Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:25]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NCc4cccnc4)c3)n2)cc1

Procedure:
Intermediate 24 was coupled with pyridine 3-carboxaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 398. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.6 (s, 1H), 8.4 (d, 1H) 8.2 (d, 1H) 7.8 (d, 1H), 7.4-7.3 (m, 3H), 7.2 (t, 1H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (d, 1H), 6.7 (d, 1H), δ 4.4 (s, 2H), δ 3.6 (t, 2H), 2.8 (t, 2H).
Reaction SMILES: [C:1](=[O:6])(OC)[O:2][CH3:3].[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]([Si](C)(C)C)[CH:17]=[CH:16][N:15]([Si](C)(C)C)[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:3][O:2][C:1]([N:15]1[CH:16]=[CH:17][CH2:18][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:7])=[CH:14]1)=[O:6]
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Reactant: COC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N1C=CCC(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of dimethyl carbonate (0.05 mL, 0.6 mmol) in 2 mL of dry THF was slowly added 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine I (0.2 mL, 0.68 mmol). A solution of TBAF in THF (0.06 mL, 0.06 mmol) was then introduced dropwise and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ether (2 times), and the combined organic layers were washed with brine and dried over K2CO3. The solvent was removed under reduced pressure and the crude material was purified by RPLC (hexanes) to afford 0.1374 g (91%) of 3-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II as a clear oil. IR (thin film, neat, NaCl): 2949, 2826, 2764, 1721, 1695, 1437, 1334, 1313, 1194, 983 cm−1. 1H NMR (300 MHz, CDCl3): δ 6.68-6.51 (m, 2H), 4.88-4.77 (m, 1H), 3.65 (s, 3H), 2.95-2.91 (m, 1H), 2.64-2.62 (m, 2H), 2.41-2.33 (m, 1H), 2.05-1.93 (m, 5H), 1.68-1.53 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 151.81, 123.15, 122.74, 120.28, 119.63, 118.08, 117.71, 106.22, 105.94, 70.37, 56.60, 53.05, 40.16, 40.08, 28.76, 28.38, 22.37, 21.56, 21.05. HRMS Calcd for C12H18N2O2: 223.1447 [M+H]+. Found: 223.1434 [M+H]+. [α]24D −65.5 (c=8, CH2Cl2).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)CCl.[C:21]1(C)C=CC=CC=1>>[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:21][C:18]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:5]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cc1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Cc2cc(F)ccc2O)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a stirred solution of 23.66 g of 95% sodium hydride (0.94 mol) in 600 mL of dry toluene was added 100.0 g of 4-fluorophenol (0.89 mol) at 0° C. The mixture was stirred at 90° C. for 1 hour until gas evolution stopped. The mixture was cooled down to room temperature and a solution of 139.71 g of 3-methoxybenzyl chloride (0.89 mol) in 400 mL of dry toluene was added. After refluxing for 24 hours, the mixture was cooled to room temperature and quenched with 500 mL of water. The organic layer was separated, dried over MgSO4, and concentrated under high vacuum. The remaining starting materials were removed by distillation. The crude dark red oil was filtered through a layer of 1 L of silica gel with neat hexane to yield 53.00 g (25.6%) of the product as a pink solid: 1H NMR (CDCl3) d 3.79 (s, 3H), 3.90 (s, 2H), 4.58 (s, 1H), 6.70-6.74 (m, 1H), 6.79-6.88 (m, 4H), 7.11-7.16 (m, 2H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]=1[CH3:14])=O.[N+]([O-])(O)=O.[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:13][N:9]1[C:8]([CH3:14])=[C:7]([C:5]2[CH:4]=[CH:3][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:31][CH:30]=3)[N:34]=2)[S:11][C:10]1=[O:12]
Reactant: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Solvent: O=[N+]([O-])O
Product: Cc1c(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)sc(=O)n1C

