 18 h while gradually warming to room temperature. The reaction was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL), 1 N HCl solution (10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (0% to 50%, 95:15:1.5, CH2Cl2/CH3OH/concentrated NH4OH in CH2Cl2) to give methyl 2-((2S,6S)-4-acetyl-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate as an oil (62.1 mg, 20%). 1H NMR and MS consistent.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:22][NH:21][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: NNC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nccc(I)c1C(=O)NNC1CCOCC1
Yield: 81.2 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (1.75 g) obtained in Step C of Example 6, tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride (0.957 g), DIEA (2.2 mL), EDCI hydrochloride (1.44 g) and HOBt (1.02 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (1.55 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.[Al].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:24][C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:14](=[O:15])[NH:13][CH:12]=1
Reactant: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Reaction time: 1 h

Procedure:
8-Fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (10 g, 49 mmol) was dissolved in 400 mL DMF and covered with aluminum foil. NBS was added in a single portion and the solution was stirred for 1 hr at which time the reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered, concentrated. The crude residue purified on silica gel and eluted with EtOAc/hexanes (0 to 75% gradient elution).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:20][C:21]1[C:26]2[CH:27]([C:33]([O:35][CH3:36])=[O:34])[CH2:28][C:29]([CH3:32])([CH3:31])[O:30][C:25]=2[CH:24]=[C:23]([C:37]([CH3:45])([CH3:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]>CCCCCC.CCCCCC.C(OCC)C.C1COCC1>[CH2:13]([O:20][C:21]1[C:26]2[C:27]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])([C:33]([O:35][CH3:36])=[O:34])[CH2:28][C:29]([CH3:32])([CH3:31])[O:30][C:25]=2[CH:24]=[C:23]([C:37]([CH3:44])([CH3:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2(CC(=O)OCC)C(=O)OC
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under anhydrous conditions, under a nitrogen atmosphere 5.31 ml. of 1.6 molar n-butyllithium in hexane is charged to a flask containing 80 ml. dry tetrahydrofuran at -78° C. A solution of 1.2 ml. (848 mg., 8.4 mmole) freshly distilled diisopropylamine is added dropwise and the resulting mixture stirred at -78° C. for three hours. Then a solution of 3.1 g. (6.85 mmole) methyl 5-benzyloxy-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran-4-carboxylate (Example 88, Part B) in 10 ml. THF is added slowly and the resulting mixture stirred for three hours at -78° C. To this is added dropwise 1.40 g. (8.4 mmole) ethyl bromoacetate and the mixture stirred for 15 minutes. The reaction is quenched by addition of acetic acid and the mixture allowed to warm to ambient temperature. The product was isolated by the procedure described in Example 3, Part A, to obtain 2.89 g. (78%) of the desired diester, Rf 0.29, hexane/ethyl ether, 3:1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].FC(F)(F)C(O)=O.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:13]([C:3]1[C:2]([NH:1][CH:23]([CH3:25])[CH3:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:14]
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1cc(NC(C)C)c(C#N)cc1C
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Methyl 5-amino-4-cyano-2-methylbenzoate (synthesized in reagent preparation 41, step 4) (240 mg, 1.26 mmol) was dissolved in 1,2-dichloroethane (7 mL) and was treated with trifluoroacetic acid (0.6 mL, 7.57 mmol), acetone (0.28 mL, 3.79 mmol), and sodium triacetoxyborohydride (802 mg, 3.78 mmol) at 45° C. for 20 min. The reaction mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate and was partitioned with dichloromethane. The aqueous portion was extracted with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10% dichloromethane in hexanes) to afford methyl 4-cyano-5-(isopropylamino)-2-methylbenzoate (224 mg, 0.96 mmol, 76% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.16 (s, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 3.77-3.74 (m, 1H), 2.40 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H); MS (EI) for C14H16N2O2: 233 (MH+).
Reaction SMILES: [F:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](F)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CNC[C@@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of (±)-1,1-dimethylethyl cis-3-fluoro-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.45 g, 1.28 mmole) in DCM (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3 hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (5.12 mmole, 1.9 g) was added with vigorous stirring at RT. After 4 h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.32 g, 99%) as a light orange oil: LC-MS (ES) m/e 253 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl.N1C=CC=CC=1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
2.0 g (9.3 mmol) L-phenylalanine methylester hydrochloride and 1.73 g (9.3 mmol) 4-nitrobenzoyl chloride were dissolved in a mixture of 10 ml dichloromethane and 5 ml pyridine and stirred over night at room temperature. The mixture was evaporated in vacuo, while a colorless solid precipitated, which was filtered by suction, recrystallized from ethanol, washed with diisopropylether, and dried in vacuo to give the title compound in colorless needles,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[O:25])[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.9 %

