Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:23]#[N:24])[C:12]([CH3:22])=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3F)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>CS(C)=O>[C:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:23]#[N:24])[C:12]([CH3:22])=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:36]3[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3=CCCC3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C3=CCCC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 4 h
Yield: 17.9 %

Procedure:
2-(Cyclopent-1-en-1-yl)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-214) (145 mg, 0.46 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (130 μl, 0.91 mmol) and (3S)-3-(dimethylamino)pyrrolidine (121 μl, 0.96 mmol) were added, followed by stirring at 95° C. for 4 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (5:1, y/v) gave the entitled compound (34 mg, 18%) as a pale yellow amorphous substance.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:16]=3[CH:15]=[CH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].CN([CH:33]=[O:34])C>>[CH:33]([C:15]1[C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:27][CH:26]=2)[CH:14]=1)=[O:34]
Reactant: COC(=O)c1cccc2c1ccn2Cc1ccc(OC)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c1c(C=O)cn2Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Phosphorus oxychloride (7.74 ml, 84.6 mmol) was added slowly to ice-cold DMF (200 mL) and the resulting mixture was stirred at 0° C. for 1 h. To this mixture was added a solution of methyl 1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.6 g, 56.4 mmol) from Step A above in DMF (100 mL) and the mixture was stirred for 2 h. The reaction mixture was poured into an ice/water mixture and the pH was adjusted to 7 by adding 1 N NaOH. The compound was extracted with ethyl acetate (3×500 mL) and the combined organic layers were washed with water (4×250 mL) and brine (4×250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (ethyl acetate/hexanes: 20-40%) to afford methyl 3-formyl-1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.7 g, 93%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.48 (s, 1H), 7.99 (s, 1H), 7.85 (dd, J=10.0, 5.0 Hz, 1H), 7.55 (dd, J=10.0, 5.0 Hz, 1H), 7.30 (t, J=10.0 Hz, 1H), 7.12 (d, J=10.0 Hz, 2H), 6.86 (d, J=10.0 Hz, 2H), 5.31 (s, 2H), 3.99 (s, 3H), 3.71 (s, 3H); MS (ESI+) m/z 324 (M+H).
Reaction SMILES: [O-]CC.[Na+].Cl.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[CH2:9][CH2:8]1.[C:20]([C:23](=[CH:26]OCC)[C:24]#[N:25])(=O)[CH3:21]>C(O)C>[CH3:21][C:20]1[C:23]([C:24]#[N:25])=[CH:26][N:19]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]2)[N:18]=1
Reactant: CCOC=C(C#N)C(C)=O
Reactant: CN1CCC(CCCNC(=N)N)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C

Procedure:
A flask containing sodium ethoxide (0.64 mL of a 21 wt % solution in ethanol, 1.7 mmol) and N-[3-(1-methyl-piperidin-4-yl)-propyl]-guanidine-HCl (200 mg, 0.85 mmol) in ethanol (2.45 mL) was aged for 15 minutes at room temperature. To the resultant mixture was then added 2-acetyl-3-ethoxy-acrylonitrile (148 mg, 1.06 mmol). The resultant mixture was warmed to 80° C. for 5 h, then cooled to room temperature and concentrated. The resultant residue was partitioned between 1 N NaOH and dichloromethane. After separation of the layers, the aqueous layer was extracted with additional dichloromethane (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C([O:39][C:40]1[C:45]([O:46]C(=O)C)=[CH:44][N:43]=[C:42]([C:50](Cl)=[O:51])[CH:41]=1)(=O)C.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][N:22]([C:50]([C:42]5[CH:41]=[C:40]([OH:39])[C:45]([OH:46])=[CH:44][N:43]=5)=[O:51])[CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(=O)Oc1cnc(C(=O)Cl)cc1OC(C)=O
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Yield: 47.9 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (255 mg) in a mixture of water (5 ml) and acetone (5 ml) was added 4,5-diacetoxy-2-pyridinecarbonyl chloride hydrochloride (309 mg), with maintaining the pH of the solution to 8.0-8.5 by addition of saturated aqueous sodium bicarbonate. After stirring for 30-minutes, acetone was removed by evaporation in vacuo and the residue was adjusted to pH 8 and stirred for 2 hours. The mixture was adjusted to pH 3.0 with 1N hydrochloric acid and chromatographed on Diaion HP-20 (50 ml), and the elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-methyl-4(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (155 mg).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[C:20]([O:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC(CCn1ccnc1)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC(CCn1ccnc1)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 1.26 g 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole in 20 ml pyridine is treated dropwise with stirring with 0.72 ml of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml water, extracted with ethyl acetate and the extracts washed, dried (MgSO4) and evaporated in vacuo to remove residual pyridine and afford 1-[3-benzoyloxy-3-(2-naphthyl)-n-propyl]imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give the hydrochloride salt.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH:25]([CH3:27])[CH3:26])[N:20]=[C:19]([Cl:28])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C>CO.Cl.O1CCOCC1>[Cl:28][C:19]1[N:20]=[C:21]([NH:24][CH:25]([CH3:27])[CH3:26])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CC(C)Nc1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)Nc1nc(Cl)nc(NN)c1F

