Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=C(C)[N:6]=[C:5]([C:10]#N)[CH:4]=1.CO.C[CH2:15][O:16][C:17]([CH3:19])=[O:18].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:10])[N:6]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:8]=1
Reactant: Cc1cc(CO)cc(C#N)n1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(CO)cc(C)n1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
A mixture of 440 mg of the 4-(hydroxymethyl)-6-methylpicolinonitrile in 3 mL of concentrated H2SO4 and 1.8 mL of H2O was stirred at 135° C. for 12 h. The temperature was decreased to 95° C., 6 mL of MeOH was added, and the solution was stirred at 95° C. for 1 h. The solution was added to ice with H2O and EtOAc. Solid NaHCO3 and sat. NaHCO3 solution were added to a pH=8. The aqueous layer was extracted with EtOAc (2×). The combined extracts washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give 393 mg of methyl 4-(hydroxymethyl)-6-methylpicolinate which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:43][C:44]([S:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:46])[CH3:45])[CH2:9][CH2:10][N:11]([CH2:19][C:20]([CH3:42])([S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:70]=C=NC(C)C)(C)C.ON1C(=O)CCC1=O.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:43][C:44]([S:47][C:48]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([CH3:45])[CH3:46])[CH2:9][CH2:10][N:11]([CH2:19][C:20]([CH3:42])([S:22][C:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:70])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCN(CCCCC(=O)O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)N=C=NC(C)C
Agent: NCCN(CCN)CCN
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCN(CCCCC(N)=O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
BAT-BM was prepared as follows. BAT acid (N9 -(t-butoxycarbonyl)-N6,N9 -bis(2-methyl-2-triphenylmethylthiopropyl)-6,9-diazanonanoic acid) (10.03 g, 10.89 mmol) and 75 mL of dry methylene chloride (CH2Cl2) were added to a 250 mL round-bottomed flask equipped with magnetic stir bar and argon balloon. To this solution was added diisopropylcarbodiimide (3.40 mL, 21.7 mmol, 199 mole %), followed by N-hydroxysuccinimide (3.12g, 27.1 mmol, 249 mole %). This solution was observed to become cloudy within 1 h, and was further incubated with stirring for a total of 4 h at room temperature. A solution of tris(2-aminoethyl)amine (30 mL, 200 mmol, 1840 mole %) in 30 mL methylene chloride was then added and stirring continued overnight. The reaction mixture was then concentrated under reduced pressure, and the residue partitioned between ethylacetate (150 mL) and 0.5M potassium carbonate (K2CO3 ; 150 mL). The organic layer was separated, washed with brine and concentrated to give the crude product N-[2-N',N'-bis(2-aminoethyl)aminoethyl)]-N9 -(t-butoxycarbonyl)-N6,N9 -bis(2-methyl-2-triphenylmethylthiopropyl)-6,9-diazanonanamide as a foam/oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:4]=1.C[O:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][C:24]=1[CH3:30]>>[CH3:30][C:24]1[CH:25]=[C:26]([S:29][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:4]=2)[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:20]([OH:31])=[O:19]
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)on2)cc1
Product: Cc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)no2)ccc1OCC(=O)O

Procedure:
Preparation of 5-chloromethyl-3-(4-trifluoromethyl-phenyl)-isoxazole (compound 45A) A solution of 4-trifluoromethyl-benzaldehyde oxime (8.9 g, 47.1 mmol) in 100 mL DCM was added to a rapidly stirred solution of propargyl chloride (47.1 mmol), triethyl amine (4.71 mmol) and 91 mL of commercial bleach (6.5% by weight) all in 50 mL DCM at 0° C. After 1 hour the layers were separated and the organic layer dried (Na2SO4), and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 25% EtOAc/hexane) gave the title compound (2.9 g, 23%) MS m/z 262 (M+1). Step 2. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 45B) The title compound was prepared in a manner analogous to Example 1F using 45A and 2C. MS m/z 438 (M+1). Step 3. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-3-phenoxy}-acetic acid (compound 45) The title compound was prepared in a manner analogous to Example 1 using 45B. IR cm−1: 1747; 400 MHz 1H NMR (DMSO-d6) δ 12.97 (br(s), 1H), 7.99 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.21 (s, 1H), 7.16 (d, 1H, J=8.5 Hz), 6.86 (s, 1H), 6.74 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.30 (s, 2H), 2.09 (s, 3H); MS m/z 424 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:14])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@H:3]([OH:14])[CH2:2][NH:1][C:23](=[O:24])[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)#[N:11]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N#Cc1ccc(OC[C@H](O)CN)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OC[C@H](O)CNC(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4{[(2R)-3-amino-2-hydroxypropyl]oxy}benzonitrile (see step (ii) above; 3.4 g, 17.7 mmol), TEA (2.69 g, 26.6 mmol) and CHCl3 (20 mL) was cooled to 0° C. before N-(benzyloxycarbonyloxy)succinimide (4.86 g, 19.5 mol) in CHCl3 (15 mL) was added slowly. The mixture was allowed to reach rt, and was stirred at that temperature overnight. The solvent was evaporated to give a residue that was dissolved in DCM. This solution was washed with water and brine and then dried (Na2SO4). Evaporation of the solvent gave 5.79 g (100%) of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(OC(=O)C)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cccc(C)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2cccc(Br)c2)n1
Yield: 7.7 %