Procedure:
1.0 g (2.97 mmol) of N-({3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide is suspended in 20 ml methanol/5 ml acetone in a 100 ml one neck round bottom flask. The suspension is treated with sodium meta periodate (666 mg, 3.12 mmole) in 20 ml water and the reaction mixture is stirred 48 hours at room temperature. The organics are removed in vacuo and the aqueous residue is filtered to remove a fine white solid. The solid is washed with water followed by diethyl ether to give 902 mg the title compound) as a solid. mp=204-205° C.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].Cl>O1CCOCC1.O1CCCC1.O.C(N(CC)CC)C>[CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:8])[CH3:2]
Reactant: NCC(=O)O
Reactant: C/C=C(/C=C/C(=O)O)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C/C=C(/C=C/C(=O)NCC(=O)O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of (E,E)-4-ethyl-2,4-hexadienoic acid (2.8 g) and N-hydroxysuccinimide (2.3 g) in dioxane (20 ml) was added dicyclohexylcarbodiimide (4.32 g). The mixture was stirred at ambient temperature overnight and then filtered. The filtrate was concentrated to dryness under reduced pressure to give a residue which was dissolved in tetrahydrofuran (100 ml). To the solution was added a solution of glycine (4.5 g) and triethylamine (8.34 ml) in water (60 ml). The resulting mixture was stirred at ambient temperature for 5 hours, acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure to give a crystalline residue. The residue was triturated with a mixture of chloroform and hexane to give N-[(E,E)-4-ethyl-2,4-hexadienoyl]glycine (1.72 g).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].[BH4-].[Na+].C(O)(=O)C>O>[OH:8][CH:7]([C:4]1[CH:5]=[CH:6][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2][CH:3]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A 25.4 g. portion of 3-(4-biphenylylcarbonyl)propionic acid is dissolved in 2 liters of water made alkaline with sodium hydroxide. A 37.8 g. portion of sodium borohydride is added and the mixture is stirred for 2 hours. The suspension is then slowly poured into 100 ml. of glacial acetic acid. The mixture is cooled and the resulting solid is filtered, washed with water and dried giving the desired product, m.p. 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-chlorophenyl)-isoxazole-4-carboxylic acid (51.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/Acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H17ClN2O2: 352.0979, found 352.0980.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[N:25]1([C:31]2[N:32]=[C:33]([CH2:38][C:39]([O-])=[O:40])[NH:34][C:35](=[O:37])[CH:36]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:39](=[O:40])[CH2:38][C:33]1[NH:34][C:35](=[O:37])[CH:36]=[C:31]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:32]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1(C)CNc2cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.3 %

Procedure:
130 mg of 4-chloro-3,3-dimethyl-2,3-dihydro-1H-indole [which can be prepared according to Tet. Let. (1987) (28), 5291-5294] and 220 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 187 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2c of example 1c) in 3 ml of N,N-dimethylformamide and 3 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours and then 15 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05: v/v), so as to give 24 mg of 2-[2-(4-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:10]#[N:11])[S:13][C:14]=2[CH:20]=1
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccccn3)cc2s1
Yield: 72 %

Procedure:
(Bromomethyl)pyridine hydrobromide (1.87 g, 7.38 mmol) and 2-cyano-6-hydroxybenzothiazole (1.00 g, 5.68 mmol) were suspended in acetone (50 mL). After introduction of potassium carbonate (1.96 g, 14.2 mmol), the suspension was refluxed for 72 h under nitrogen. After cooling down the mixture and filtering the solids, the filtrate was concentrated and the residue was purified by silica gel chromatography using 50%-75% ethyl acetate in heptane. A yellowish solid was obtained in 72% yield. MS (ESI+): m/z 267.90 (M+H)+; calc'd: 268.05.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([S:10][CH3:11])=[N:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOC(C)=O>[CH3:15][O:14][C:12]([C:3]1[N:4]=[C:5]([S:10][CH3:11])[N:6]([CH3:9])[C:7](=[O:8])[C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(SC)n(C)c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(SC)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 18.7 %

Procedure:
In a round-bottomed flask, methyl 5-hydroxy-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (55.0 g, 239 mmol) and potassium carbonate (33.0 g, 239 mmol) were combined with DMF (200 ml) to give a black suspension. Benzyl bromide (40.9 g, 239 mmol) was added and the resulting mixture was stirred at room temperature for 3.5 days. The reaction was quenched by the addition of cold water. The mixture was filtered to provide a brown solid. Chromatography (SiO2; 10% to 50% EtOAc in hexanes) provided the desired product as an off-white solid (14.3 g; 18%). LCMS: m/z=321 (MH+).