Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[C:13]([SH:15])[CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].[C:16](C1OC2C(CCC)=C(S)C=CC=2C(=O)C=1)(O)=O>>[C:1]([C:4]1[O:5][C:6]2[CH:14]=[C:13]([SH:15])[CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([O:3][CH3:16])=[O:2]
Reactant: CCCc1c(S)ccc2c(=O)cc(C(=O)O)oc12
Reactant: O=C(O)c1cc(=O)c2ccc(S)cc2o1
Product: COC(=O)c1cc(=O)c2ccc(S)cc2o1

Procedure:
Following the procedure of Step 4 of Example 1 but substituting an equivalent amount of the acid from Step 3 above for 2-carboxy-7-mercapto-8n-propyl-4-oxo-4H-1-benzopyran, there was obtained the title compound, m.p. 147°-150°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16](=[O:26])[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[N:19]=[C:10]23)=[C:4]([O:28][CH3:29])[CH:3]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl>[F:36][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:28][CH3:29])[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16](=[O:26])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)[N:19]=[C:10]12
Reactant: COc1cc(F)ccc1C(O)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1cc(F)ccc1C(F)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
To a solution of 0.290 g (0.73 mmol) of (+/−)-10-[(4-fluoro-2-methoxy-phenyl)-hydroxy-methyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one (example 4) in dichloromethane (14 mL) under argon at −78° C. was added 0.294 g of diethylaminosulfur trifluoride (1.83 mmol) diluted in 5 ml of dichloromethane. The reaction was allowed to increase to room temperature. The reaction was stirred at room temperature for 2 h; the mixture was quenched at 0° C. with the addition of methanol and stirred overnight. A saturated solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated solution of sodium chloride and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 2% of methanol and 0.2% of ammonia) to afford 0.072 g (25%) of a white solid as an isomer mixture (95/5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][N:6]1[CH2:30][C@:29]2([C:31](=[O:37])[CH2:32][O:33]C(=O)C)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:38])[CH2:7]1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][N:6]1[CH2:30][C@:29]2([C:31](=[O:37])[CH2:32][OH:33])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:38])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COC(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CN1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Temperature: 0 °C
Yield: 44.9 %

Procedure:
A solution of compound 158 (75 mg, 0.136 mmol) in ethanol (5 ml) is degassed with nitrogen for 15 minutes and cooled to 0° C. Then K2CO3 (9.43 mg, 0.068 mmol) is added and the mixture is stirred at 0° C. with continuous degassing for 1 hour. The reaction mixture is partitioned between water and AcOEt. The combined organic phases are concentrated and crude is purified by silica gel flash chromatography (eluent DCM/EtOH=99/1 to 95/5) to yield the title compound (31 mg, 0.061 mmol, 45% yield).
Reaction SMILES: [ClH:1].COC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=C(N)C=1.[CH3:28][O:29][C:30]1[CH:52]=[CH:51][C:33]([O:34][C:35]2[CH:44]=[C:43]3[C:38]([CH2:39][CH:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:41][O:42]3)=[CH:37][CH:36]=2)=[C:32]([N+:53]([O-])=O)[CH:31]=1>>[ClH:1].[CH3:28][O:29][C:30]1[CH:52]=[CH:51][C:33]([O:34][C:35]2[CH:44]=[C:43]3[C:38]([CH2:39][CH:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:41][O:42]3)=[CH:37][CH:36]=2)=[C:32]([NH2:53])[CH:31]=1
Reactant: COc1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)C3)c([N+](=O)[O-])c1
Agent: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1
Agent: Cl
Product: COc1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)C3)c(N)c1

