Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Br[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Reactant: NC[C@H]1COc2ccc(O)cc2O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4ccc(O)cc4O3)cc2o1
Temperature: 86 °C

Procedure:
(S)-2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (3.53 g, 16.2 mmole), 7-(3-bromopropoxy)coumarin (4.17 g, 14.7 mmole), and diisopropylethylamine (5.00 ml, 28.7 mmole) were combined in 300 ml of DMF and heated at 86° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 300 g of silica gel using first 75% ethyl acetate/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the free base redissolved in warm methanol. Five ml of 4N isopropanolic HCl was added, the mixture was brought to a boil on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 2.24 g of the title compound precipitated as an white solid, monohydrochloride, m.p. 245°-248° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:19])[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)=[O:10])[CH2:5][CH2:4]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=1.[BH4-].[K+]>C1(C)C=CC=CC=1>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]([N:6]2[CH2:7][CH2:8][C:3]([F:19])([CH2:2][NH:1][CH2:31][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[N:30]=3)[CH2:4][CH2:5]2)=[O:10])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: NCC1(F)CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Reactant: O=Cc1cccc(-c2ccco2)n1
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CNCc2cccc(-c3ccco3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.687 g of (4-aminomethyl-4-fluoropiperidin-1-yl)-(3-chloro-4-fluorophenyl)methanone (2.38 mmol) and 0.371 g of 6-furan-2-yl-pyridine-2-carbaldehyde (2.38 mmol) are mixed in 25 ml of toluene. The solution is heated under reflux under a nitrogen atmosphere for 2 hours, removing the water formed continuously. The toluene is evaporated off, the residue is taken up in 25 ml of methanol and then 0.257 g of potassium borohydride (4.51 mmol) is added in portions. The reaction mixture is stirred for 5 hours at room temperature and then the methanol is evaporated off. The residue is taken up in chloroform, the organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 98:2). 0-65 g of a yellow oil is obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([C:10]2[CH2:11][CH2:12][N:13](CC3C=CC=CC=3)[CH2:14][CH:15]=2)[S:8][CH:9]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].C(OC(Cl)=O)=C>ClCCCl>[CH3:4][C:2]([C:5]1[N:6]=[C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[S:8][CH:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1csc(C2=CCN(Cc3ccccc3)CC2)n1
Agent: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(C)(C)c1csc(C2=CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.5 g 4-(4-(1,1-dimethylethyl)-2-thiazolyl)-1-phenylmethyl-1,2,3,6-tetrahydropyridine, 2.5 g K2CO3 and 50 ml 1,2-dichloroethane are treated dropwise at -10° to -7° under stirring with 3.75 ml chloroformic acid vinyl ester. The mixture is stirred at -10° to -7° for 3 hours. The solvent is evaporated, the residue partitioned between water and hexane, and the water phase extracted with hexane. The combined organic layers are washed with saturated brine solution, filtered and dried (Na2SO4). The solvent is evaporated and the oily residue is added under ice-cooling to 20% aqueous hydrochloric acid. The mixture is heated on a steam bath for 4 hours, then cooled to room temperature and extracted once with dichloromethane. The aqueous acidic solution is filtered, made alkaline with aqueous NaOH and extracted with ethyl ether. After evaporation of ether, the heading compound is obtained as an oily residue. M.p. of the hydrogenmaleinate is 170°-171°.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:3])=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCCCCOCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCOCc1ccccc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Jones reagent was added dropwise to an ice cooled solution of 5-benzyloxy-pentan-1-ol 28 (5 g, 25.74 mmol) in acetone (170 ml). Addition of the Jones reagent was stopped when the acetone solution acquired a persistent yellow color with the concurrent formation of green chlomium salts. The mixture was filtered and concentrated in vacuo to give an oily crude product that was purified by a flash chromatography (EtOAc/hexanes, 1:3) to give compound 29 (4.98 g, 93%) as a colorless oil: TLC Rf=0.68 (silica gel, 50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 5H), 4.502 (s, 2H), 3.51-3.47 (t, 3J=6 Hz, 2H), 2.41-2.36 (t, 3J=6.8 Hz, 2H), 1.79-1.64 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 179.713, 138.651, 128.609, 127.870, 127.795, 73.158, 69.968, 33.915, 29.243, 21.749; HRMS calcd for C12H16O3+Na+ 231.0997; found 231.0992 [M+Na+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]([OH:20])=[C:15]([Br:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[CH2:22]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:23]1[O:25][CH2:24]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:27]([O:26][CH2:22][CH:23]([OH:25])[CH2:24][O:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([C:10]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH2:24][CH:23]([OH:25])[CH2:22][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:15]([Br:21])[CH:14]=2)([CH3:12])[CH3:11])=[CH:5][C:6]=1[Br:9])[CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Reactant: CCCCOCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)COc1c(Br)cc(C(C)(C)c2cc(Br)c(OCC(O)COCCCC)c(Br)c2)cc1Br