Procedure:
A solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (597 mg, 1.15 mmol) in MeOH (5 mL) and 4.0M HCl in dioxane (5 mL) was stirred at room temperature overnight. After filtering away the precipitate, the solvent was removed in vacuo, providing the crude 2-chloro-5-fluoro-6-hydrazino-N-(1-methylethyl)-4-pyrimidinamine, presumably as the tri-HCl salt. LCMS: (M+H)+: 219.9.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[C:2]=[S:3].Cl.[NH2:15][CH2:16][C:17]#[N:18]>C(N(CC)CC)C>[NH2:15][C:16]1[N:1]([CH:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)[C:2](=[S:3])[NH:18][CH:17]=1
Reactant: N#CCN
Reactant: S=C=NC1CCc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Product: Nc1c[nH]c(=S)n1C1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.92 g, 10.1 mol), prepared as in Example 10, and aminoacetonitrile hydrochloride (0.94 g, 10.1 mmol) in 1.41 mL of triethylamine was heated at 60° C. for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (elution: methylene chloride followed by 3% methanol in methylene chloride). The purified residue was recrystallized from ethyl acetate/hexane. The residue (1.06 g) and 44 mL of 0.1N potassium hydroxide was stirred under nitrogen for 15 minutes. The residue was isolated by filtration, washed with water, air dried and then stirred with methylene chloride. Filtration and drying gave 5-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione, m.p. 169°-171° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](Cl)=[O:12])[CH3:9].CN(C1C=CC=CN=1)C.[Si]([O:30][C:31]1[CH:36]=[C:35]([O:37][Si](C(C)(C)C)(C)C)[CH:34]=[CH:33][C:32]=1[C@H:45]1[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]1)(C(C)(C)C)(C)C>ClCCl>[C:11](=[O:12])([O:10][CH2:8][CH3:9])[O:51][C@H:48]1[CH2:47][CH2:46][C@H:45]([C:32]2[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=2[OH:30])[CH2:50][CH2:49]1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (0.5 ml), ethylchloroformate (0.5 ml) and dimethylaminopyridine (cat.) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250 mg) in anhydrous dichloromethane (5 ml). After 72 hr at room temperature, the reaction mixture was partitioned between-ethyl-acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (5 ml) and was stirred with fluoride resin (500 mg) for 16 h at room temperature. The resin was filtered through a pad of celite, which was washed well with methanol. The combined filtrates were concentrated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v), and then preparative HPLC to give the title compound (4 mg, 3%) as a cream solid. δH (CD3OD) 1.20-1.30 (3H, m), 1.40-1.60 (4H, m), 1.80-1.95 (2H, m), 2.00-2.20 (2H, m), 2.70-2.84 (1H, m), 4.06-4.20 (2H, m), 4.50-4.60 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d); m/z (ES−) 279 (M−H−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]#[C:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:2]>[Pd].O.C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([OH:20])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:11][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
Palladium on carbon (5%, 1 g) in water (10 mL) was added to a solution of 1,1-dimethylethyl 4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate (Description 76, 14.6 g, 0.046 mol) in ethanol (200 mL) and the mixture was shaken under hydrogen (45 psi) for 90 minutes. The mixture was filtered through a glass fibre pad and the solvent was evaporated under reduced pressure to give the title compound. m/z (ES+) 302 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]#[CH:25]>>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1)[C:24]#[CH:23]
Reactant: C#CCBr
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Product: C#CCOc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (100 mg, 0.45 mmol) and 3-bromoprop-1-yne (129 mg, 0.93 mmol) according to the general procedure IV to give 105 mg (72%) of a pure light brown oily product. Rf=0.56 (EtOAc:PE, 1:1); 1H NMR (CDCl3): δ 7.46 (dt, J=6.3 Hz, 1.8 Hz, 2H), 7.28-7.25 (m, 1H), 7.19, 7.15 (m, 3H), 7.12 (dd, J=2.5 Hz, 1.3 Hz, 1H), 6.96 (ddd, J=8.3 Hz, 2.8 Hz, 1.0 Hz, 1H), 4.70 (d, J=2.5 Hz, 2H), 3.67 (s, 3H), 2.96 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.54 (t, J=2.4 Hz, 1H); 13C NMR (CDCl3): δ 173.1, 157.3, 141.0, 131.8, 129.4, 128.3, 125.0, 124.4, 121.0, 117.4, 115.6, 89.3, 88.8, 78.3, 75.7, 55.9, 51.6, 35.4, 30.8; MALDI-MS m/z 341.4 (M+Na+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[S:10]([CH:13]([CH3:16])[CH:14]=O)[C:11]#[N:12]>>[ClH:9].[Cl:9][C:6]1[N:7]=[CH:8][C:3]([N:2]2[CH:14]=[C:13]([CH3:16])[S:10][C:11]2=[NH:12])=[CH:4][CH:5]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CC(C=O)SC#N
Agent: Cl
Product: Cc1cn(-c2ccc(Cl)nc2)c(=N)s1

