Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)[C:2]#N.[Br:9][CH2:10]CBr.O=O.C[O-].[Na+]>O.CCOCC.CO>[Br:9][CH2:10][CH2:2][S:1][C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: N#CSc1ccc[nH]1
Agent: C[O-]
Agent: O=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: BrCCSc1ccc[nH]1

Procedure:
A stirred mixture of 2-thiocyano-pyrrole (8.7 g, 0.07 m; J. Org. Chem., 22 (1957) 1500), 1,2-dibromoethane (155 ml) and methanol (140 ml) was ice-bath cooled in an oxygen-free atmosphere, and sodium methoxide (9.5 g, 0.17 m) added. The resultant highly-colored mixture was allowed to stir cold and then at ambient temperature overnight. The resultant mixture was distributed between ether and water (500 ml), the ether extracts washed, dried and concentrated to a residue which on chromatography on silica gel using a hexane and then 20% ethylacetate/hexane system as eluant yielded 2(2-bromoethylthio)pyrrole (4.6 g). This was dissolved in dry N,N-dimethylformamide (80 ml), covered with an oxygen-free atmosphere, ice-bath cooled, and reacted with sodium hydride (1.2 g of 60% dispersion in mineral oil). After stirring overnight at ambient temperatures the reaction mixture was partitioned between ether and water, the ether layer washed with water until the dimethylformamide was removed, dried and concentrated to 2,3-dihydropyrrolo(2,1-b)thiazole.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:17]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CC(C)=O.[OH-].[Na+].O>[C:1]([NH:8][CH:9]([C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC(=O)CCC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)CCC(=O)O

Procedure:
A solution of the keto-ester (5) (16.0 mg, 0.046 mmoles) in acetone (0.39 ml) and sodium hydroxide (0.118 M, 0.39 mls) is stirred at room temperature for 2.0 hours. The solution is diluted with water and extracted once with ethyl acetate. The aqueous phase is acidified to pH 3 with citric acid and extracted thrice with ethyl acetate. The ethyl acetate is washed with water and saline and dried over magnesium sulphate. Evaporation of the solvent affords the pure keto-acid (6). (14.7 mg, 100%) as a colourless gum. νmax (CHCl3): 1710, 1490 cm-1. τ(CHCl3): 2.8 (5H, multiplet, C6H5), ca 3.6 broad (D2O-exchangeable, COOH), 4.95 (1H multiplet, D2O-exchangeable, NH), 5.66 (1H, multiplet, CH), 6.86-7.65 (6H, complex, 3×CH2), 8.62 (9H, s, BOC--tBu).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CCN(CC)CC>C(Cl)Cl.C(Cl)Cl.CS(C)=O>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: OCc1ccc(-c2ccncc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccncc2)cc1
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride in CH2Cl2 (15 mL, 1M) is added, dropwise, DMSO (3 mL). The resulting solution is stirred for 5 minutes then a solution of 4-[pyridin-4-yl]-benzyl alcohol (2.80 g, 15 mmol) (reference example 13a) in CH2Cl2/DMSO (27 mL, 3:1 CH2Cl2/DMSO) is added dropwise. The resulting mixture is stirred 5 minutes then Et3N added (15 mL, 108 mmol) in one portion. The cold bath is removed and stirring continued for 15 minutes. The reaction mixture is then diluted with ethyl acetate, washed with water and then brine, dried over MgSO4 and concentrated. The crude, orange solid product is used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:11]=[C:12]=[O:13]>[Sn].O>[CH2:4]([N:11]=[C:12]=[O:13])[CH2:5][CH2:6][CH2:6][CH2:5][CH2:4][N:11]=[C:12]=[O:13].[CH3:1][CH2:2][O:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [N-]=C=O
Agent: [Sn]
Solvent: CCOCCC(=O)OCC
Solvent: O
Product: O=C=NCCCCCCN=C=O

