Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][CH:10]=2)[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Reactant: ClCc1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate [Example 55(b)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:24]1[CH:23]=[C:22]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[C:14]([CH:15]=2)[CH2:29][O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)OCc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)OCc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reaction time: 5 h

Procedure:
3-[2-Dimethylcarbamoyloxymethyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (83 mg, 1.638 mmol) was dissolved in 3 ml of CH2Cl2. TFA (0.5 ml) was added and the mixture was stirred for 5 hours. The solution was concentrated under reduced pressure to give dimethyl-carbamic acid 5-(3-fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-benzyl ester, MS (M+H)=407.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10](/[C:16](/[CH3:27])=[CH:17]/[C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:7]CCC[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>>[C:2]([C:8]1[CH:9]=[C:10](/[C:16](/[CH3:27])=[CH:17]/[C:18]2[CH:26]=[CH:25][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])([CH3:7])([CH3:1])[CH3:3]
Reactant: COc1ccc(/C(C)=C/c2ccc(C(=O)O)cc2)cc1C1(C)CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: COc1ccc(/C(C)=C/c2ccc(CO)cc2)cc1C(C)(C)C

Procedure:
1.41 g (4.35 mmol) of the acid obtained in Example 29 are treated with 330 mg of lithium aluminium hydride. The reaction mixture is refluxed for 2 h 30 min and it is then treated with a saturated ammoniumchloride solution and then extracted with 300 ml of ether. After drying and evaporation of the organic phase, the residue is recrystallized from hexane to give 1.21 g (90%) of the expected derivative which melts at 88°-90° C.
Reaction SMILES: [S:1]([C:16]1[CH:21]=[C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19]([OH:28])=[CH:18][C:17]=1[CH3:29])[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][C:3]=1[CH3:15].[OH:30]O>CO>[S:1]([C:16]1[CH:21]=[C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19]([OH:28])=[CH:18][C:17]=1[CH3:29])([C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][C:3]=1[CH3:15])=[O:30]
Reactant: OO
Reactant: Cc1cc(O)c(C2CCCCC2)cc1Sc1cc(C2CCCCC2)c(O)cc1C
Solvent: CO
Product: Cc1cc(O)c(C2CCCCC2)cc1S(=O)c1cc(C2CCCCC2)c(O)cc1C
Reaction time: 8 h

Procedure:
To a solution of crude oily 4,4'-thiobis(6-cyclohexyl-3-methylphenol) (10.5 g) in methanol (40 ml) is gradually added dropwise 30% hydrogen peroxide (6.5 g) at room temperature. The mixture is stirred for a while at the same temperature, and left standing at 50° C. for 3 hours and overnight at room temperature. The precipitated crystals are filtered off, washed with cool methanol and dried to give 4,4'-sulfinylbis(6-cyclohexyl-3-methylphenol), m.p. 151°-153° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:13][NH:14][CH3:15].O>CN(C)C=O>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CNC
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 g of 5-chloro-2-nitrobenzonitrile was dissolved in 150 ml of dimethylformamide, and 150 ml of a 50% aqueous solution of dimethylamine was added thereto. After cooling the heat generated, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the precipitate thus formed was collected by filtration, washed with water and then with methanol to obtain 64.5 g of 5-dimethylamino-2-nitrobenzonitrile (melting point: 174°-175° C.).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(=O)(O)[O-].[Na+].[I-].[Na+].[Br-].Cl.[CH2:32](O)[CH3:33]>CN(C)C=O>[CH2:32]=[CH:33][CH2:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 70 °C