Procedure:
Condensation between 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate afforded the title compound. Anal. RP-HPLC: tR=17.5 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>95%). 1H-NMR (DMSO-d6) δ: 2.48 (3H, s, CH3), 3.03 (4H, m, 2×morph-NCH2), 3.08 (3H, s, CH3), 3.72 (4H, m, 2×morph-OCH2), 6.85 (1H, d, J=5.2, pyrim-H), 6.89 (2H, d, J=9.2, 2×ArH), 7.57 (2H, d, J=9.2, 2×ArH), 8.36 (1H, d, J=5.2, pyrim-H) and 9.35 (1H, s, NH). MS (ESI+) m/z 384[M+H]+ (C19H21N5O2S requires 383.5).
Reaction SMILES: [CH3:1]N(CCC1C=CC=CC=1)C(=O)COC1C=C2C(=CC=1)NC=C2.C[C:25]1[CH:41]=[CH:40][C:28]([CH2:29][O:30]C2C=C3C(=CC=2)NC=C3)=[CH:27][CH:26]=1.C(O[C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][CH:54]=[C:53]2[CH:59]=[O:60])C1C=CC=CC=1.CC1C=CC(COC2C=C3C(=CC=2)NC=C3C=O)=CC=1>>[CH3:1][C:51]1[CH:50]=[CH:58][CH:57]=[C:56]2[C:52]=1[C:53]([CH:59]=[O:60])=[C:54]([O:30][CH2:29][C:28]1[CH:40]=[CH:41][CH:25]=[CH:26][CH:27]=1)[NH:55]2
Reactant: Cc1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CN(CCc1ccccc1)C(=O)COc1ccc2[nH]ccc2c1
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cc1ccc(COc2ccc3[nH]cc(C=O)c3c2)cc1
Product: Cc1cccc2[nH]c(OCc3ccccc3)c(C=O)c12

Procedure:
When N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide is replaced in the procedure of Example 6 with 5-benzyl-oxyindole and 5-(4-methylbenzyloxy)indole then the products obtained are 5-benzyloxyindole-3-carboxaldehyde and 5-(4-methylbenzyloxy)indole-3-carboxaldehyde. NMR confirms these structures.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.[OH-].[Na+].O>COCCO>[O:1]=[C:2]1[C:11]2[C:10]([O:12][CH2:13][CH:15]3[O:17][CH2:16]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2cccc(O)c21
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: O=C1CCCc2cccc(OCC3CO3)c21

Procedure:
To the solution heated to 80° C. of 3.2 g of 8-hydroxy 1-tetralone and 20 ml of epichlorohydrin in 20 ml of 2-methoxy ethanol is added 1.8 g of sodium hydroxide and the mixture is heated to reflux for 1 hour. Water is added and the mixture is extracted with methylene chloride. The organic phase is separated, dried and the solvent is evaporated.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:18][C@H:19]1[CH2:24][C:23]2[C:25]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:25]2[C:23]3[CH2:24][C@H:19]([NH:18][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=4[C:2]([F:1])([F:17])[F:16])[CH2:20][O:21][C:22]=3[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2C(F)(F)F)CO3)CC1
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A solution of 2,4-bis(trifluoromethyl)benzoic acid (195 mg, 0.755 mmol) in thionyl chloride (4 mL) was heated at 55° C. for 45 min. The excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (170 mg, 0.687 mmol) and triethylamine (144 μL, 1.03 mmol) in anhydrous methylene chloride (20 mL) with stirring. The reaction mixture was left overnight at room temperature and was washed with a 2 M NH3 solution (10 mL) followed by a portion of brine. The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 100 mg (30% yield) of the title compound as a white powder: mp 202-203° C.; [α]21D−51° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 487 (16, M+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].CCN(C(C)C)C(C)C.[C:25]1([C:35](Cl)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>ClCCl.C(OCC)(=O)C>[C:25]1([C:35]([NH:15][C@H:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)[CH2:11][CH2:10]2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cccc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
(3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (1.098 mmol, 1 eq) was dissolved in dichloromethane, and DIPEA (2.5 eq) and naphthalene-1-carboxylic acid chloride (1.0 eq) were added under a protecting gas atmosphere at 0° C. The reaction mixture was stirred for 1.5 h at RT. Then the reaction mixture was diluted with ethyl acetate, washed 1× with 10% ammonium chloride solution and 1× with sat. NaCl solution, dried over magnesium sulfate and purified by column chromatography (silica gel, cyclohexane:ethyl acetate 3:1). Yield: 58%
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][Si:9]([CH3:26])([CH:24]=[CH2:25])[C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][Si:9]([CH3:26])([CH:24]=[CH2:25])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1
Reactant: C=C[Si](C)(C)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[Si](C)(C)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
At 0° C., 10 ml TFA was slowly added dropwise in the CH2Cl2 solution of compound 14. The reaction mixture was stirred at 0° C. for 2 hours. After adjusting pH to 8 by adding saturated Na HCO3, the reaction mixture was extracted by ethyl acetate. The organic layer was dried and evaporated to give a crude product, which was purified using column chromatography to give the product (7 g, 72%).
Reaction SMILES: O1CCOCC1.Cl.Cl.[Cl:9][C:10]1[C:11]([CH:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[N:14][CH:15]=1.C(N(CC)CC)C.Cl[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1>C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:31])=[O:32])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:48]2[N:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[N:14][CH:15]=1
Reactant: Clc1ncccn1
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCCCNc2ncccn2)ncc1Cl
Temperature: 80 °C
Reaction time: 19 h
Yield: 65.1 %