Procedure:
2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane (i.e., tetrabromobisphenol A) (136 g; 0.25 mole), butyl glycidyl ether having an epoxide content of 7.45 equiv./kg (67.1 g; 0.5 equiv.), and benzyltrimethylammonium chloride (0.5 g) were stirred at 120° C. for 1 hour and at 150° C. for 41/2 hours. The mixture had a residual epoxide content of 0.01 equiv./kg, indicating that the reaction was substantially complete.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC/C=C/CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC/C=C/CCOS(=O)(=O)c1ccc(C)cc1
Yield: 99 %

Procedure:
This compound was synthesized as a colorless oil from (E)-hex-3-en-1-ol (130.0 mg, 1.30 mmol), TsCl (322.2 mg, 1.69 mmol), Et3N (196.6 mg, 1.95 mmol), and DMAP (158.8 mg, 1.30 mmol) in 99% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.74 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.50 (dtt, J=15.3, 6.3, 1.3 Hz, 1H), 5.27-5.14 (m, 1H), 4.00 (t, J=6.9 Hz, 2H), 2.43 (s, 3H), 2.36-2.23 (m, 2H), 2.03-1.86 (m, 2H), 0.91 (t, J=7.5 Hz, 3H);
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[C:17]([F:26])[CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].IC.[C:30](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[C:17]([F:26])[CH:16]=1)([CH3:30])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Di-tert-butyl[4-(1,3-dioxolan-2-yl)-3-fluorophenyl]malonate (2.45 g, 6.41 mmol), iodomethane (0.80 mL, 12.85 mmol) and potassium carbonate (1.78 g, 12.9 mmol) were suspended in DMF (10 mL) and heated at 70° C. for 3 hours in a sealed tube. A further portion of iodomethane was added (0.60 mL, 9.64 mmol) and heating continued at 75° C. for 3 hours. Room temperature was attained, H2O (150 mL) was added and the products extracted into Et2O (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave the clean product (orange oil). 1H NMR (CDCl3) δ 7.47 (t, J=8.1 Hz, 1H), 7.19 (dd, J=8.1, 1.8 Hz, 1H), 7.17 (dd, J=12.0, 1.8 Hz, 1H), 6.07 (s, 1H), 4.13 (m, 2H), 4.03 (m, 2H), 1.74 (s, 3H), 1.45 (s, 18H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH2:2][CH3:3].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CCCc1noc(N2CCC(=O)CC2)n1
Product: CCCc1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared as its hydrochloride salt from 1-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 13): tR=0.79 min; Mass spectrum (ESI+): m/z=251 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C.CN(C=O)C>O>[N:28]1([C:26]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:13][CH2:12][C:11]5[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=5[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH:25]=2)=[O:27])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2ccccc21
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccnc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1)N1CCc2ccccc21

Procedure:
100 mg (0.41 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 110 mg (0.43 mmol) (2-chloropyridin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 3.0 mL (17.4 mmol) DIPEA. The reaction mixture was refluxed for 5 h with stirring. Then 1 mL DMF were added and the mixture was stirred overnight at 130 C. After cooling water was added, the precipitate formed was suction filtered and purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH2:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[Cl:3][C:1]([O:19][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
29 ml of a 20% toluene solution of phosgene (55.98 mmoles) was added to tetradecyl alcohol (4 g, 18.66 mmoles) and the reaction mixture was left to stand for 20 hours under stirring at room temperature. After solvent evaporation, the residue was taken up with hexane and evaporated to dryness (several times) to give 5.1 g product as colourless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].[C@@H]1(N)CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C=O.[Cu]I>[F:27][C:4]1[CH:3]=[C:2]([N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:13]2[CH2:17][CH2:16][C@@:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[O:18]3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4F)CC3)C2)c2ccccc21
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCCC5=O)cc4F)CC3)C2)c2ccccc21

