Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 61, 31 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 93.7%) was a white foam: [α]23589=−23.24° (c=0.37, chloroform); EI-HRMS m/e calcd for C20H22Cl2N4O4S (M+H)+ 485.0812, found 485.0822.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:16]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution (15 ml) of methyl 4-[chloro(hydroxyimino)methyl]benzoate (0.425 g) and 1-ethynyl-4-trifluoromethylbenzene (0.534 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (0.697 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethyl acetate to give methyl 4-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoate (0.563 g, yield 65%) as colorless needle crystals. melting point: 183–184° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: ClCCCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,-) cis 7-Benzyloxy-4-[4-(4-chlorobutyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.60 mmol) and morpholine (240 mg, 3 mmol). Reaction time 4 days. The evaporated product was crystallised from ether-petrolether, and further purified by silica column chromatography using methanol-methylene chloride (1+19) as eluent.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[NH:22][CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.ClC(Cl)(O[C:40](=[O:46])OC(Cl)(Cl)Cl)Cl.[N:48]1[CH:53]=[CH:52][CH:51]=[CH:50]C=1.[NH4+].[Cl-].N1CCCC1>C(Cl)Cl.CCOC(C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:12][N:13]=1)[C@@H:20]1[CH2:21][N:22]([C:40]([N:48]2[CH2:50][CH2:51][CH2:52][CH2:53]2)=[O:46])[C@H:23]([CH2:25][CH3:26])[CH2:24]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Reactant: c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
[3,5-Bis(trifluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (84 mg, 0.17 mmol) and triphosgene (71 mg, 0.24 mmol) are dissolved in CH2Cl2 (2 mL). The reaction mixture is stirred at room temperature for 1 hour after addition of pyridine (15 mg, 0.19 mmol). Saturated aqueous NH4Cl and EtOAc are added, then extracted with EtOAc. The combined organic layer is dried over Na2SO4 then concentrated under reduced pressure. The resulting residue is dissolved in CH2Cl2 (1.5 mL) and then pyrrolidine (60 mg, 0.85 mmol) is added. The reaction mixture is stirred at room temperature for 12 hours. Saturated aqueous NH4Cl and CH2Cl2 are added, then extracted with CH2Cl2. The combined organic layer is dried over MgSO4, then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give ((2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrrolidin-1-yl-methanone (45 mg, 36%); ESI-MS m/z: 596 [M+1]+, Retention time 4.52 min (condition B).
Reaction SMILES: [CH2:1]([Si:5]([C:18]1([CH2:24][CH:25]([CH3:27])[CH3:26])SCCCS1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[OH2:28]>CC#N.Cl[Hg]Cl>[CH2:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:18](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Reactant: O
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCC[Si](C(=O)CC(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 26 (4.64 g 11.2 mmol) in CH3CN (300 mL) was added water (10 mL) and HgCl2 (15.26 g, 56.21 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted with hexane (50 mL). The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concentration to dryness in vacuo at rt gave crude ketone 33 as a yellow oil (3.2 g, 88%): Rf=0.80 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=6.4 Hz, 4H), 7.44 (m, 6H), 5.88 (m, 1H), 4.99 (dd, J=17.1, 1.6 Hz, 1H), 4.91 (dd, J=10.2, 1.6 Hz, 1H), 2.50 (d, J=6.6 Hz, 2H), 2.14 (m, 2H), 1.36 (m, 2H), 0.95 (m, IH), 0.76 (d, J=6.7 Hz, 6H); IR (neat) 3068 (m), 3046(m), 2956(s), 2925 (m), 2864 (m), 1956 (w), 1886 (w), 1826(w), 1641 (s), 1471 (m), 1431 (s), 1113 (s), 1000 (m), 910 (m), 743 (s), 702 (s) cm−1; MS (FAB) m/e (rel. intensity) 323 (MH+, 15), 322 (24), 321 (89), 267, (17), 236 (36), 198 (20), 182 (63), 169 (100), 167 (15), 159 (31); HRMS (FAB) calcd for C21H25OSi: 321.1675 (MH+−2). found: 321.1670.
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30]([O:32]C)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCOCC1.C(O)(=O)C>O>[C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30]([OH:32])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)CC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.8 %