Procedure:
To a 1,4-dioxane solution (1.0 ml) of the N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (76 mg, 0.136 mmol) obtained in Example 173 were added triethylamine (76 μl, 0.54 mmol) and 2-chloropyrimidine (23 mg, 0.20 mmol). The resulting mixture was stirred at 80° C. for 19 hours. The reaction mixture was allowed to cool to room temperature, followed by dilution with ethyl acetate. The diluted mixture was washed with water and brine, dried and concentrated. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to give the title compound (50 mg, 65%). The compound was crystallized in ethanol to afford a white solid (36 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([CH:36]=O)=[C:31]([Cl:38])[CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([C:36]2[NH:20][C:15]3[CH:14]=[C:13]([C:11]4[O:12][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][N:10]=4)[CH:18]=[CH:17][C:16]=3[N:19]=2)=[C:31]([Cl:38])[CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Reaction time: 72 h

Procedure:
To a 20 ml scint. vial was added 0.3783 g (1.32 mmol) 4- [5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine, 04000 g (01.32 mmol) of 3-(3,5-Dichloro-4-formyl-phenyl)-propionic acid tert-butyl ester (step A), and 6 mL of DMSO. To this dark brown solution was added 0.0321 g (0.198 mmol) of FeCl3. Allowed to stir open to air for 72 h. Extracted with EtOAc, and washed with water, brine and dried with Na2SO4. Purified on silica gel (ACN/DCM, 1:9 to 4:6) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.64 (t, J=7.33 Hz, 2 H) 2.92 (t, J=7.26 Hz, 2H) 7.60 (s, 2 H) 7.72 (d, 2 H) 7.78 (d, J=8.59 Hz, 0.5 H) 7.92 (d, J=8.46 Hz, 0.5 H) 8.00-8.09 (m, 1 H) 8.17-8.22 (m, 2 H) 8.31 (s, 0.5 H) 8.50 (s, 0.5 H) 13.32 (d, J=11.24 Hz, 1 H). MS (m/z) 571.1 M (+1), tR=1.59, Meth 10
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1CCOCC1>C(Cl)(Cl)Cl>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Reactant: CC1CCNCC1
Solvent: C1COCCN1
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2ccc(CO)cc2[N+](=O)[O-])CC1
Temperature: 50 °C