Procedure:
A solution of 24 ml (200 mMol) of 2,6-dimethyl pyridine and 25.6 ml (207 mMol) of 3-bromobenzaidehyde in 38 ml of acetic anhydride is heated under reflux for 7.5 hours. The acetic anhydride is then evaporated in vacuo, and the residue is dissolved in 500 ml of 4N hydrochloric acid and twice extracted with 200 ml each of hexane. The water phase is then extracted four times with 300 ml each of tert.-butyl methyl ether. The combined organic phases are washed twice with 300 ml each of a saturated solution of NaHCO3 in water, then once with 300 ml of brine (300 ml), dried over sodium sulfate, filtrated and evaporated in vacuo yielding 4.2 g of the title compound as colorless crystals of melting point 58-590.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O:3]C)=[O:2].[OH-:33].[Na+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:18][CH2:17][C:16](=[O:33])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCCCC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2(C#Cc3ccc(C(=O)O)cc3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 54.6 %

Procedure:
A stirred solution of 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane (0.146 g, 0.326 mmol) in dry methanol (5 mL) was treated with 10% aqueous sodium hydroxide solution (0.46 mL, 1.15 mmol) under an argon atmosphere as described in Example 13. The crude acid was purified by chromatography (silica, ethyl acetate/methylene chloride/formic acid; 10:90:1), the product fractions washed with water three times, was stripped in vacuo, was crystalized with ether and was dried in vacuo to afford the titled compound as a white solid (0.077 g, 55%), mp 170°-171° C. Anal. (C27H28O5) calcd: C 74.98, H 6.53 found: C 74.78, H 6.54.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][C:20]=2[CH:21]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>CO.O>[C:26]1([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:32])=[O:2])=[O:14])=[CH:21][C:20]=3[CH:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 50 °C
Yield: 84 %