Procedure:
To methyl [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetate (0.5241 g) and lithium hydroxide monohydrate (0.94 g) were added 1,4-dioxane (20 mL) and water (5 mL). The resulting suspension was stirred at room temperature for 3 days. The reaction solution was brought to dryness and the residue was diluted with water. Acetic acid (1.0 mL) was then added to the solution and it was extracted with 25% ethanol/chloroform. The extract was dried over (MgSO4) and the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, 10% methanol/chloroform) to give the title compound (0.36 g), which was then converted to its hydrochloride by hydrochloric acid to give the title compound as a white solid (0.3805 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.CCN(CC)CC.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][C@@H:52]([C@@H:57]([CH3:62])/[CH:58]=[CH:59]\[CH:60]=[CH2:61])[C@@H:53]([CH3:56])[CH:54]=[O:55])=[CH:46][CH:45]=1>C(Cl)Cl>[OH:55][C@@H:54]([C@H:53]([CH3:56])[C@@H:52]([O:51][CH2:50][C:47]1[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=1)[C@@H:57]([CH3:62])/[CH:58]=[CH:59]\[CH:60]=[CH2:61])[C@@H:15]([CH3:16])[C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:17]
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)C=O
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone (2.18 g, 9.34 mmol) and methylene chloride (15 mL) is cooled to −20° C. (n-Bu)2BOTf (1.0 M in DCM, 8.7 mL, 8.7 mmol) is introduced dropwise. The reaction is allowed to warm to 0° C. NEt3 (1.15 9, 11.34 mmol) is added and the mixture is stirred at 0° C. for 1 h, then cooled to −78° C. A solution of (2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal (1.95 g, 6.77 mmol) in DCM (10 mL) is added dropwise at −70° C. for 10 min. After 1 h at −74° C., the mixture is warmed to 0° C. The reaction is quenched with pH 7 buffer (15 mL). The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C., stirred for 40 min at room temperature, and concentrated. The residue is extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with saturated aqueous NaHCO3, brine, and concentrated. Flash chromatography gives the desired compound (3.4 g, 96.4%) as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][C:20](C(OCC)=O)=[C:21]([OH:22])[C:13]1=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:13]1=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(O)c2cc3cc(OCc4ccccc4)ccc3n2CC1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 220 °C
Yield: 79.7 %

Procedure:
The reaction mixture of ethyl 2-(benzyloxy)-9-hydroxy-6,7-dihydropyrido[1,2-a]indole-8-carboxylate (1.22 g, 3.36 mmol) in acetic acid (36 mL) and H2O (3 mL) was heated at 220° C. for 10 min under microwave irradiation. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound (780 mg) as a yellow solid. LCMS m/z=292.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.45 (m, 2H), 2.73 (t, J=6.4 Hz, 2H), 4.23 (t, J=5.9 Hz, 2H), 5.11 (s, 2H), 7.15 (dd, J=8.9, 2.4 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.22 (s, 1H), 7.25-7.30 (m, 1H), 7.30-7.35 (m, 1H), 7.36-7.42 (m, 2H), 7.45-7.50 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([F:32])[CH:34]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: Fc1cccc(CBr)c1
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cccc(F)c2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 3-fluorobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.38 (m, 2H) 6.91-7.10 (m, 4H) 6.67-6.81 (m, 1H) 5.74-5.95 (m, 2H) 5.18-5.50 (m, 1H) 4.12-4.30 (m, 2H) 3.62-3.74 (m, 3H) 2.61-2.77 (m, 2H) 2.07-2.17 (m, 2H) 1.93-2.08 (m, 3H) 1.05 (s, 9H); LCMS (m/z) ES+=533 (M+1).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:3])[CH3:2].[C:19](OC(C)=C)(=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:19]([O:13][C:9]1[CH2:10][CH2:11][CH2:12][C:8]=1[CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:21])[CH3:20]
Reactant: CCCCCC(CCC1CCCC1=O)OC(C)=O
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCCC(CCC1=C(OC(C)=O)CCC1)OC(C)=O

Procedure:
2-(3-Acetoxyoctyl)cyclopentanone (85 g.) [prepared as described in (d) above], isopropenyl acetate (125 ml.) and p-toluenesulphonic acid (2 g.) were refluxed for 24 hours allowing the acetone formed during the reaction to slowly distil from the head of a Dufton column. The excess isopropenyl acetate was then distilled off and the residue cooled, shaken with 2N sodium carbonate solution and extracted with diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulphate and the ether removed in vacuo. Distillation of the residue gave 1-acetoxy-2-(3-acetoxyoctyl)cyclopent-1-ene (85 g.), b.p. 108°-110° C./0.03 mm.Hg; nD26 = 1.459.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F)([O-:13])=[O:12].O>CC(C)=O>[CH2:7]([NH:10][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a suspension of potassium carbonate (1.0 g) in acetone (10 ml) was added 2-propyn-1-amine (0.26 g, 4.73×10-3 mole). 2,4-Dinitrofluorobenzene (1.32 g, 7.10×10-3 mole) was gradually added with stirring and the reaction mixture was refluxed two hours. After cooling it was poured into excess water and filtered. Recrystallization of the crude solid from ethanol afforded yellow needles; m.p. 151°-152° C. Yield: 0.99 g (95%). I.R. (KBr): 3367 (NH), 3268 (CH), 1618, 1590, 1333 and 1311 cm-1 (Ar-NO2).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:28][CH3:29])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:15]([O:28][CH3:29])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1N1CCCC1=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (8.5 mg, 0.043 mmol), 1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (0.014 mL, 0.078 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C19H22ClN6O2 (M+H)+: m/z=401.1. found: 401.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH2:8][CH2:9][N:10]([C:12]2C=CN=CC=2)[NH2:11])[CH:7]=1.C[O:21][CH2:22]Cl.[OH-].[Na+].[C:26](O)(=O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH2:12][N:10]([NH:11][C:27]1[CH:26]=[CH:12][N:10]=[CH:9][CH:8]=1)[CH2:9][CH:8]2[O:21][CH3:22]
Reactant: COCCl
Reactant: COc1ccc(Cl)cc1CCN(N)c1ccncc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COC1CN(Nc2ccncc2)Cc2c(Cl)cccc21
Temperature: 0 °C
Yield: 52 %