Procedure:
In order to prepare the test coating, 100 grams of the above oligomer were mixed with 0.1 gram of T-12 tin catalyst, and 20 grams of EEP solvent. A second component was prepared from 126.4 grams of isocyanate multifunctional oligomer biurets formed by the reaction product between hexamethylene diisocyanate and water and 20 g of EEP solvent. Three mil wet films were cast from the mixed components which dried hard in two hours and had a Sward hardness of 10 in 24 hours.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16](=O)OC(C)(C)C)[CH2:9][CH2:8]1>O1CCCC1>[CH3:16][NH:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][O:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCN1CCOCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution of LiAlH4 (7.72 g, 208.65 mmol, 3.00 equiv) in tetrahydrofuran (60 mL) at 0-5° C. was added dropwise a solution of tert-butyl 2-morpholinoethylcarbamate (16 g, 62.61 mmol, 1.00 equiv, 90%) in tetrahydrofuran (40 mL). The resulting solution was then stirred for 2 h at 70° C. in an oil bath. The reaction was then quenched by the addition of 7.7 mL of water, 7.7 mL of 15% sodium hydroxide, and 23.1 mL of water. The solids were filtered out. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (0.5% triethylamine) (20:1) to afford 4.2 g (42%) of N-methyl-2-morpholinoethanamine as a brown oil.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C([O:17][C@@H:18]1[C@H:22]([O:23]C(=O)C2C=CC=CC=2)[C@@H:21]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[O:20][C@H:19]1[N:42]1[CH:50]=[N:49][C:48]2[C:43]1=[N:44][C:45]([Cl:52])=[N:46][C:47]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:52][C:45]1[N:46]=[C:47]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]2)[C:48]2[N:49]=[CH:50][N:42]([C:43]=2[N:44]=1)[C@@H:19]1[O:20][C@H:21]([CH2:32][OH:33])[C@@H:22]([OH:23])[C@H:18]1[OH:17]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCCC(O)C1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCC(O)C4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 7.6 %

Procedure:
The title compound was prepared according to method A as described above by reacting 1-amino-3-hydroxypiperidine (prepared from 3-hydroxypiperidine as outlined in Example 6) (0.60 g, 5.9 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 3.94 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-(3-hydroxypiperidinyl) adenosine (0.12 g, 8%) (after column chromatography) as a foam (a mixture of diastereoisomers); 1H NMR (DMSO-d6) δ 3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, m, H-2'), 5.08 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 8.43 (1H, br s, H-8), 9.45 (1H, 2 br s, N--H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14](=[O:16])[CH3:15])=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1.[Br-:17].[Br-].[Br-].C([N+](CC)(CC)C1C=CC=CC=1)C.C([N+](C1C=CC=CC=1)(CC)CC)C.C([N+](C1C=CC=CC=1)(CC)CC)C>O1CCCC1>[Br:17][CH2:15][C:14]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1)=[O:16]
Reactant: CC(=O)c1ncc(OCC(F)(F)F)cc1Cl
Reactant: [Br-]
Agent: CC[N+](CC)(CC)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 189.3 %

Procedure:
To 1.1 g of 1-[3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanone in 20 ml of tetrahydrofuran, 1.6 g of triethylphenylammonium tribromide was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the precipitated solid was filtered off through celite, and the solvent was evaporated under reduced pressure to obtain 1.3 g of the desired crude product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>C1COCC1>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:20])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)CCCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Temperature: 70 °C