Procedure:
5-Methoxy-2-(3-phenylchroman-7-yloxy)phenylamine hydrochloride was prepared as described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine hydrochloride in Example 3(b) using 310 mg of 7-(4-methoxy-2-nitrophenoxy)-3-phenylchroman. 1H NMR (400 MHz, d6-DMSO) δ: 7.32-7.35 (m, 4H), 7.23-7.29 (m, 1H), 7.05 (d, 1H, J 8.4 Hz), 6.76 (d, 1H, J 8.8. Hz), 6.46 (d, 1H, J 2.8 Hz), 6.43 (dd, 1H, J 8.4, 2.5 Hz), 6.28 (d, 1H, J 2.5 Hz), 6.24 (dd, 1H, J 8.8, 2.8 Hz), 4.24 (dd, 1H, J 10.4, 3.4 Hz), 4.05 (t, 1H, J 10.4 Hz), 3.18 (m, 1H), 2.88-3.01 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4]C[C:2]1=[O:7].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:14]([Cl:17])(Cl)[Cl:15]>>[Cl:15][C:14]1([Cl:17])[CH2:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7]
Reactant: ClC(Cl)Cl
Reactant: O=C1CCCCN1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C1NCCCC1(Cl)Cl
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of piperidin-2-one (42, 25.0 g, 252.2 mmol) in CHCl3 (250 mL) was treated with PCl5 (158 g, 756.5 mmol, 3.0 equiv) at 0-5° C., and the resulting reaction mixture was stirred at 0-5° C. for 10 min before being warmed up to reflux for 2 h. When HPLC showed the reaction was complete, the reaction mixture was cooled down to 5-10° C. before being transferred into an ice water (500 mL) with caution. The resulting mixture was stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (50 mL), dried over MgSO4, and concentrated in vacuo. The residual solids were treated with 30% EtOAc/hexane (50 mL) before being collected by filtration. The crude pale-yellow solids were dried in vacuo at 30-35° C. for 12 h to afford the desired 3,3-dichloro-piperidin-2-one (43, 27.96 g, 42.36 g theoretical, 66%) as bright-yellow oil, which solidified upon standing at room temperature in vacuo. For 43, CIMS m/z 166/170 (M+−H, C5H7Cl2NO).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:31][CH3:32])[CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:22]>C(O)CC>[CH2:31]([N:23]([CH2:21][CH3:22])[CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25]1)[CH3:32]
Reactant: CCN(CC)C1CCCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CCCO
Product: CCN(CC)C1CCCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-(diethylamino)-hexahydro-1H-azepine to give colorless crystals, mp. 222°-224° C. (n-propanol).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[Mg].[CH3:6][C:7]1[CH:12]([CH:13]=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][CH:8]=1.[NH4+].[Cl-]>CCOCC>[CH3:6][C:7]1[CH:12]([CH:13]([OH:14])[CH2:3][CH:2]=[CH2:1])[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][CH:8]=1
Reactant: CC1=CCCC(C)(C)C1C=O
Reactant: C=CCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)C1C(C)=CCCC1(C)C
Reaction time: 3 h

Procedure:
Allyl chloride (5 ml.) was added under nitrogen to a suspension of magnesium (28.8 g.) in 300 ml. of dry ether. According to the usual procedure of a Grignard reaction, allyl chloride (85 g.) and α-cyclocitral (152 g.) in 100 ml. of dry ether were added at such a rate as to maintain the solvent at reflux. At this temperature, the mixture was left during 3 h. and poured then into an NH4Cl aqueous solution.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[CH2:28]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[O:38])[CH2:33][CH2:32]1)[C:29]#[CH:30]>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.[Cu]I.CN(C=O)C>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([CH2:28][C:29]#[C:30][C@@:9]2([N:8]3[C:18]4[N:19]=[CH:2][N:3]=[C:4]([NH2:20])[C:5]=4[N:6]=[CH:7]3)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:36][CH2:35]1)=[O:38]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@]1(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoadenosine (0.602 g, 1.531 mmol) in freshly degassed DMF (20 mL) was added degassed triethylamine (1.20 mL, 8.54 mmol), Pd(PPh3)4 (85 mg, 0.074 mmol), CuI (catalytic), and 2-chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.588 g, 2.117 mmol). The mixture was stirred at room temperature under and inert atmosphere for 20 h. Silica bound Pd(II) scavenger Si-thiol (400 mg) and Pd(0) scavenger Si-TAAcOH (619 mg) were added and stirring continued a further 72 h. The suspension was filtered through celite and the resulting solution evaporated to dryness. The crude was purified by column chromatography, eluting with a gradient of DCM/MeOH (0-4%) to afford the pure product as a white solid: yield 0.733 g, 88%.
Reaction SMILES: C([O:5][C:6](=[O:57])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:35][C:36](=[O:56])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[CH2:38]([NH:37][C:36]([O:35][CH:11]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][S:9][CH2:8][CH2:7][C:6]([OH:57])=[O:5])=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)O)OC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 6,7-bis(octadecylcarbamoyloxy)-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 7 (1010 mg) in trifiuoroacetic acid (3 ml)-dichloromethane (0.5 ml) was stirred at room temperature for 1 hour, followed by solvent concentration under reduced pressure, to yield the title compound (938 mg, yield 99%) as a colorless solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[C:17]([CH3:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(OCC)(=O)C.C(O)C>[NH2:8][C:9]1[C:17]([CH3:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:1])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(Br)ccc(C(=O)O)c1N
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c(C)c1N
Reaction time: 16 h
Yield: 87.9 %