Procedure:
Lithium aluminum hydride (3.3 g) was added portionwise to a suspension of N-[2-(5-chloro-2-methoxyphenyl)ethylidine]-N-pyridin-4-ylhydrazine hydrochloride (13.4 g) in tetrahydrofuran (215 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hrs, and sodium sulfate decahydrate was added. The mixture was filtered, and the filtrate was concentrated to provide 11.8 g of N-[2-(5-chloro-2-methoxyphenyl)ethyl]-N-pyridine-4-ylhydrazine, as an oil. A solution of N-[2-(5-chloro-2-methoxyphenyl)ethyl]-N-pyridine-4-ylhydrazine (11.8 g) and chloromethyl methyl ether (3.8 g) in acetic acid (170 mL) was heated under reflux for 2 hrs and then cooled to 0° C. Sodium hydroxide solution (50%) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 10% methanol/ethyl acetate. The appropriate fractions were collected and concentrated to provide 6.54 g (52%) of product. Recrystallization from ethyl acetate provided the analytical sample, mp 152-154° C. (dec).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)c1ccccc1S
Reactant: ClCCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1SCCCCl
Temperature: 25 °C
Yield: 39.1 %

Procedure:
With stirring at room temperature, 15.4 g (99.9 mmols) of thiosalicylic acid was added by small portions to 50 ml of a solution of 2.44 g (101.7 mmols) of sodium hydride in dimethylformamide. The solution was dropwise added to 100 ml of a solution of 15.7 g (99.7 mmols) of 1-bromo-3-chloropropane in dimethylformamide with stirring under ice cooling. The mixture was stirred under ice cooling for further an hour and a half. After the reaction, an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with ethyl acetate 10 times. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =50/1) to afford 9.0 g (yield: 39%) of 1-chloro-3-(2-hydroxycarbonylphenylthio)propane.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C.[Cu]I>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Ic1ccccc1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 82 °C
Yield: 73 %

Procedure:
N-BOC4-ethynylpiperidin, 0.5 g (2.40 mmol), and iodobenzene, 0.29 mL (2.64 mmol) were dissolved in triethylamine (9 mL) and argon was passed through for a few minutes. Copper(I) iodide, 0.087 g (0.5 mmol), and bis[triphenylphosphine]palladium dichloride, 0.070 g (0.1 mmol), were added and the mixture was heated to 82° C. in a closed vessel for 17 hours. TLC analysis indicated complete reaction. Triethylamine was evaporated and the mixture was purified by silica gel chromatography (75 mL) using heptane/ethyl acetate (4+1) as eluant. Evaporation of pure fractions gave 0.497 g (73%) of N-BOC4-(phenylethynyl)piperidine. The protected piperidine, 0.497 g (1.74 mmol), was dissolved in dichloromethane and trifluoroacetic acid (1 mL) was added. The reaction was completed within 20 hours and the mixture was evaporated to give an oil. NMR analysis showed pure ammonium trifluoroacetate, contaminated with trifluoroacetic acid. The product was dissolved in dichloromethane and extracted with aqueous sodium hydrogen carbonate and water. Evaporation of solvent gave 0.284 g (88%) of the sub-titled compound.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19]CCO)[C:15]([OH:17])=[O:16])[N:13]=1.[CH:23]([O:26]C(C)C)(C)C>C(O)=O>[CH:23]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:6][CH2:5][O:4][CH:1]=[O:3])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:26]
Reactant: Nc1nc(C(=NOCCO)C(=O)O)cs1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(C)C
Solvent: O=CO
Product: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of formic acid (1.6 g.) and acetic anhydride (3.6 g.) was stirred at 50° C. for an hour. After cooling, 2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetic acid (syn isomer, 1 g.) was added to the solution and stirred at room temperature for 3 hours. Diisopropyl ether was added to the resultant solution, and the precipitates were filtered out. The filtrate was concentrated in vacuo, and the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 0.7 g.).