Procedure:
Dissolve trans-5-chloro-pentanoic acid-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-amide (22.7 g, 65.1 mmol) in anhydrous THF (500 mL), add sodium hydride (60% dispersion in mineral oil, 13.0 g, 0.32 mol) by portions and heat the reaction mixture at 70° C. for 18 hours. Cool the reaction mixture to room temperature, quench with water (200 mL) and extract with DCM (3×100 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain trans-1-(4-[tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one as a white solid (15.0 g, 74%): MS (ES+) m/z=312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][S:22][CH2:23][CH2:24][CH:25]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:25][CH2:24][CH2:23][S:22][CH3:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CSCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCSC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (150 mg, 0.547 mmol) in 1,2 dichloroethane (2 mL) was added 3-(methythio)propionaldehyde (82 μL, 0.821 mmol), acetic acid (156 μL, 2.74 mmol), and sodium triacetoxyborohydride (232 mg, 1.09 mmol) respectively. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(methylthio)propyl]amino}-2-pyridinecarboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=1.5 Hz, 1 H), 7.73 (t, J=5.1 Hz, 1 H), 7.11 (dd, J=8.4, 5.5 Hz, 2 H), 6.96 (t, J=8.6 Hz, 2 H), 6.82 (s, 1 H), 4.40 (q, J=7.1 Hz, 2 H), 3.90 (s, 2 H), 3.24 (m, 2 H), 2.58 (m, 2 H), 2.07 (s, 3 H), 1.90 (m, 2 H), 1.41 (t, J=7.1 Hz, 3 H); MS m/z 363 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH3:20])[C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>CN(C=O)C.O>[CH2:1]([N:8]([CH2:19][CH3:20])[C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(Cc1ccccc1)c1cccc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1)c1cccc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3-[benzyl(ethyl)amino]-2-methylbenzoic acid (91% purity, 296 mg, 1.0 mmol) in DMF (10 ml) was added DIPEA (440 μl, 2.5 mmol) and HATU (570 mg, 1.5 mmol). The reaction was stirred at room temperature for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 222 mg, 1.3 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured onto 150 ml of water and stirred for 20 min. The product was filtered, air dried under vacuum and then purified using RP-HPLC. The resulting solid was triturated with diethyl ether and isolated by filtration to afford the title compound as an off white solid (86 mg, 21%). LC-MS 99%, m/z=404.3, 1H NMR (500 MHz, Chloroform-d) δ 12.04 (s, 1H), 7.33-7.23 (m, 4H), 7.21 (t, J=6.8 Hz, 1H), 7.14-7.05 (m, 3H), 7.05-6.99 (m, 1H), 5.92 (s, 1H), 4.53 (d, J=5.9 Hz, 2H), 4.06 (s, 2H), 2.92 (q, J=6.9 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H), 0.92 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:14](=O)[CH3:15])\[CH3:13])[CH:9]=2)[NH:4][N:3]=1.[N:17]([O-])=O.[O:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1>CC(O)C>[CH3:15][C:14]1[NH:25][C:24]2[O:20][N:21]=[CH:22][C:23]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:12]=1[C:13]#[N:17]
Reactant: CC(=O)/C(C)=C/c1ccc2[nH]nc(C)c2c1
Reactant: O=N[O-]
Reactant: Nc1ccno1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)c2cnoc2N1

Procedure:
A mixture of 50 mg (0.22 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutane-nitrite (Example 2A) and 19 mg (0.22 mmol) 1,2-oxazol-5-amine in propan-2-ol (1.0 ml) was stirred at reflux temperature overnight. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to yield 45 mg (69% of th.) of the racemic title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27])[C@H:12]([C:21]([OH:23])=[O:22])[CH2:11][CH2:10][C:9]3=[O:24].[C:28](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.O>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27])[C@H:12]([C:21]([O:23][CH3:28])=[O:22])[CH2:11][CH2:10][C:9]3=[O:24]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CC[C@H]3C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@@H]1CCC(=O)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Temperature: 25 °C