Procedure:
A solution of (R)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 18 (1.39 g, 3.24 mmole) in methanol (30 ml) was treated with a solution of lithium hydroxide monohydrate (149 mg, 3.56 mmole) in water (2 ml) and heated to 50° C. for 3 hrs. It was then cooled to room temperature, acidified with 1M HCl, extracted with ethyl acetate, separated, washed, dried, and evaporated. The residue was crystallized to give about 1.13 g of (R)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid 19, mp. 154-156° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:42])[NH:38][CH2:39][CH2:40][NH2:41])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:43])[C@@H:9]1[OH:44])([CH3:4])([CH3:3])[CH3:2].[N:46]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=2)[CH2:51][CH2:50][CH:49]([NH:52][C:53](N2C=CN=C2)=[O:54])[CH2:48][CH2:47]1>CC(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:42])[NH:38][CH2:39][CH2:40][NH:41][C:53]([NH:52][CH:49]2[CH2:48][CH2:47][N:46]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)[CH2:51][CH2:50]2)=[O:54])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:43])[C@@H:9]1[OH:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of {(1S,2R,3S,4R)-4-[2-(2-amino-ethylcarbamoyl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-carbamic acid tert-butyl ester (2.5 g, 4.05 mmol) in IPA (10 ml) is added imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate C) (151 ml of a 10 mg/ml solution in DCM, 5.56 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with DCM/MeOH (25:1 increasing to 15:1). The resulting solid is further purified by dissolving in DCM and washing the solution with water, drying (MgSO4) and concentrating in vacuo to afford the title product. (MH+ 820.7)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)co3)cc2)nc1Cl
Yield: 48.5 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-1,3-oxazole-4-carboxylate obtained in Example (96c) (0.12 g, 0.32 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 56 mg of the title compound as a light brown solid (48%).
Reaction SMILES: [C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:26]=3[CH3:27])=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[C:26]=3[CH3:27])=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(-n2ncc(C(=O)Nc3ccc(C4(C#N)CCC5(CC4)OCCO5)nc3)c2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-n2ncc(C(=O)Nc3ccc(C4(C#N)CCC(=O)CC4)nc3)c2C)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-5-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carboxamide (181 mg) described in Example E3 in a mixed solvent of acetic acid (2 ml), water (0.5 ml) and 1N hydrochloric acid aqueous solution (0.5 ml) was stirred at 100° C. for two hours. After the reaction, a saturated aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with a column chromatography to give the titled compound (96 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH:13]([CH3:17])[CH2:12]2)[S:5][C:6]=1[C:7]([O:9]C)=O.[CH:18]([NH2:20])=O>>[CH3:17][CH:13]1[CH2:12][N:11]([C:4]2[S:5][C:6]3[C:7](=[O:9])[N:20]=[CH:18][NH:1][C:2]=3[N:3]=2)[CH2:16][CH2:15][O:14]1
Reactant: NC=O
Reactant: COC(=O)c1sc(N2CCOC(C)C2)nc1N
Product: CC1CN(c2nc3[nH]cnc(=O)c3s2)CCO1
Temperature: 25 °C
Yield: 73 %

Procedure:
The solution of methyl 4-amino-2-(2-methylmorpholino)thiazole-5-carboxylate (1.4 g, 5.4 mmol) in formamide (5 mL) was stirred at 200° C. for 1.5 hours. The mixture was cooled to ambient temperature. The precipitate was collected through filtration and washed with water to give the desired product (1.0 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 12.42 (br, 1H), 8.09 (s, 1H), 3.93˜3.82 (m, 3H), 3.61-3.54 (m, 2H), 3.24 (m, 1H), 2.92 (m, 1H), 1.16 (m, 3H); LC-MS: 253 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.C(Cl)(Cl)Cl.[I-].[K+]>[CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=3[O:35][CH3:36])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc(C(C2CCCCC2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2ccc(F)cc2)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.03 g, 0.207 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was cooled to room temperature and filtered. The 1-butanol was removed by rotary evaporation to give a brown oil. This oil was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel. Elution was performed using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl acetate. Separate fractions of similar purity were combined and solvent was removed to give a yellow oil. This oil was dried in vacuo overnight at 80° C. to give 7.36 g (73.8%) of title compound.
Reaction SMILES: BrC1C(=O)[NH:4][C:5](=[O:8])[NH:6]C=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>ClC(Cl)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:4][C:5]([NH2:6])=[O:8]
Reactant: Fc1cccc(F)c1CBr
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC(Cl)Cl
Product: NC(=O)NCc1c(F)cccc1F
Temperature: 80 °C
Yield: 84.5 %

Procedure:
A suspension of 5-bromouracil (18.45 g, 96.6 mmol) in 300 mL of dichloroethane was treated with N,O-bis(trimethylsilyl)acetamide (48 mL, 39.5 g, 194 mmol). The reaction mixture was heated at 80° C. for 3 hr under the nitrogen. The solution was cooled down to ambient temperature, 2,6-difluorobenzyl bromide (25 g, 120 mmol) was added and the reaction mixture was heated at 80° C. overnight under the protection of nitrogen. The reaction was cooled down, quenched with MeOH (15 mL), and partitioned between dichloromethane (500 mL) and water (250 mL). The organic layer was washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product was triturated with ether, filtered, and washed with ether three times to give compound 1 (15.2 g, 50%) as a white solid; MS (CI) m/z 316.90, 318.90 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].C1C=C[NH+]=CC=1.[O-:18][Cr](Cl)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cc1ccccc1Cl
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(=O)c1ccccc1Cl
Reaction time: 21.5 h

