Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H](N[C:24](=[O:43])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:26]=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.O=C1CCCN1C1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[CH:65]12[CH2:71][CH:68]([CH2:69][CH2:70]1)[CH2:67][CH:66]2[NH:72][C:73](=[O:90])[C@H:74]([CH2:87][C:88]#[CH:89])[CH2:75][C@H:76]([OH:86])[C@@H:77]([NH2:85])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[CH2:78]([C@H:77]([NH:85][C:24](=[O:43])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:26]=1)[C@@H:76]([OH:86])[CH2:75][C@H:74]([C:73](=[O:90])[NH:72][CH:66]1[CH2:67][CH:68]2[CH2:71][CH:65]1[CH2:70][CH2:69]2)[CH2:87][C:88]#[CH:89])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: C#CC[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Agent: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: C#CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E5 from 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D8) and (2R,4S,5S)-5-amino-4-hydroxy-6-phenyl-2-prop-2-ynylhexanoic acid bicyclo[2.2.1]hept-2-ylamide (D36).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([CH3:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:23][C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[C:10]4[CH:9]=[C:8]([CH3:24])[CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[NH:1][C:33]2=[O:35])=[CH:14][CH:15]=1)([CH3:22])[C:20]#[N:21]
Reactant: Cc1ccc2ncc(N)c(Nc3ccc(C(C)(C)C#N)cc3)c2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-methyl-quinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation J, 190 mg, 0.6025 mmol) and triethylamine (0.12 ml, 0.901 mmol) in CH2Cl2 (10 mL) was added over 40 min to a solution of triphosgene (195 mg, 0.6139 mmol) in 5 mL of CH2Cl2 at 0° C. The reaction mixture was stirred for 20 min at this temperature then was quenched with saturated aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to obtain the title compound as brown solid. Yield: 145 mg (70%); 1H NMR (DMSO-d6, 300 MHz): δ 11.641 (s, 1H), 8.678 (s, 1H), 7.864-7.892 (d, 1H, J=8.4 Hz), 7.782-7.810 (d, 2H, J=8.4 Hz), 7.629-7.657 (d, 2H, J=8.4 Hz), 7.342-7.371 (d, 1H, J=8.7 Hz), 6.625 (s, 1H), 2.147 (s, 3H), 1.801 (s, 6H); MS: m/z 343 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].Cl.[CH3:20][NH:21][CH3:22].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][N:21]([CH3:22])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18]
Reactant: CNC
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CN(C)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.12 mmol), dimethylamine hydrochloride (911 mg, 11.16 mmol), potassium iodide (1.85 g, 11.16 mmol) and potassium carbonate (1.54 g, 11.16 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile was added, and the yellow suspension stirred at room temperature for 18 hours. The reaction was placed in a heating block at a temperature of 60° C. for 2 hours. After cooling to room temperature, the reaction was filtered through celite and the celite pad washed with methanol and the filtrate concentrated to afford a yellow solid. No further purification was performed. Yield: 520 mg crude material. 1H NMR (DMSO) δ: 8.11 (d, J=2.4 Hz, 1H), 8.06 (dd, J=2.7 Hz, 9.3 Hz, 1H), 7.41 (d, J=9 Hz, 1H), 3.94 (t, J=7.2 Hz, 2H), 2.99 (t, J=6.9 Hz, 2H), 2.73 (s, 6H), 2.59 (t, J=8.1 Hz, 2H), 2.45 (t, J=1.5 Hz, 2H), 1.86 (t, J=7.5 Hz, 2H). MS (ESI): 278.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[O:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.N1CCCCC1>CO.C(OCC)(=O)C>[O:1]=[C:2]1[C:11](=[CH:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCOCC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCOCC1)C2=O
Yield: 49.4 %

Procedure:
A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.9 mmol), tetrahydro-pyran-4-carbaldehyde (3.2 mmol), and piperidine (3.2 mmol) in 6 mL of methanol was heated to 65° C. overnight. The cooled mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel, eluting with ethyl acetate in hexane from 10% to 40%, to give 430 mg of the desired product. ES-MS m/z 301 (M+H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][NH:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:51]#N.[Na+].CCOC(C)=O>CC(O)=O>[C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:51])[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C12CNOC(C(n3ccc(=O)[nH]c3=O)O1)C2OCc1ccc2ccccc2c1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2OCc1ccc2ccccc2c1