Procedure:
A mixture of (1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (10 mg, 0.00002 mol, prepared by methods analogous to those used for the synthesis of example 238), 2-pyrrolidinone (2.4 mg, 0.000028 mol), copper(I) iodide (0.2 mg, 0.000001 mol), trans-1,2-cyclohexanediamine (0.28 μL, 0.0000023 mol), and potassium carbonate (6.4 mg, 0.000046 mol) in toluene (0.5 mL) and N,N-dimethylformamide (0.5 mL) was microwave irradiated at 110° C. for 30 minutes. The crude product was purified with prep-HPLC. LCMS: m/z 435.2 (M+H+); 457.1 (M+Na+).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=2)[C:20]#[N:21])=[O:16])[C:12]([CH2:26][CH3:27])=[C:11]([O:28]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[CH2:26]([C:12]1[C:11](=[O:28])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:20]#[N:21])=[O:16])[CH3:27]
Reactant: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(=O)c1cc(C)cc(C#N)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1c(C(=O)c2cc(C)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Reaction time: 1.5 h
Yield: 738.8 %

Procedure:
3-(2,6-Bis-benzyloxy-5-ethyl-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (41) (4.5 g, 9.7 mmol) in anhydrous ethanol (30 ml) and THF (30 ml) was stirred with 10% palladium on carbon (250 mg) under an atmosphere of hydrogen. After 1.5 hr, the mixture was filtered through celite pad and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, chloroform:methanol (95:5)) to afford 20.3 g (84%) of a white solid; m.p. 253-254° C.; 1H NMR (200 MHz, DMSO-d6) δ: 0.84 (3H, t, J=7.0 Hz), 1.96 (2H, q, J=7.0 Hz), 2.45 (3H, s), 8.06 (1H, s), 8.11 (1H, s), 8.33 (1H, s), 11.05 (1H, s), 8.28 (1H, s); m/z (EI): 283 (M+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(Cl)Cl.[C:13]1([CH2:21][NH2:22])[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[BH4-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:21][NH:22][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: Fc1ccc(CNCc2ccc(CNCc3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a solution of 4-fluorobenzaldehyde (2.482 g, 20.00 mmol) in a mixed solvent (20 mL of methylene chloride nd 10 mL of i-propanol) at rt, was added 1,4-phenylenedimethanamine (1.362 g, 10 mmol, Aldrich). The reaction mixture was stirred at rt for 5 h. To this mixture, sodium borohydride (0.567 g, 15.0 mmol, 1.5 eq) was added, and it was stirred at rt overnight. The reaction mixture was quenched by adding 10 mL of MeOH and 10 mL of aq. NaHCO3. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by ISCO system, eluting with CH2Cl2/EtOAc to give the title compound (2.45 g, 66%) as a viscous material, MS (ESI): 353.1 (M+H)+.
Reaction SMILES: [CH:1]([CH2:4][CH2:5][C:6](O)=[S:7])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2-].[Li+].[CH3:25][C@@H:26]1[C@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1.C([Li])CCC>ClCCl.C(Cl)(Cl)Cl>[CH:1]([CH2:4][CH2:5][C:6]([N:27]1[C@H:26]([CH3:25])[C@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28]1=[O:37])=[S:7])([CH3:3])[CH3:2]
Reactant: CC(C)CCC(O)=S
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)CCC(=S)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 54.1 %