Procedure:
To a solution of 2-chlorophenylacetone (7.14 g, 42 mmol) in CH2Cl2 (184 mL), PCC (27 g, 127 mmol, 3 eq) and pyridine (10 mL, 127 mmol, 3 eq) in three portions were added over five hours at reflux under vigorous stirring. After the addition was complete, the mixture was further refluxed under vigorous stirring for 21.5 h. The mixture was filtered through a pad of silica gel, washed the pad with CH2Cl2, and concentrated under reduced pressure to provide a dark red syrup. The residue was purified by column chromatography on a 120 g of Redi-Sep™ column using 0-15% gradient of EtOAc in hexane over 40 min as eluent to provide 1-(2-chlorophenyl)propane-1,2-dione as yellow liquid. 1H NMR (choroform-d) δ ppm 7.66 (1H, dd, J=7.6, 1.8 Hz), 7.48-7.54 (1H, m), 7.37-7.46 (2H, m), 2.58 (3H, s). Mass Spectrum (ESI) m/e=182.9 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10]I.Cl>C1COCC1.CCOCC.[Zn]>[ClH:7].[Cl:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: ClCCCI
Reactant: C1CSCCN1
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: ClCCCN1CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
Step 1. To a solution of thiomorpholine (1.0 g, 9.7 mmol) and 1-chloro-3-iodopropane (1.98 g, 9.7 mmol) in dry THF (30 ml) was added activated zinc powder (0.64 g, 9.7 g atom). After the mixture was stirred at rt overnight, it was filtered, washed with EtOAc (20 ml), and concentrated. The residue was dissolved in EtOAc (50 ml), washed with 10% aq. NaHCO3 (10 ml), water (2×10 ml), dried over MgSO4, and concentrated. The residue was dissolved in ether (20 ml) before a 1 M ethereal HCl solution (9.7 ml, 9.7 mmol) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (2×10 ml), and dried to afford 4-(3-chloropropyl)thiomorpholine hydrochloride (0.40 g, 19%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 2.20-2.25 (m, 2H), 2.78-2.81 (m, 2H), 3.09-3.27 (m, 6H), 3.68-3.71 (m, 2H), 3.74 (t, J=6.4 Hz, 2H), 11.20 (brs, 1H). Step 2. To a solution of OZ288 (0.38 g, 1.07 mmol) in dry acetonitrile (50 ml) were added powdered NaOH (0.09 g, 2.13 mmol) and tetrabutylammonium hydrogensulfate (0.07 g, 0.21 mmol). After the mixture was stirred at rt for 30 min, 4-(3-chloropropyl)thiomorpholine hydrochloride (0.23 g, 1.07 mmol) was added. The mixture was stirred at 60° C. overnight before the inorganic solid was filtered off and washed with EtOAc (2×25 ml). After removal of the solvents in vacuo, the residue was dissolved in EtOAc (50 ml). The organic layer was washed with water, brine, dried over MgSO4, and concentrated to afford OZ462 free base (0.433 g, 81%) as a colorless solid. To a solution of the above free base (0.41 g, 0.82 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.08 g, 0.82 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried under vacuum at 40° C. to afford trioxolane OZ462 (0.42 g, 86%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.32-2.41 (m, 2H), 2.46-2.54 (m, 1H), 2.70 (d, J=14.7 Hz, 2H), 2.80 (s, 3H), 2.96-3.07 (m, 2H), 3.24-3.34 (m, 2H), 3.45-3.54 (m, 2H), 3.87 (d, J=11.8 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 11.19 (brs, 1H); 13C NMR (125.7 MHz, CDCl3) δ 23.66, 24.86, 26.44, 26.84, 31.57, 34.66, 34.76, 36.37, 36.75, 39.42, 41.97, 54.35, 56.23, 64.61, 108.32, 111.36, 114.22, 127.74, 139.14, 156.40. Anal. Calcd for C30H45NO7S2: C, 60.48; H, 7.61; N, 2.35. Found: C, 60.60; H, 7.54; N, 2.17.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22]Br.CS(C)=O.[OH-].[Na+]>O>[C:15]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1ccc(Sc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(C#N)(CBr)c1ccc(Sc2ccccc2)cc1
Yield: 101.5 %

Procedure:
To a mixture of 31 g (0.1 mole) of 2-(4-phenylthiophenyl) hexanenitrile, 22 g (0.13 mole) of dibromomethane and 100 ml of dimethyl sulfoxide is added 12 g (0.15 mole) of 50% sodium hydroxide solution dropwise with stirring. Reaction mixture is stirred at 60° for 1/2 hour and then poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 38 g of product.