Procedure:
Steps (S1)-(S3) of Scheme 9 are as described for the corresponding reactions of Scheme 8. In step (S4) of Scheme 9, noroxymorphone prepared as described above is taken up in a solvent, e.g., ethanol or dimethyl formamide, to which sodium bicarbonate, sodium iodide, and ally bromide are added. The mixture is heated to a temperature of about 70° C. and the reaction allowed to proceed until deemed complete. The pH is adjusted with hydrochloric acid and naloxone is isolated as the hydrochloride salt. In a similar manner, in step (S5) of Scheme 9, noroxymorphone prepared as described above is taken up in a solvent, e.g., ethanol or dimethyl formamide, to which sodium bicarbonate, sodium iodide, and cyclopropylmethyl bromide are added. The mixture is heated to a temperature of about 70° C. and the reaction allowed to proceed until deemed complete. The pH is adjusted with hydrochloric acid and naltrexone is isolated as the hydrochloride salt.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:12]=1[CH2:13][C:14]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C(OCC)=O)[C:15]([O:17]CC)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)C.Cl>O>[CH2:3]([O:10][C:11]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:12]=1[CH2:13][CH:14]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:15]([OH:17])=[O:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cc(I)ccc1OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
400 ml of a 1N sodium hydroxide solution are added to a suspension of 58 g (97 mmol) of diethyl 2-(2-benzyloxy-5-iodobenzyl)-2-tert-butoxycarbonylaminomalonate (Example 5A) in 800 ml of a mixture of ethanol and water (7:3). After 3 h under reflux and after cooling to room temperature, the pH of the reaction mixture is adjusted to about pH 2 with conc. hydrochloric acid. The reaction mixture is evaporated. The residue is taken up in MTBE and water. The aqueous phase is extracted three times with MTBE. The combined organic phases are dried over sodium sulfate, filtered and concentrated. After drying in vacuo 47 g (97% of theory) of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: OCC1CCCCO1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCCO3)cc2)cc1

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone (0.39 g, 1.00 mmol) and 2-hydroxymethyltetrahydropyran (174 mg, 1.5 mmol) were converted to the title compound by the procedure of Example 1 using 390 mg (1.5 mmol) of triphenylphosphine and 0.24 mL (1.5 mmol) of diethyl azodicarboxylate the only difference being that the total reaction time was 3 hours giving a thick syrup.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C1CCC(N=C=NC2CCCCC2)CC1.Cl>C(OCC)(=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([O:14][C:13]([F:12])([F:22])[F:23])[CH:16]=2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C(=O)Nc2cccc(OC(F)(F)F)c2)cc1
Temperature: 60 °C
Yield: 38 %

Procedure:
to a solution of 300 mg of 4-carboxybenzaldehyde (2 mmoles) and 382 mg of 3-(trifluoromethoxy)aniline (2 mmoles) in 5 ml of ethyl acetate is added 830 mg of dicyclohexycarbodiimide (DCC) (4 mmoles). The reaction mixture is heated at 60° C. overnight and then poured into 60 ml of 1 N HCl solution. The mixture is extracted twice with 30 ml of ethyl acetate. The combined organic extracts are washed with 50 ml of water, 50 ml of a saturated solution of sodium bicarbonate and brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel giving 233 mg of 4-Formyl-N-(3-trifluoromethoxy-phenyl)-benzamide (yield=38%). Analytical LC/MS method A: ([M+H]+): 310, RT: 5.60 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][OH:46])#[CH:38].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[CH2:45][OH:46])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#Cc1ccccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5ccccc5CO)nn4)nn23)CC1
Reaction time: 48 h
Yield: 43.4 %

Procedure:
To a stirred clear solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0946 g, 0.189 mmol), (2-ethynylphenyl)methanol (0.125 g, 0.947 mmol) and DIEA (0.165 ml, 0.947 mmol) in THF (5 mL) was added CuI (0.072 g, 0.379 mmol) at rt. After 48 h, the reaction mixture was diluted with Et2O (50 mL), washed with 1% NH4OH (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0521 g, 0.082 mmol, 43.6% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.51-7.55 (m, 1H), 7.45-7.49 (m, 1H), 7.33-7.38 (m, 2H), 6.54 (s, 1H), 5.96-6.05 (m, 1H), 5.89 (br. s., 1H), 5.82 (s, 2H), 5.45 (d, J=16.87 Hz, 1H), 5.26-5.38 (m, 1H), 5.18 (qd, J=1.58, 10.40 Hz, 1H), 4.64 (s, 2H), 4.13-4.28 (m, 2H), 4.00 (d, J=5.2 Hz, 2H), 2.62 (s, 3H), 1.83-2.04 (m, 3H), 1.65-1.73 (m, 1H), 1.31 (s, 3H), 1.22-1.26 (m, 12H). LCMS (M+H)=632.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-tert-butyl-benzenesulfonamide to general procedure II. Pale-yellow solid. MS (ISP) 524.5 [(M+H)+]; mp 238-239° C.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]2[CH2:10][CH2:11][C@H:6]([N:19]=[N+:20]=[N-:21])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](c2ccc(F)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](c2ccc(F)cc2)CC1