Procedure:
Add (trimethylsilyl)diazomethane (16.5 mL, 33 mmol, 2 M in hexane) to a solution of 2-amino-4-bromo-3-methyl-benzoic acid (3.8 g, 16.5 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) at room temperature and stir the solution for 16 h. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate, to afford the title compound (3.54 g, 88%). MS (ES+): 245 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7].[OH2:13]>CC#N>[OH:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(CBr)cc(C(=O)O)c1
Reactant: O
Solvent: CC#N
Product: Cc1cc(CO)cc(C(=O)O)c1

Procedure:
To a solution of 3-bromomethyl-5-methyl-benzoic acid (3.90 g, 17 mmol) in water (30 mL) and MeCN (30 mL), Cu(NO3)2 hemipentahydrate (12.77 g, 68 mmol) followed by water (50 mL) was added. The turquoise mixture was refluxed for 2 h before it was concentrated to about half of the original volume. The dark green solution was extracted three times with EA (150 mL). The org. extracts were washed twice with water (2×50 mL), combined, dried over Na2SO4, filtered and concentrated. The white residue was separated by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 95% MeCN in water containing 0.5% of formic acid) to give 3-hydroxymethyl-5-methyl-benzoic acid as a white solid (897 mg; LC-MS*: tR=0.17 min; [M−1]−=164.86), along with the title compound as a white solid (160 mg). To a solution of the above 3-hydroxymethyl-5-methyl-benzoic acid (947 mg, 5.70 mmol) in MeCN (40 mL), MnO2 (1.49 g, 17.1 mmol) was added and the resulting mixture was stirred at 80° C. for 16 h before another portion of MnO2 (1.21 g, 13.9 mmol) and acetonitrile (40 mL) was added and stirring was continued at 80° C. for 4 h. The mixture was filtered over a glass fibre filter, the colourless filtrate was concentrated and purified by prep. HPLC (as above) to give the title compound (504 mg) as a white solid. LC-MS*: tR=0.26 min; [M−1]−=162.88; 1H NMR (D6-DMSO): δ 2.47 (s, 3H), 7.96 (s, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 10.06 (s, 1H), 13.28 (m, 1H).
Reaction SMILES: ClC1C(N)=CC=CN=1.C(=O)C1C=CC=CC=1.[CH:17](=[N:24][C:25]1C(Cl)=[N:27][CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.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>[C:18]1([C:17]2[C:28]([NH2:27])=[CH:29][CH:30]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1ncccc1N=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Nc1cccnc1Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: Nc1cccnc1-c1ccccc1
Temperature: 25 °C