Procedure:
The title compound was prepared from 5-amino-2-chloropyridine hydrochloride and 2-thiocyanatopropanal as described for Example 160A. The title compound was used without additional purification.
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C=O.COC1C=C(C=C(OC)C=1OC)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:61]=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[C:47]([CH2:49][CH2:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55]([OH:57])=[O:56])=[O:52])=[O:48].[Br:68]Br>C(O)(=O)C>[Br:68][CH:49]([C:47](=[O:48])[C:46]1[CH:61]=[C:62]([O:66][CH3:67])[C:63]([O:64][CH3:65])=[C:44]([O:43][CH3:42])[CH:45]=1)[CH2:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55]([OH:57])=[O:56])=[O:52]
Reactant: COc1cc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)cc(OC)c1OC
Reactant: BrBr
Agent: COc1cc(C(=O)CCC(=O)O)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(Br)CC(=O)N2CCC[C@H]2C(=O)O)cc(OC)c1OC

Procedure:
As described in Example 52, 3,4,5-trimethoxybenzaldehyde is converted to 3-(3,4,5-trimethoxybenzoyl)propionic acid. The preceding compound is converted to the hydroxysuccinimide ester as described in Example 15 and coupled to L-proline as described in Example 16. The 1-[3-(3,4,5-trimethoxybenzoyl)propionyl]-L-proline is reacted with bromine in acetic acid as in Example 20 to give 1-[3-bromo-3-(3,4,5-trimethoxybenzoyl)propionyl]-L-proline. The preciding compound is reacted with potassium thioacetate in ethanol-water as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[NH:1]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 96.6 %