Procedure:
A mixture of 4.22 g. of trans 4-(p-fluorophenyl)cyclohexanol methanesulfonate (obtained as in Example 17) and an equal weight of sodium azide in 45 ml. of dimethylformamide is heated at about 95° C. for about 12 hours. The mixture is taken to dryness on a rotary evaporator and the residue dissolved in water and benzene. The organic layer is washed with water and brine to yield cis 4-(p-fluorophenyl)cyclohexan-1-ylazide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].Cl.[CH3:9][NH:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:9][N:10]([CH3:11])[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: CNC
Reactant: CC(=O)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 21.77 gm (180.5 mMol) 5-chloro-2-pentanone, 13.40 gm (164.3 mMol) dimethylamine hydrochloride and 50.0 gm (361.8 mMol) potassium carbonate in 150 mL acetonitrile was stirred at room temperature for 2 days and then at reflux for 2 hours. The reaction mixture was then cooled to room temperature and partitioned between water and dichloromethane. The phases were separated and the aqueous phase again extracted with dichloromethane. All organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The desired product was then isolated by distillation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC)=O.[F:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34](=[NH:37])[NH:35][NH2:36]>C1COCC1>[F:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34](=[NH:37])[NH:35][NH:36][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14]
Reactant: N=C(NN)c1cc(F)ccc1F
Reactant: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=N)c1cc(F)ccc1F
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
The crude (R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (4 g, 16.2 mmol) was converted to a mixed anhydride by adding Et3N (3.38 ml, 24.26 mmol), ethyl chloroformate (1.931 g, 17.79 mmol) in anhydrous THF (32.4 ml, 0.5 M) at −5° C. to 0° C. The mixture was stirred at −5° C. for 30 min. The resulting solid was filtered off and additional anhydrous THF was added to wash the precipitate. The resulting reaction solution was then added to a THF solution of 2,5-difluorobenzimido-hydrazide (2.77 g, 16.18 mmol) at −5° C. Then the reaction was gradually warmed to room temperature and stirred for overnight. Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product, which was purified on silica gel column (50% EtOAc in Hexanes) to afford (R)-tert-butyl (1-(2-((2,5-difluorophenyl)(imino)methyl)hydrazinyl)-3-methoxy-3-methyl-1-oxobutan-2-yl)carbamate (1 g, 15%). LC/MS (uplc): MH+ 401.2, 0.61 min.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[C:18](Cl)[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH:21]1[CH2:25][CH2:24][CH2:23][O:22]1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:26][NH2:27]>CO>[CH2:1]([N:4]([C:11]1[N:19]=[C:18]([NH:27][CH3:26])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH:21]1[CH2:25][CH2:24][CH2:23][O:22]1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCN(c1nc(Cl)nc2c1ncn2C1CCCO1)C1CCCCC1
Reactant: CN
Solvent: CO
Product: C=CCN(c1nc(NC)nc2c1ncn2C1CCCO1)C1CCCCC1
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 8.5 g. (22 mmole) 6-(N-allyl-N-cyclohexylamino)-2-chloro-9-tetrahydrofuran-2-ylpurine and 150 ml. methanol, which has been saturated with methylamine, is heated to 100° C. in an autoclave for 48 hours. The reaction mixture is then evaporated, the residue is taken up in dichloromethane, washed with water, dried and evaporated. After chromatography with dichloromethane, there are obtained 6.4 g. of the title compound (82% of theory) in the form of an oil.
Reaction SMILES: OC1C=CC(CC=O)=CC=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][CH2:16][OH:17].C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[OH:11][C:12]1[CH:13]=[C:14]([CH2:15][CH:16]=[O:17])[CH:18]=[CH:19][CH:20]=1
Reactant: OCCc1cccc(O)c1
Agent: O=CCc1ccc(O)cc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=CCc1cccc(O)c1
Yield: 22 %

