Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[O:20]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Reactant: Oc1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccccc1)c1ccc(I)cc1

Procedure:
In a similar manner as in Example 29, 14.2 g of methyl α-bromo-α-(p-iodophenyl)acetate is reacted with 4.70 g of phenol in methanol to yield a white to light pink solid, mp 68°-71° C. Recrystallization from petroleum ether yields the product as white crystals, mp 72.5°-74° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[N:13]=[CH:12][NH:11][C:10]=1[CH3:9])=[S:23]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1nc[nH]c1C
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g) and cysteamine hydrochloride (23.0 g) in acetic acid (200 ml) was heated under reflux for 10 hours. Following cooling to 15°-20°, the solid which crystallised was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride m.p. 189°-192°. Potassium carbonate (7.75 g) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g) in water (120 ml). The solution was stored at room temperature for 15 minutes and methyl isothiocyanate (5.15 g) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5°. The product was collected and recrystallised from water to give N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea, m.p.150°-152°.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([C:40]([O:42][CH3:43])=[O:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OC)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To 1.5 g (3.3 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide Example (586) dissolved in 25 ml of ethyl acetate and cooled to -5° C., was added 1.2 g (15 mmole) of pyridine and, finally, 1.3 g (13 mmole) of methyl chloroformate in 10 ml of ethyl acetate was added over 30 minutes. After an additional 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 0.7 g of the desired compound, mp 142°-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1Cl
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccccc3Cl)C2)cc1

Procedure:
2-Chlorobenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.2 mmol) and 2-chlorobenzyl carbonochloridate (68 mg, 0.22 mmol) according to General Procedure H to give 20 mg (21.3%) of pale yellow solid. Anal. Calcd. for C26H31ClN4O2 m/z 466.2, found: 467.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.44 (d, J=8.7 Hz, 2H), 7.38 (m, 2H), 7.29 (m, 2H), 6.98 (d, J=9 Hz, 2H), 5.1 (s, 2H), 3.69 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 3.02 (m, 1H), 2.79 (d, J=8.4 Hz, 2H), 2.54 (m, 1H), 2.05 (m, 1H), 1.92 (m, 2H), 1.79 (m, 3H), 1.64 (m, 1H), 1.34 (m, 5H), 1.22 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:10][C@@:9]2([C:18]3[C:13](=[CH:14][C:15]([Cl:28])=[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)[CH2:12][O:11]2)[C@H:8]([OH:29])[C@@H:7]([OH:30])[C@@H:6]1[OH:31])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@H:5]1[O:10][C@@:9]2([C:18]3[C:13](=[CH:14][C:15]([Cl:28])=[C:16]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=4)[CH:17]=3)[CH2:12][O:11]2)[C@H:8]([OH:29])[C@@H:7]([OH:30])[C@@H:6]1[OH:31]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN=[N+]=[N-])[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 59.5 %

Procedure:
To a solution of (1S,3′R,4′S,5′S,6′R)-6′-(azidomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (25 mg, 0.056 mmol) in 0.5 mL of THF/H2O (4:1), was added PPh3 (43 mg, 0.164 mmol). The solution was stirred at room temperature for 4.5 h. Then the volatiles were removed under reduced pressure using a rotary evaporator. The resulting residue was purified by preparative HPLC to give 14 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.39 (s, 1H), 7.23 (s, 1H), 7.10 (s, 4H), 5.16 (d, J=12.8 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 4.13 (d, J=15.6 Hz, 1H), 4.05 (d, J=15.6 Hz, 1H), 4.02-3.94 (m, 1H), 3.75 (dd, J=4.1, 1.1 Hz, 2H), 3.34-3.32 (m, 2H□, 2.98-2.91 (m, 1H □, 2.60 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H); MS ESI (m/z) 420 (M+1)+, calc. 419.
Reaction SMILES: [CH2:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=[C:7]4[CH:6]=[CH:5][CH:4]3[CH2:3][CH:2]1[C:20]([OH:22])=[O:21]>O.O.O.O.[N+]([O-])([O-])=O.[Zn+2].[N+]([O-])([O-])=O>[CH2:12]1[C:11]2[C:16]3=[C:7]([CH:8]=[C:9]([C:17]([OH:19])=[O:18])[CH:10]=2)[CH2:6][CH2:5][C:4]2=[C:15]3[C:14](=[CH:1][C:2]([C:20]([OH:22])=[O:21])=[CH:3]2)[CH2:13]1
Reactant: O=C(O)c1cc2c3c4c(ccc3c1)CC(C(=O)O)CC4C=C2
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O
Product: O=C(O)c1cc2c3c(c1)CCc1cc(C(=O)O)cc(c1-3)CC2
Temperature: 105 °C