Procedure:
To 2-chloro-3-aminopyridine (1.06 g, 8.24 mmol) in toluene (25 mL) was added benzaldehyde (0.878 g, 8.27 mmol). The reaction mixture was stirred at reflux in a Dean-Stark apparatus until GC/MS analysis of the reaction mixture no longer showed starting material. The reaction mixture was cooled to room temperature and the toluene solution containing benzylidene-(2-chloro-pyridin-3-yl)-amine was added to a mixture of phenylboronic acid (1.30 g, 10.7 mmol), sodium carbonate (2.66 g, 25.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.38mol %) in water (10 mL). The reaction mixture was heated to 100° C. for 30 minutes, cooled to room temperature and poured into 1N aqueous sodium hydroxide (10 mL). The aqueous layer was removed and the toluene layer was extracted with 1N aqueous hydrochloric acid (twice with 15 mL). The aqueous layer was neutralized to pH 12 with 6N aqueous sodium hydroxide and extracted with MTBE (twice with 20 mL). The MTBE extracts were dried over magnesium sulfate, filtered and concentrated to afford 2-phenyl-3-aminopyridine as a solid which crystallized from diisopropyl ether (1.26 g, 90% yield). M. p.=87-68° C. 1H NMR (300 MHz, CDCl3) δ3.88 (bs, 2), 7.02-7.11 (m, 2), 7.28-7.53 (m, 3), 7.6714 7.71 (m, 2), 8.13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ122.57, 122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93, 144.93.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:23]([O:25]C(C)(C)C)=[O:24])([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:10][CH:9]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[CH2:14]([O:13][C:11]([CH:9]1[CH2:10][C:8]1([C:23]([OH:25])=[O:24])[C:16]([OH:18])=[O:17])=[O:12])[CH3:15]
Reactant: CCOC(=O)C1CC1(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC1(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 123.7 %

Procedure:
TFA (4.5 g, 39.7 mmol) was added into a solution of 1,1-di-tert-butyl 2-ethyl cyclopropane-1,1,2-tricarboxylate (4.9 g, 13.2 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for 48 h. The solvent was evaporated in vacuo and the excess TFA was lyophilized to afford 2-(ethoxycarbonyl)cyclopropane-1,1-dicarboxylic acid (3.3 g, 100%). 1H NMR (300 MHz, CD3OD): δ 1.23-1.29 (t, J=6.9 Hz, 3H), 1.60-1.64 (m, 1H), 1.85-1.88 (m, 1H), 2.48-2.53 (m, 1H), 4.10-4.18 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:30])=[CH:11][C:12]([NH2:29])=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25]COC)C1C=CC=CC=1>CO.Cl.[OH-].[OH-].[Pd+2]>[NH2:29][C:12]1[N:13]=[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:9]([OH:8])=[C:10]([CH3:30])[CH:11]=1
Reactant: COCOCCCCCCCCCCc1nc(N)cc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N)nc(CCCCCCCCCCO)c1O

Procedure:
To a stirred solution containing 113 mg (0.27 mmol) of 5-(benzyloxy)-6-(10-(methoxymethoxy)decyl)-4-methylpyridin-2-amine in 10 mL of methanol were added two drops of concentrated HCl and the mixture was stirred at reflux for 16 h. To the mixture were added 5 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/N). The reaction mixture was stirred at 23° C. under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrated was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×1 cm). Elution with 17:3 dichloromethane-methanol afforded the expected product as white solid: yield 22 mg (29%); mp: 138-139° C.; silica gel TLC Rf 0.20 (17:3 dichloromethane-methanol); 1H NMR (methanol-d4) δ 1.28-1.35 (m, 12H), 1.48-1.58 (m, 4H), 2.13 (s, 3H), 2.60 (dd, 2H, J=7.6, 7.6 Hz), 3.51 (t, 2H, J=6.8 Hz) and 6.25 (s, 1H); 13C NMR (methanol-d4) δ 15.21, 25.51, 28.78, 29.15, 29.20, 29.22, 29.22, 29.28, 31.49, 32.23, 61.58, 108.39, 139.23, 141.68, 146.88 and 152.45; mass spectrum (APCI+), m/z 281.2231 (M+H) (C16H29N2O2 requires 281.2229).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[C:2]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C.[BH4-].[Na+].CO.Cl>O1CCCC1>[OH:8][CH2:7][C:3]1[C:2]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccnc1-c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: OCc1cccnc1-c1cccnc1
Temperature: 20 °C
Yield: 84.4 %