Procedure:
(S)-1,3-Dimethyl-2,4,10-trioxo-5-phenyl-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizine-7-carboxylic acid (1.85 g, 5.04 mmol), potassium carbonate (2.088 g, 15.11 mmol) and dimethyl sulfate (1.444 mL, 15.11 mmol) were combined in acetone (50 mL) and water (5 mL). The mixture was heated at reflux for 1.5 hours, then cooled to room temperature and evaporated under vacuum. The residue was partitioned between DCM and water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-80% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[C:16]([NH:24][C@H:25]([C:30](O)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(Cl)Cl.CCN(CC)CC>[C:16]([NH:24][C@H:25]([C:30]([NH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: NCC1CCCN1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)NCC1CCCN1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoylleucine (0.12 mmol) in CHCl3 (1 mL) was treated with EDCI (23 mg), HOBt (16.2 mg) and Et3N (15.2 μL), and stirred at 25° C. for 16 h. The reaction mixture was diluted with CH2Cl2 (0.5 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL), dried by filtration through a PTFE membrane and concentrated to afford 2-{(N-benzoylleucyl)aminomethyl}-1-(4-chlorobenzyl)pyrrolidine (compound No. 344) (74 mg, quant): The purity was determined by RPLC/MS (85%); ESI/MS m/e 442 (M++H, C25H32ClN3O2).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([C:10]([Cl:16])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc2ccccn12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (5.270 g, 32.5 mmol) in DCM (200 ml) was treated with oxalyl chloride (3.13 ml, 35.8 mmol) followed by the addition of DMF (0.252 ml, 3.25 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed in vacuo to afford the title compound as a hydrochloride salt;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:5][CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCCCl)c2c1CCCC2
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C(=O)CCCN2CCCC2)c2c1CCCC2
Temperature: 60 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
A mixture of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-4-chloro-1-butanone (4.0g), pyrrolidine (4.27g), potassium iodide (0.3g) and potassium carbonate (2.0g) in absolute N,N-dimethylformamide (30 ml) was stirred at 60° C. for 10 hours. The reaction mixture was filtered and then the filtrate was partitioned into water and ethyl acetate. The organic layer was extracted, washed with water and then dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was evaporated in vacuo to give the residue. The residue was dissolved in ethyl ether. The ethyl ether solution was extracted with 1N hydrochloric acid. The aqueous layer was neutralized with ammonia water and then extracted with ethyl ether. The ethyl ether was dried over anhydrous magnesium sulfate. The solution was filtered and the filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-4-pyrrolidino-1-butanone (3.7 g; yield: 82%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)C=NC=1.Cl.Cl.N[C@H](C1C=C[N:39]=[C:38]([Cl:42])[N:37]=1)[C@@H](C1C=C(F)C=CC=1F)O>>[Cl:42][C:38]1[N:39]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:3]=[CH:2][N:37]=1
Reactant: N[C@H](c1ccnc(Cl)n1)[C@H](O)c1cc(F)ccc1F
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Agent: Cl
Product: O=C1N[C@H](c2ccnc(Cl)n2)[C@@H](c2cc(F)ccc2F)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-2-amino-2-(2-chloropyrimidin-4-yl)-1-(2,5-difluorophenyl)ethanol 2HCl. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=4.9 Hz, 1H), 8.69 (s, 1H), 7.68 (d, J=5.2 Hz, 1H), 7.50-7.28 (m, 3H), 5.71 (d, J=5.5 Hz, 1H), 5.04 (d, J=5.5 Hz, 1H), Mass spec.: 312.1 (MH)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S-:14][C:15]#[N:16].[K+].BrBr.O>C(O)(=O)C>[NH2:16][C:15]1[S:14][C:12]2[CH:13]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: CCCCCCc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCc1ccc2nc(N)sc2c1
Yield: 49.9 %

Procedure:
In a 2 liter-reaction vessel, 50.0 g (0.28M) of p-hexylaniline, 54.8 g (0.56M) of potassium thiocyanate and 400 ml of acetic acid were placed and cooled below 10° C. To the mixture, a solution of 45.0 g of bromine in 135 ml of acetic acid was added dropwise in 40 minutes below 10° C. under strong stirring, followed by reaction for 1.5 hours below 10° C. After the reaction, 500 ml of water was poured into the reaction mixture, followed by heating to dissolve the resultant precipitate. The resultant solution was filtered under heating. Ammonia water was added to the filtrate until the resultant solution became basic, followed by cooling with ice to precipitate a crystal. The crystal was recovered by filtration, followed by washing and drying to obtain a crude product. The crude product was recrystallized from a mixture solvent of n-hexane/benzene (1/1) to obtain 33.0 g of 2-amino-6-hexylbenzothiazole (Yield: 49.9 %).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Br)c1Cl
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-chlorobenzoic acid (1.79 mmol) in 12 mL THF were added N,O-dimethylhydroxylamine HCl (2.32 mmol), EDC.HCl (4.29 mmol) and pyridine (2.68 mmol) at 0° C. The cooling bath was removed and stirring was continued at RT overnight. The reaction was diluted with DCM and extracted with water, sat. aq. NH4Cl solution, sat. aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to EtOAc gives the desired compound as colorless oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([O:18][CH3:19])[C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:21][C:22]([F:34])([F:33])[CH2:23][CH2:24][S:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:17][C:14]([F:15])([F:16])[CH:13]([O:18][CH3:19])[CH2:12][CH2:11][CH:28]([S:25]([CH2:24][CH2:23][C:22]([F:33])([F:34])[F:21])(=[O:27])=[O:26])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(OC)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.7 %

Procedure:
To a solution of 1.0 g of 4,4,4-trifluoro-3-methoxy-butyl p-toluenesulfonate and 0.8 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 0.4 g of potassium carbonate at room temperature, and the stirred at room temperature for 4 days. The reaction mixture was heated to 60° C., stirred at the same temperature for 20 hours, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.62 g of methyl 6,6,6-trifluoro-5-methoxy-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (24)).