Procedure:
Exact amounts of tetrahydropyrene-2,7-dicarboxylic acid, (4,4′-HPDCH2) (0.015 g, 0.05 mmol), and zinc nitrate tetrahydrate, Zn(NO3)2.4H2O, (0.052 g, 0.20 mmol), were dissolved in 10 ml DEF and placed in a Parr Teflon-lined stainless steel vessel (23 mL). The vessel was sealed and heated at a constant rate (2° C./min) to 105° C. for 20 h and then cooled to room temperature at a rate of 1° C./min. The resultant sample (76%) was filtered and washed with DEF (3×5 mL) yielding IRMOF-11.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 37.9 %

Procedure:
Prepared according to the method described in Example 65 from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), 4-chlorobenzeneboronic acid (0.180 g) and tetrakis(triphenylphosphine)palladium(0) (40 mg) in toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml) and ethanol (1 ml) with heating at reflux for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid (0.104 g).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-2].[Zn+2:19].[C:20](=[S:22])=[S:21]>>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:20](=[S:21])[S-:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Zn+2:19].[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:20](=[S:21])[S-:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: S=C=S
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCN(CCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 48.40 g of di-n-octylamine and 8.10 g of zinc oxide. Carbon disulfide, 16.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give, upon a pale yellow liquid with a Zn content of 8.1%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([C:16]3([NH:20]C(=O)OCC4C=CC=CC=4)[CH2:19][O:18][CH2:17]3)[CH3:15])[NH:12][CH:13]=2)=[CH:5][CH:4]=1>CO>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([C:16]3([NH2:20])[CH2:17][O:18][CH2:19]3)[CH3:15])[NH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(c1nc(-c2ccc(C(F)(F)F)cc2)c[nH]1)C1(NC(=O)OCc2ccccc2)COC1
Solvent: CO
Product: CC(c1nc(-c2ccc(C(F)(F)F)cc2)c[nH]1)C1(N)COC1
Yield: 63.3 %