Procedure:
To a solution of compound 52 (1 mmol) in CH3COOH (5 mL) and trithylortoformate (1 mL), 20% aq. HCHO (0.16 mL, 1.1 mmol) was added at 0° C. After 15 minutes NaBH3CN (2 mmol) is added. After an additional 1 hour the mixture is poured into EtOAc (250 mL), washed with saturated aqueous NaHCO3 (2×250 mL), dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography gave compound 53 in 90% isolated yield.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:25])[C@@H:10]([C:22]([OH:24])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([CH2:28][CH2:27][N:11]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:10]([C:22]([OH:24])=[O:23])[C@@H:9]([CH3:25])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(CCO)OCc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@@H](C(=O)O)N(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of O-benzyl-N-benzyloxycarbonyl-L-threonine (1.15 g), benzyl 3-hydroxypropionate (604 mg) and 4-N,N-dimethylaminopyridine (41 mg) in methylene chloride (20 ml) was added N,N-diethylaminopropyl-N'-ethylcarbodiimide hydrochloride (641 mg) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for an hour. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed successively with 0.1 N hydrochloric acid, water, 10% aqueous sodium hydrogen carbonate, water and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on silica gel eluting successively with a 1:1 mixture of methylene chloride and hexane, methyl chloride and a 50:1 mixture of methylene chloride and acetone to give 2-benzyloxycarbonylethyl O-benzyl-N-benzyloxycarbonyl-L-threonine (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][NH:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][NH:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CNC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: CNC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)CC1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid methyl-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH:11]C(OCC2C=CC=CC=2)=O)[O:8][CH:9]=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH2:11])[O:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1coc(CNC(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1coc(CN)n1
Temperature: 20 °C
Yield: 83.4 %

Procedure:
2-(Benzyloxycarbonylaminomethyl)oxazole-4-carboxylic acid methyl ester (0.439 g) (prepared as described in; Journal of Peptide Science (1999), 5(9), 392-398) was dissolved in ethyl acetate (13 ml) and hydrogenated with vigorous stirring at 20° C. and 1 atmosphere of pressure using 10% palladium on carbon catalyst (0.20 g) for 4 hours. The mixture was filtered using celite filter aid and the solvent evaporated from the filtrate in vacuo to give the title compound as a yellow solid (0.197 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([C:36]2[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[CH3:41][N:40]1[C:36]([C:34]([NH:33][C:29]2[CH:28]=[C:27]([C:25]#[C:26][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]4[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=4)([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:32]=[CH:31][CH:30]=2)=[O:35])=[CH:37][C:38]([CH3:42])=[N:39]1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 460, methyl (3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate (202 mg, 0.492 mmol) and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (153 mg, 0.64 mmol), were converted to the title compound as a light yellow solid foam (275 mg, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)N2CCOCC2)C1

Procedure:
Using 1-benzyloxycarbonyl-4-(t-butoxycarbonyl)-piperazine-2-carboxylic acid and morpholine, 1-benzyloxycarbonyl-4-(t-butoxycarbonyl)-2-[(morpholin-4-yl)carbonyl]piperazine was obtained in a similar manner to Example 4 to be mentioned below. In ethyl acetate, a 4M hydrogen chloride/ethyl acetate solution was added thereto and the whole was reacted to obtain 1-benzyloxycarbonyl-2-[(morpholin-4-yl)carbonyl]piperazine. The compound was heated to reflux for 1 day in toluene in the presence of bromobenzene, tris(dibenzylideneacetone)dipalladium(0), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium t-butoxide to obtain 1-benzyloxycarbonyl-2-morpholinocarbonyl-4-phenylpiperazine. Further, thus obtained compound was stirred at room temperature for 1.5 days in ethanol in the presence of 10% palladium/carbon under a hydrogen atmosphere of normal pressure. After filtration of insoluble matter, the residue obtained by evaporation of the solvent was dissolved in ethanol, 10% palladium/carbon and ammonium formate were added thereto, and the whole was stirred at an oil bath temperature of 70° C. for 2.5 days to obtain an objective compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20][SH:21].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:20]([S:21][C:13](=[O:15])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:16]([CH3:18])[CH3:17])[CH3:19]
Reactant: CCS
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution containing (R)-2-benzyloxycarbonylamino-3-methyl-butyric acid (5.0 g, 20.0 mmol) in anhydrous CH2Cl2 (20 mL) is added DMAP (258 mg, 2.0 mmol) followed by chilled EtSH (1.6 mL, 22.0 mmol). Dicyclohexylcarbodiimide (4.5 g, 22.0 mmol) is added in one portion and the reaction is complete after 30 min. The solid material is removed by vacuum filtration and the filtrate is concentrated. The crude product is purified by flash silica gel chromatography (hexane to 8:1 hexane/EtOAc) to provide (R)-2-benzyloxycarbonylamino-3-methyl-thiobutyric acid S-ethyl ester (5.21 g, 88%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ0.85 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 2.27 (m, 1H), 2.88 (q, J=7.5 Hz, 2H), 4.35 (dd, J=9.5, 4.6 Hz, 1H), 5.13 (s, 2H), 5.25 (br d, J=9.5 Hz, 1H), 7.30-7.36 (m, 5H) ppm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[C:4]([CH2:11]Br)[CH:3]=1.C1C[O:16]CC1.[OH-].[Li+].Cl>O.CO>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([CH2:11][OH:16])[CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1sc(Br)cc1CBr
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(Br)cc1CO
Temperature: 90 °C