Procedure:
56.5 g of 5-acetamino-1,3-benzodioxole in 250 ml of glacial acetic acid were nitrated as described above with a solution of 30 ml of nitric acid in 100 ml of glacial acetic acid in a 500 ml sulfonation flask equipped with stirrer, thermometer and dropping funnel. The crystals, removed by filtration under suction, were ashed thoroughly with water and dried overnight at about 60° C. in vacuo. There were obtained 68.3 g (96.6% of theory) of 5-acetamino-6-nitro-1,3-benzodioxole of melting point 211°-213° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH:30]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH:30]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)C(=O)O
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 98 (124 mg, 0.31 mmol) in THF/water, 2:1 (9 mL) was added lithium hydroxide monohydrate (26 mg, 0.62 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organics were dried and evaporated to yield the title compound (65 mg, 0.17 mmol, 55%) as a white solid. Mp 128-132° C. [α]D20+36.8 (c. 0.1, EtOH). 1H NMR (CD3OD, 300 MHz): δ 8.71 (d, J=8.1 Hz, 1H, ArH4″); 8.66 (d, J=8.4 Hz, 1H, ArH3″); 7.79 (s, 1H, ArH1″); 7.76 (s, 1H, ArH10″); 7.51 (m, 5H, ArH7″, ArH6″, ArH5″, ArH2″ and ArH1″); 7.32 (m, 2H, Ar′H); 4.76 (dd, J=5.1, 9.0 Hz, 1H, H2); 3.29 (dd, J=4.8, 13.5 Hz, 1H, H3a); 3.03 (dd, J=8.7, 13.5 Hz, 1H, H3b); 1.95 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 384 (50%) [MH+]. HRMS calcd for C25H22NO3 384.1600, found 384.1628.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14].O>CN(C)C=O>[F:1][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14]
Reactant: [F-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)F)c(C=O)c1F
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To 96.3 g (1660 mmol) of spray-dried potassium fluoride, was added a solution of 129.2 g (664 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde in 1000 ml of dimethylformamide. The resulting reaction mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature and to it was added 4 L of water. The aqueous phase was extracted with ethyl acetate. The combined organic phase were washed with brine, dried over sodium sulphate and evaporated under vacuum to give the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.[O:28]1[CH2:31][C:30](=[O:32])[CH2:29]1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30]3([OH:32])[CH2:31][O:28][CH2:29]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a mixture of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (2.9 g, 9 mmol) in THF (50 mL) at −78° C. was added 2.5 M of n-BuLi (9 mL, 22 mmol) dropwise. The reaction was stirred at −78° C. for 30 minutes and then 3-oxetanone (1.3 mL, 18 mmol) was added, continue stirred for 2 hours at −78° C. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was purified by Isco chromatography with 0-100% EtOAc/hexane to give pure 3-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)oxetan-3-ol as a white solid (2.5 g, 70% yield). LC/MS (ESI+): m/z 397 (M+H)
Reaction SMILES: C([Li])CCC.[Li+].CC([N-]C(C)C)C.[S:14]1[C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][S:21][C:17]=2[N:16]=[N:15]1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:25][C:20]1[S:21][C:17]2[N:16]=[N:15][S:14][C:18]=2[C:19]=1[C:22]([OH:24])=[O:23]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1csc2nnsc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(Cl)sc2nnsc12
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
79 ml (201.6 mmol) of n-butyllithium (1.6M in hexane) are added at -30° C., under nitrogen, to a solution of 20.4 g (201.6 mmol) of diusopropylamine in 200 ml of tetrahydrofuran (THF). After 20 minutes' stirring at -20° C., the LDA solution so prepared is added dropwise at -90° C., under nitrogen, by means of a capillary, to a suspension of 15.0 g (80.6 mmol) of thieno[2,3-d]1,2,3-thiadiazole-6-carboxylic acid in 150 ml of THF. After 90 minutes' stirring at -50° C., a solution of 42.0 g (177.2 mmol) of hexachloroethane in 70 ml of THF is added at -90° C. and the reaction mixture is heated to room temperature within a period of 2 hours. Then the reaction mixture is poured onto 2 litres of water, the aqueous phase is extracted with diethyl ether and acidified with concentrated hydrochloric acid, and the product is isolated by filtration. There are obtained 17.55 g of light-brown solid having a melting point of 255°-265° C. (decomposition).
Reaction SMILES: [CH:1]1([CH2:18][C:19]([C:21]2[S:25][C:24]([CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Cl>CCOCC>[CH:1]1([CH2:18][C:19]([C:21]2[S:25][C:24]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=Cc1ccc(C(=O)CC2CCCCCCCCCCCCCCCC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C=Cc1ccc(C(=O)CC2CCCCCCCCCCCCCCCC2)s1
Temperature: 25 °C

Procedure:
A mixture of 23.0 g (0.05 mole) of the above ester and 250 ml of ethanol are heated to reflux, 100 ml of 1 N aqueous sodium hydroxide is added and the mixture refluxed for 3 hours, then cooled to room temperature. The mixture is acidified to pH 1 with 1 N hydrochloric acid, ether is added and the layers separated. The ether layer is washed with water and evaporated to dryness to give 3-[5-(cycloheptadecylacetyl)-2-thienyl]-2-propenoic acid. This acid is added to 6.9 g (0.06 mole) of α,α-dichloromethyl methyl ether in 100 ml of dichloromethane. The mixture is refluxed overnight then evaporated to dryness to give the corresponding acid chloride which is added to 200 ml of tetrahydrofuran. To the above mixture is added 100 ml of strong ammonium hydroxide solution. The mixture is stirred overnight, is diluted with 500 ml of water and filtered. The precipitate is washed with water and dried to give 3-[5 -(cycloheptadecylacetyl)-2-thienyl]-2-propenamide.