Procedure:
Benzyl [3-(1-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}ethyl)oxetan-3-yl]carbamate (Preparation 8, 0.95 g, 2.13 mmol) was dissolved in methanol (20 mL) and hydrogenated at room temperature and 100 psi. The reaction mixture was then filtered over Arbocel© and the resulting filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as a solid (0.42 g, 63%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:13]([OH:17])[C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]([OH:17])[C:14]([O:16][CH3:22])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To solution of [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetic acid (510 mg, 1.77 mmol) in benzene (10 mL) was added MeOH (1.5 mL) followed by (trimethylsilyl)diazomethane (1.06 mL of a 2M solution in hexanes, 2.12 mmol). After 10 minutes, the reaction was quenched with several drops of HOAc (add until yellow color disappears). The reaction was concentrated and purified by flash chromatography with 10 to 80% EtOAc/hexanes to afford methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate. 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 2H), 7.85 (s, 1H), 5.32 (s, 1H), 3.83 (s, 3H), 3.68 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH2:21]NCCC2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:74][CH2:75][CH2:76][C:77]1[CH:121]=[CH:120][C:80]([O:81][CH2:82][CH2:83][N:84]([CH3:119])[C:85]([C:87]2[CH:88]=[C:89]([S:93]([C:96]3[CH:97]=[C:98]4[C:103](=[C:104]([CH3:106])[CH:105]=3)[N:102]=[CH:101][C:100]([C:107]([NH2:109])=[O:108])=[C:99]4[NH:110][C:111]3[CH:116]=[CH:115][CH:114]=[C:113]([O:117][CH3:118])[CH:112]=3)(=[O:95])=[O:94])[CH:90]=[CH:91][CH:92]=2)=[O:86])=[CH:79][CH:78]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:66][Si:67]([C:70]([CH3:71])([CH3:73])[CH3:72])([CH3:69])[CH3:68])[CH2:21][NH:74][CH2:75][CH2:76][C:77]2[CH:121]=[CH:120][C:80]([O:81][CH2:82][CH2:83][N:84]([CH3:119])[C:85]([C:87]3[CH:88]=[C:89]([S:93]([C:96]4[CH:97]=[C:98]5[C:103](=[C:104]([CH3:106])[CH:105]=4)[N:102]=[CH:101][C:100]([C:107]([NH2:109])=[O:108])=[C:99]5[NH:110][C:111]4[CH:116]=[CH:115][CH:114]=[C:113]([O:117][CH3:118])[CH:112]=4)(=[O:94])=[O:95])[CH:90]=[CH:91][CH:92]=3)=[O:86])=[CH:79][CH:78]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCN)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 140, using Intermediate 95 in place of Intermediate 94. ES/MS calcd for C60H67N6O9SSi+ 1075.45. Found m/z=1075.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[F:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[F:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ccncc2F)c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(-c2ccncc2F)c1

Procedure:
4-(2-chloro-5-nitrophenyl)-3-fluoropyridine (1 eq) was stirred with Iron (0), (3 eq), in acetic acid for 10 hours at room temperature. Reaction neutralized with sodium carbonate and filtered to remove iron. Reaction partitioned between ethyl acetate and water. Organic layer separated and washed with brine, dried over sodium sulfate and concentrated to give 4-chloro-3-(3-fluoropyridin-4-yl)benzenamine. HPLC=1.72 min; MS: MH+=223.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]2[C:19](O)([CH3:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:9]=2[O:10][CH:11]=1)[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH3:40][C:41]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]2[C:19]([CH3:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:22][Si:44]([C:41]([CH3:43])([CH3:42])[CH3:40])([CH3:46])[CH3:45])[C:9]=2[O:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCc1coc2c1C(C)(O)c1ccccc1C2=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCc1coc2c(O[Si](C)(C)C(C)(C)C)c3ccccc3c(C)c12
Temperature: 0 °C
Yield: 369.9 %