Procedure:
In a 15 mL microwave reaction vial, was added methyl 5-bromo-3-(bromomethyl)thiophene-2-carboxylate (700 mg, 2.23 mmol), THF (4 mL) and MeOH (1 mL). To above solution was added lithium hydroxide (53.4 mg, 2.23 mmol, 1.0 eq) in water (1 mL). The reaction was heated in microwave reactor for 30 min at 90° C. The reaction was cooled down to r.t., neutralized with 1N HCl, extracted with EtOAc, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 235.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)cc(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (see example 16) (1.0 g, 2.78 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (1.36 g, 3.34 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 1 h, then isopropyl 2-bromoacetate (624 mg, 3.34 mmol, 1.2 eq) was added and the reaction mixture was stirred for h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue obtained was purified by column chromatography, (EtOAc:petroleum ether 0:1 to 1:20) to give the title compound as a colourless oil (0.8 g, 62%).
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4](=[NH:8])[O:5]CC.[O:16]1CCC[CH2:17]1>C1(C)C=CC=CC=1>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:3]1[O:2][C:17](=[O:16])[NH:5][C:4]1=[O:8]
Reactant: CCOC(=N)C(O)c1ccccc1C
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 3, ethyl 1-hydroxy-1-(2-methylphenyl)methanecarboximidate hydrochloride (14.4 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-methylphenyl)oxazolidine-2,4-dione (9.1 g., 77%, m.p. 111°-113° C., m/e 191).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:13])[C:10]=2[CH:11]=O)[CH:7]=1.Cl.[NH2:15][CH2:16][CH:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19](OCC)=[O:20].C(N(CC)CC)C.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:13])[C:10]=2[CH2:11][N:15]2[CH2:16][CH:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]2=[O:20])[CH:7]=1
Reactant: CCCC(CN)CC(=O)OCC
Reactant: Cc1nn2cc(Br)cnc2c1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(C)nn3cc(Br)cnc23)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21 (0.83 mmol, 1 eq, 200 mg) in MeOH (10 ml), is added ethyl 3-(aminomethyl)hexanoate hydrochloride x31 (0.916 mmol, 1.1 eq, 192 mg) and the resulting solution is stirred at room temperature for 5 minutes. Triethylamine (0.916 mmol, 1.1 eq, 128 □l) is then added and the mixture is heated at 65° C. for 1 hour. After this time1 hour, sodium borohydride is added (0.916 mmol, 1.1 eq, 34 mg). The reaction mixture is then heated at 65° C. for 2 hours. Water (100 ml) is added and the resulting mixture is extracted with CH2Cl2 (3×100 ml). The combined organic layers are combined, washed with brine (100 ml) and dried over MgSO4. Volatiles are removed under reduce pressure and purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 97/3/0.3) to give 130 mg of 1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 184 as a solid.
Reaction SMILES: [CH2:1]([SH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[H-].[Na+].Br[CH:25]1[CH2:28][CH2:27][CH:26]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[CH2:1]([S:21][C:26]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28][CH2:25]1)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Reactant: CCOC(=O)C1CCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC1(C(=O)OCC)CCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene-1-thiol (305 mg, 1.00 mmol) in dry DMF (10 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). After fifteen minutes ethyl 2-bromo-cyclobutane carboxylate (170 μL, 1.05 mmol) was added and the mixture was stirred for 1.5 hour at 0° C. The reaction was quenched by addition of sat. aq. NH4Cl (20 mL). Heptane (50 mL) was added, and the phases were separated. The water phase was extracted with heptane (2×25 mL). The combined organics were washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated to give 409 mg of the title compound as a crude oil. Purification by flash chromatography on silica gel using isocratic elution (heptane:acetone 98:2) afforded 243 mg (56% yield) of the title compound as oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[CH:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[Br:28][C:26]1[CH:27]=[C:22]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (2.00 g, 7.18 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.87 g, 10.77 mmol), Pd2(dba)3 (657 mg, 0.718 mmol), XantPhos (665 mg, 1.15 mmol), Cs2CO3 (7.72 g, 23.7 mmol) and dioxane (40 mL) were added. The reaction mixture was heated at 100° C. for 40 hrs. Ethyl acetate (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Methylene chloride/ether (1:2, 5 mL) was added followed by sonication, the precipitate was filtered as 301a, yellow solids, 1.946 g (58%).