Procedure:
To a continually stirred, ice-cold solution of 2,3′-bipyridine-3-carboxylic acid (0.28 g, 1.40 mmole) in dry tetrahydrofuran (10 ml) and triethylamine (0.20 ml, 1.43 mmole) ethyl chloroformate (0.14 ml, 1.46 mmole) was added drop-by-drop over a 30 minute period. The precipitated product was then filtered and washed several times with tetrahyrofuran (3×2 ml). The THF phases were combined, cooled to +10° C., and while stirring under an argon atmosphere, sodium borohydride (0.185 g, 4.9 mmole) was added and then methanol (0.90 ml, 22.2 mmole) was added drop-by-drop over a 1 hour period during which time the temperature increased to 20° C. (Soai et al., 1987). The material was stirred for an additional 1 hour at room temperature. Then, 1N hydrochloric acid was carefully added, the solvent was evaporated under vacuum to 5 ml and washed with dichloromethane (3×5 ml). Sodium carbonate (0.85 g) was added to the aqueous phase, which was then extracted with dichloromethane. The combined fractions were dried with magnesium sulfate and evaporated under vacuum (2 Hg mm, 45° C.) giving a pure product (0.22 g, 84%). 1H-NMR, δ, ppm, 8.71 (1H, dd, J=2.1, 0.6 Hz, C2′-H), 8.55 (1H, dd, J=4.8, 1.5 Hz, C6-H), 8.52 (1H, dd, J=4.8, 1.8 Hz, C6′-H), 7.95 (1H, dd, J=7.8, 1.5 Hz, C4-H), 7.91 (1H, ddd, J=7.8, 2.1, 1.8 Hz, C4′-H), 7.35 (1H, ddd, J=7.8, 4.8, 0.6 Hz, C5′-H), 7.31 (1H, dd, J=7.8, 4.8 Hz, C5-H), 4.58 (2H, s, CH2—O).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C1(C)C(C)=CC=CC=1>O>[N:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:7](=[O:9])[CH2:6][C:4]3([CH2:3][CH2:2][CH2:1][CH2:5]3)[CH2:12][C:10]2=[O:11])=[CH:15][CH:16]=1
Reactant: Nc1ccncc1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC2(CCCC2)CC(=O)N1c1ccncc1

Procedure:
The starting material is prepared as follows: The mixture of 200 g of 3,3-tetramethyleneglutaric anhydride, 57 g of 4-aminopyridine and 1,500 ml of xylene is stirred and refluxed on a water separator for 3 days. After cooling slightly, the xylene solution is decanted from a small amount of oily material, and after cooling in an ice bath, the collected residue dissolved in 1,500 ml of boiling ethanol, the solution cooled to 5°, filtered and the residue dried, to yield the 8-(4-pyridyl)-8-azaspiro[4,5]decan-7,9-dione melting at 208°-211°.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.C(O/[CH:16]=[C:17](/[C:23](=O)[C:24]([F:27])([F:26])[F:25])\[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]([C:24]([F:27])([F:26])[F:25])=[N:2][NH:3][CH:16]=1)=[O:19])[CH3:22]
Reactant: NN
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 146.66 mmol) in ethanol (500 mL) at −20° C. was added DIPEA (45.3 mL, 266.66 mmol) followed by stirring at this temperature for 10 minutes. Ethyl (2Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (Preparation 113, 32 g, 133.33 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and diluted with EtOAc. The organic solution was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30% EtOAc in hexane to afford the title compound (13 g) that was taken directly on to the next step.
Reaction SMILES: C([S:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)C.[Li+].[OH-]>O1CCCC1>[SH:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([OH:24])=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CC(=O)SCC1(C(=O)NCC(O)C(=O)OCc2ccccc2)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(O)CNC(=O)C1(CS)CCc2ccccc2C1
Reaction time: 4 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (4.41 g, 10.0 mmol) in deoxygenated tetrahydrofuran (50 mL). To this solution add 1N LiOH (30 mL, 30.0 mmol) and stir under an atmosphere of argon for 4 hours. Concentrate the solution in vacuo then purify the residue by column chromatography (acetic acid:ethyl acetate:hexane) to give the title compound.