Procedure:
3-hydroxyphenylacetaldehyde was prepared by a synthesis analogous to that of 4-hydroxyphenylacetaldehyde (Heterocycles, 2000, 53, 777-784). 3-Hydroxyphenethyl alcohol (1.0 g, 7.5 mmol, Aldrich) was dissolved in dimethylsulfoxide (8 mL, Aldrich). TEA (2.0 mL, 14 mmol, Aldrich) was added slowly with stirring. Pyridine-sulfur trioxide (SO3.py) complex (2.4 g, 15 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (8 mL, Aldrich) and this solution was added drop-wise to the alcohol, with vigorous stirring. After stirring for 1 h at room temperature, the reaction was quenched with ice-cold water, then extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (3:1, then 1:1) yielded 225 mg (22%) of 3-hydroxyphenylacetaldehyde.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][C:2]1=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]([NH:9][C@@H:10]1[C:21](=[O:22])[N:12]2[CH:13]([C:18]([O-:20])=[O:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12)=[O:8].[Na+].Cl>O>[S:3]1[CH2:4][CH2:5][S:1][C:2]1=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]([NH:9][C@@H:10]1[C:21](=[O:22])[N:12]2[CH:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12)=[O:8]
Reactant: CCOC(=O)C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])C(C)(C)S[C@H]12)=C1SCCS1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)C(C)(C)S[C@H]12)=C1SCCS1
Yield: 73982.5 %

Procedure:
To a solution of sodium 6β-[(1,3-dithiolan-2-ylidene)(ethoxycarbonyl)acetamido]-2,2-dimethylpenam-3-carboxylate (46 mg, 0.1 mmol) in 1 mL of H2O was added one drop (38 mg) of cone. HCl solution at 0° C. The mixture was extracted with dichloromethane several times. The combined organic layer was washed with H2O and saturated NaCl solution, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (32 g, 74% yield) as a yellow oil: 1H NMR (D2O) δ 1.40 (3H, t, J=7Hz, CH2CH3), 1.55 and 1.66 (each 3H, s, C2 -(CH3)2), 3.33 (4H, s, SCH2CH2S), 4.31-4.41 (3H, m, C3 -H and OCH2CH3), 5.57 (1H, d, J=4Hz, C5-H), 5.82 (1H, dd, J=4 and 9Hz, C6-H), 9.03 (1H, d, J=9Hz, NH).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[CH3:20]OC(OC)N(C)C>C(Cl)(Cl)Cl>[CH3:20][N:14]1[C:15](=[O:16])[C:17]([CH3:18])=[CH:19][N:11]([C@@H:6]2[O:7][C@H:8]([CH2:9][OH:10])[C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:5]2)[C:12]1=[O:13]
Reactant: COC(OC)N(C)C
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClC(Cl)Cl
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(C)c1=O

Procedure:
3'-Azido-3'-deoxythymidine (0.5 g; 1.9 mMol) and N,N-dimethylformamide dimethylacetal (Zemlicka, Coll. Czech. Chem. Comm. 35, 3572 (1972)) (0.9 mL; 7.5 mMol) were refluxed in 20 mL CHCl3 for 48 hours. The solvent was removed in vacuo and the material placed on a silica solumn. Elution with EtOAc/CHCl3 (1:1 v/v) resulted in pure material as a viscous oil: 0.26 g (0.9 mMol, 47%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12](Br)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([O-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].O.C1C2C(=CC=CC=2)C=CN=1>C1CCCCC1.[Cu-]=O>[CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(COCc2ccccc2)cc1Br
Reactant: [O-]c1ccccc1
Agent: O=[Cu-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Solvent: c1ccc2cnccc2c1
Product: Fc1ccc(COCc2ccccc2)cc1Oc1ccccc1
Yield: 75 %

Procedure:
A mixture of 1 mol of 3-bromo-4-fluoro-benzyl benzyl ether, 1.1 mol of sodium phenolate, 0.12 mol of copper(I) oxide, 80 g of 4 MgCO3.Mg(OH)2.4 H2O and 1,500 ml of isoquinoline was heated to 160° C. for 12 hours. The reaction mixture was then cooled, diluted with cyclohexane and filtered. The filtrate was washed with dilute hydrochloric acid and water, dried over sodium sulphate and filtered and the filtrate was distilled. 4-Fluoro-3-phenoxy-benzyl benzyl ether was obtained in the form of a yellow oil of boiling point 135° C./1 mbar in a yield of 75% of theory.