Procedure:
A solution of 24.0 mg (0.076 mmol, 1.0 eq) of alcohol 16 in 5.0 mL of dry CH2Cl2 was stirred in a 5 mL round bottom flask at room temperature under argon. To this solution was added 36.6 μL of Et3SiH (0.229 mmol, 3.0 eq). The solution was then cooled to 0° C. in an ice water bath. After cooling, 28.0 μL (0.220 mmol, 2.9 eq) of BF3-Et2O was slowly added and the resulting solution was stirred until all the starting material was consumed by TLC (1:1 hexane:EtOAc, Rf=0.56). After alcohol 16 was completely consumed (˜15 minutes), 69.0 mg (0.456 mmol, 6.0 eq) of TBSCl and 31.0 mg (0.456 mmol, 6.0 eq) of imidazole were added at once and the ice water bath was removed. The solution was then stirred at room temperature until the reaction was complete by TLC (1:1 hexane:EtOAc, Rf=0.80). Upon completion (˜18 hours) the solution was diluted with CH2Cl2 and washed with a saturated aqueous NH4Cl solution. The aqueous layer was then extracted twice with CH2Cl2 and the combined organic fractions were dried over MgSO4 and concentrated. Silica gel chromatography (hexane/EtOAc) yielded 116 mg (69%) of 17 as a colorless solid, Rf 0.80 (1:1 hexane:EtOAc). Mp: 92.4-93.5° C. 1H-NMR (500 MHz, CDCl3): 8.31 (1H, m), 8.10 (1H, m), 7.47 (3H, m), 4.20 (2H, q, J=7.1 Hz), 3.29 (2H, t, J=7.6 Hz), 2.93 (3H, s), 2.78 (2H, t, J=7.7 Hz), 1.28 (3H, t, J=7.2 Hz), 1.15 (9H, s), 0.27 (6H, s). 13C-NMR (500 MHz, CDCl3): 172.93, 143.40, 143.25, 132.82, 130.16, 127.98, 125.74, 124.02, 123.87, 123.69, 122.69, 119.97, 118.53, 60.84, 34.56, 26.24, 21.79, 18.93, 14.45, 14.42, −3.86. IR (cm−1): 2960 (m), 2854 (w), 1740 (vs), 1630 (w), 1461 (m), 1389 (s), 1247 (m), 1117 (m), 985 (s), 828 (s), 752 (s). Anal. Calcd. for C24H32O4Si: C, 69.86; H, 7.82. Found: C, 70.18; H, 8.02.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([S:23](F)(=[O:25])=[O:24])[N:17]=1>C(COC)OC>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][S:23]([C:18]1[N:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[N:19]=1)(=[O:24])=[O:25]
Reactant: Cc1cccc(Cl)c1N
Reactant: Cc1cc(C)nc(S(=O)(=O)F)n1
Agent: [Li]CCCC
Solvent: COCCOC
Product: Cc1cc(C)nc(S(=O)(=O)Nc2c(C)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-6-methylaniline (0.5 g, 3.5 mmol) in dimethoxyethane (15 mL) cooled to 0° C. was added butyl lithium (2.2 mL, 3.5 mmol) and the mixture was allowed to stir for 15 minutes. Then 4,6-dimethyl-2-pyrimidinesulfonyl fluoride (0.66 g, 3.5 mmol), prepared according to Brown and Hoskins, J. Chem. Soc. Perkin 1, 522-527 (1972) was added. The mixture stirred with warming to 25° C. for 1 hour. The mixture was concentrated and the residue triturated with butyl chloride. The resultant solid was acidified with 1N HCl and the solid was filtered. The product was a yellow-brown solid, m.p. 215°-219° C. NMR (200 MHZ) D6 -Acetone: δ 8.2 (bs, 1H), 7.4 (s, 1H), 7.2 (bs, 3H), 2.5 (s, 6H) and 2.35 (s, 3H).
Reaction SMILES: C(OC(=O)[CH:7]([C:20]#[N:21])[C:8](=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[N+:16]([C:12]1[CH:11]=[C:10]([CH2:9][C:8](=[O:19])[CH2:7][C:20]#[N:21])[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)C(C#N)C(=O)Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=O)Cc1cccc([N+](=O)[O-])c1
Yield: 63.2 %

Procedure:
To a solution of 2-cyano-4-(3-nitrophenyl)-3-oxo-butyric acid tert-butyl ester (9.5 g, 31 mmol) in toluene (40 mL) was added TFA (4 mL) and the solution was heated at reflux for 2 h, then the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 4.0 g of 4-(3-nitrophenyl)-3-oxo-butyronitrile (37% over 2 steps).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>CCOC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][N:11]1[CH2:24][CH2:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)c1ccc(COCc2ccccc2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1CC(C(=O)OCC)CCC1COCc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 12.7 %