Procedure:
226 mg of 3-isopropylthiopropionic acid was dissolved in 1.5 ml of dry dichloromethane. 0.22 ml (1.0 eq) of triethylamine was added thereto, and then the mixture was cooled with ice. 0.19 ml of pivaloyl chloride was added thereto under stirring to obtain a gelled reaction solution. The reaction solution was stirred at 10° C. for 10 minutes and then cooled with ice. A dichloromethane solution of lithium amide prepared from 270 mg of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.96 ml of 1.5M n-butyl lithium was prepared, and the solution was added to the previous reaction solution under cooling with ice. The mixture was stirred at room temperature overnight, and then the reaction solution was diluted with 20 ml of chloroform. After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution, the chloroform solution was dried over anhydrous magnesium sulfate. The chloroform solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1) to obtain 240 mg of (4R,5S)-3-(3-isopropylthiopropionyl)-4-methyl-5-phenyl-2-oxazolidinone as colorless transparent syrup (yield: 51%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].S(Cl)(Cl)=O>>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: Cc1csc2nc[nH]c(=O)c12
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: Cc1c(S(=O)(=O)Cl)sc2nc[nH]c(=O)c12
Reaction time: 0.17 h

Procedure:
5-Methylthieno[2,3-d]pyrimidin-4(3H)-one (2 g, 12 mmol) was added portionwise into chlorosulfonic acid (8.0 mL, 120 mmol) maintaining the internal temperature below 0° C. After addition the reaction was stirred for 10 minutes, thionyl chloride (4.4 mL, 60 mmol) added drop wise, the mixture stirred for 0.5 hours at ambient temperature and then at reflux for 2 hours. The solution was poured onto crushed ice, the precipitated solid collected by filtration, washed with ice-water, and dried under vacuum to give cream solid. (1.1 g, 34%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]>CC#N>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCBr)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
Potassium carbonate (0.758 g, 0.48 mmol) was added to a solution of 1,4-dibromo butane (1.18 g, 5.49 mmol) and methyl 4-hydroxy-3-methoxybenzoate (0.5 g, 2.74 mmol) in CH3CN (10 mL). After stirring for 12 h at 80° C., the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic phase was dried using Na2SO4 and evaporated to give the crude methyl 4-(4-bromobutoxy)-3-methoxybenzoate which was purified by column chromatography using hexanes:ethyl acetate to give the pure product as a colorless solid (0.692 g, 80%). 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H, J=8.3 Hz), 7.51 (s, 1H), 6.83 (d, 1H, J=8.2 Hz), 4.07 (t, 2H, J=5.7 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.47 (t, 2H, J=6.4 Hz), 2.04-2.00 (m, 4H). LC-MS (ESI) Calcd for C13H17BrO4 [M+H]+: 317.03, 319.03. Found: 316.90, 318.90.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Si:30]([O:37][CH2:38][C:39]([C:41]1[N:42]=[CH:43][N:44]2[CH:48]=[CH:47][S:46][C:45]=12)=[O:40])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].[Cl-].[NH4+]>C1COCC1>[Si:30]([O:37][CH2:38][C:39]([C:41]1[N:42]=[CH:43][N:44]2[C:48]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:47][S:46][C:45]=12)=[O:40])([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(C(=O)CO[Si](C)(C)C(C)(C)C)ncn12
Reaction time: 0.5 h

Procedure:
Tri-n-butylstannyl chloride (2.97 ml) and 16.0 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order to a solution of 2.37 g of 7-t-butyldimethylsilyloxyacetylimidazo[5,1-b]thiazole in 80 ml of THF in an argon atmosphere at −73° C. The mixture was stirred at the same temperature for 30 min. An ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 2:1). Of two main components, the fraction, which had been eluted earlier, was collected to give 484 mg of 7-t-butyldimethylsilyloxyacetyl-3-(tri-n-butylstannyl)-imidazo[5,1-b]thiazole.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:22])[O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH2:9]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:22])[O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])[CH2:9]1
Reactant: C[C@H](OC(=O)N[C@H]1CCN(Cc2ccccc2)C1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](OC(=O)N[C@H]1CCNC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-1,1,1-trifluoropropan-2-yl [(3S)-1-benzylpyrrolidin-3-yl]carbamate (1.82 g) in THF (20 ml) and MeOH (20 ml) was added 20% palladium hydroxide on activated carbon (200 mg). The resulting solution was placed under a H2 atmosphere (balloon pressure) and stirred at room temperature for 15 hours. The solution was obtained by filtration through Celite and, washing the filter cake with MeOH, was concentrated in vacuo to give (2S)-1,1,1-trifluoropropan-2-yl(3S)-pyrrolidin-3-ylcarbamate as a pale yellow oil.