Procedure:
To an EtOAc solution (0.9 mL) of 14c (271 mg, 1.0 mmol) was added 2 M ethereal HCl (3.6 mL), and then the solvent was removed in vacuo and the residual 14c.HCl salt was dissolved in MeOH (5.4 mL) and PtO2 (14 mg) was added. The mixture was hydrogenated under 1 atm of H2 (1 h). The catalyst was filtered, and the solvent was removed in vacuo. The residue was dissolved in aqueous 1 N NaOH (3.5 mL) and extracted with EtOAc (3×15 mL). The organic extracts were combined, dried (Na2SO4), concentrated, and then dissolved in ethyl acrylate (1.1 mL, 10 mmol) and stirred at 80° C. (20 h). The reaction was concentrated to dryness and the residue was separated by PTLC (EtOAc/hexanes=2/3) to give 15c (48 mg, 13%) and 17 (32 mg, 12%), respectively. Compound 15c: clear oil; Rf 0.57 (EtOAc/hexanes=1/1); IR (neat) 2978, 2935, 2862, 1731, 1454, 1372, 1181 cm−1; 1H NMR (CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.64-1.77 (m, 4H), 2.43-2.54 (m, 3H), 2.66 (dd, J=3.9, 12.2 Hz, 1H), 2.82-2.97 (m, 4H), 3.45 (dd, J=5.9, 9.6 Hz, 1H), 3.66 (dd, J=5.4, 9.6 Hz, 1H), 4.12 (q, J=7.2 Hz, 4H), 4.47 (1/2 AB, J=12.2 Hz, 1H), 4.52 (1/2 AB, J=12.2 Hz, 1H), 7.27-7.34 (m, 5H), 13C NMR (CDCl3) 14.1, 14.2, 23.3, 25.9, 33.1, 40.6, 50.1, 50.3, 57.6, 60.1, 60.2, 69.3, 73.2, 127.4, 127.5 (2C), 128.3 (2C), 138.3, 172.7, 174.1 ppm; MS (+CI) 378 [M+1]+; Mr (+CI) 378.228 63 [M+1]+ (calcd for C21H32NO5 378.228 05). Compound 17 (King et al., “Substituted Benzamides with Conformationally Restricted Side Chains. 5. Azabicyclo[xyz] Derivatives as 5-HT4 Receptor Agonists and Gastric Motility Stimulants”, J. Med. Chem. 1993, 36, 683-689) (cis- and trans-mixture): yellow oil; Rf 0.44 (EtOAc/hexanes=1/1); IR (neat) 2974, 2924, 2814, 1735, 1455, 1377 cm−1; 1H NMR (CDCl3) δ 1.00 (d, J=6.6 Hz, 1.4H), 1.10 (d, J=6.6 Hz, 1.6H), 1.23-1.28 (m, 6H), 1.40-2.01 (m, 4H), 2.18-2.31 (m, 1H), 2.42-2.59 (m, 4H), 2.67-2.88 (m, 2H), 3.03-3.10 (m, 1H), 4.08-4.17 (m, 4H), 13C NMR (CDCl3) 13.7 (2C), 14.2 (2C), 19.9 (2C), 23.1 (2C), 27.4 (2C), 32.7, 33.8, 41.2, 42.2, 48.8, 49.6, 49.8, 53.3, 54.1, 55.1, 60.2 (2C), 60.3 (2C), 172.8 (2C), 174.1 (2C) ppm; MS (+CI) 272 [M+1]+; Mr (+CI) 272.186 63 [M+1]+ (calcd for C14H26NO4 272.186 18).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][CH2:6][C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)([CH2:8][O:9]CC2C=CC(OC)=CC=2)[CH2:4][O:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[CH3:1][C:2]1([CH3:27])[O:3][CH2:4][C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)([CH2:8][OH:9])[CH2:6][O:7]1
Reactant: COc1ccc(COCC2(c3ccc(F)c(F)c3)COC(C)(C)OC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)OCC(CO)(c2ccc(F)c(F)c2)CO1
Reaction time: 4 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-(3,4-difluorophenyl)-5-(4-methoxybenzyloxymethyl)-1,3-dioxane (360 mg, 1 mmol) in 10 ml of an 18:1 v/v mixture of dichloromethane-water was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (350 mg, 1.5 mmol) in small portions. The reaction mixture was stirred for 4 hours, then filtered and evaporated; purification on a silica column eluting with dichloromethane/methanol (19:1 v/v) afforded 2,2-dimethyl-5-(3,4-difluorophenyl) 5-hydroxymethyl-1,3-dioxane as a yellow oil. Nmr δ 7.2-7.0 (3H,m), 4.05 (2H,d), 4.00 (2H,d), 4.00 (2H,s), 1.75 (1H,broad), 1.4 (6H,d).