Procedure:
A stirred suspension of (4-fluoro-3-nitro-phenyl)-methanol (171 mg, 1 mmol), 4-methyl piperidine (95 mg, 0.96 mmol) PS morpholine (400 mg, 1 mmol), and chloroform (3 mL) was heated at 50° C. for 2 hrs. The reaction was evaporated onto celite and purified by flash chromatography to give [4-(4-methyl-piperidin-1-yl)-3-nitro-phenyl]-methanol (i). 1H NMR (CDCl3, 300 MHz): δ 7.8 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.6 (s, 2H), 3.2 (d, 2H), 2.8 (dd, 2H), 1.8-1.3 (m, 5H), 1.0 (d, 3H).
Reaction SMILES: COC(N1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])CC1)=O.[CH:18]([O-])([O-])OCC.CC1(C)O[C:30](=O)[CH2:29][C:27](=O)[O:26]1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[OH:26][C:27]1[C:15]2[C:13](=[C:12]3[C:11](=[CH:17][CH:16]=2)[N:8]=[CH:9][CH:10]=[CH:18]3)[N:14]=[CH:30][CH:29]=1
Reactant: COC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC([O-])[O-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Oc1ccnc2c1ccc1ncccc12
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of 3-(4-methoxycarbonyl-1-piperazinyl)aniline (0.75 g, 3.2 mmol), ethyl orthoformate (0.50 g, 3.4 mmol), Meldrum's acid (0.48 g, 3.4 mmol) was stirred at 110° C. for 1.5 hours. The reaction mixture was added with diphenyl ether (10 ml) and stirred at 240° C. for 1.5 hours. After allowing to cool, n-hexane was added to the mixture. The resulting precipitates were collected by filtration and purified by column chromatography (Wako Gel™ C-200, methylene chloride methanol=10 : 1) to obtain the titled compound (320 mg, 35%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][N:7]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)[CH2:3][OH:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:29]=[C:30]=[O:31])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>ClCCl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:9]2[CH2:10][N:7]([CH2:6][CH2:5][C@H:2]([NH:1][C:30]([NH:29][C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=3)=[O:31])[CH2:3][OH:4])[CH2:8]2)=[CH:17][CH:16]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: COc1cc(N=C=O)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.2 g, 0.74 mmol) in dichloromethane (6 ml) is treated with 3,5-dimethoxy-phenyl-isocyanate (0.12 g, 0.667 mmol). The reaction mixture is stirred at ambient temperature for 24 hours and then evaporated. The crude product is purified by flash silica chromatography (elution gradient 3:97 to 7:93 methanol/dichloromethane) to afford 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea. [MH]+ 449.9.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: OC(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of Intermediate 2B (115 mmol) in anhydrous CH2Cl2 (320 mL) was added Dess-Martin periodinane (50.2 g, 118 mmol) portionwise at 0° C. The reaction was stirred at 0° C. for 0.5 h then at rt for 3 h. To the reaction was added 100 mL of sat'd aq Na2CO3 and 250 mL of EtOAc. The reaction was stirred for another 2 h. The insoluble material was removed by filtration. The layers were separated. The organic layer was washed with sat'd aq Na2CO3. Additional solids that formed upon standing overnight were removed. The organic solution was washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated to provide a dark brown liquid, which was purified by silica gel chromatography (220 g silica gel, elute with EtOAc in hexanes to provide Intermediate 2C (26 g, 76%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[N:9][C:8](OC)=[CH:7][CH:6]=2)[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2]
Reactant: CCc1cc(=O)c2nc(OC)ccc2[nH]1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCc1cc(=O)c2c([nH]1)CCCN2
Yield: 73.3 %

Procedure:
Compound E5 (5.0 g) was dissolved in glacial acetic acid (50 ml) and catalytically hydrogenated at atmospheric pressure over platinum oxide (0.5 g). When hydrogen uptake ceased, the catalyst was removed by filtration through diatomaceous earth. The solvent was removed by evaporation and the residue purified by flash chromatography eluting with ethyl acetate/methanol/aqueous ammonia (17:2:1 v/v), to give 2-ethyl-5,6,7,8-tetrahydro-1,5-naphthyridin-4(1H)-one (D5) (3.2 g), m.p. 206°-209° C. (after trituration with ethyl acetate); NMR (d6 -DMSO): 1.15(t,3H), 1.7-1.9(m,2H), 2.35(q,2H), 2.55(t,2H), 3.1(t,2H), 5.75(s,1H), 10.6-11.1(br s,1H).
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.C(N(CC)CC)C>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
Alkene 1b (2 g, 8.6 mmol) was dissolved in 50 mL of dry CH2Cl2 with 2.4 mL of anhydrous triethylamine. The flask was purged with argon and cooled in an ice bath. Pivaloyl chloride (1.6 g, 2 eq.) was added dropwise over one hour. The cooling bath was removed and stirring continued for 3 hours at room temperature. The solution was washed with aq. K2CO3 and then water, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 5% triethylamine in hexane yielding 1.95 g of dioxetane 1e: 1H NMR (CDCl3) δ 7.34-6.98 (m, 4H), 3.198 (s, 3H), 2.47 (sept, 1H), 2.33 (sept, 1H), 1.36 (s, 9H), 1.24 (d, 6H, J=6.9 Hz), 0.92 (d, 6H, J=6.9 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][CH2:11][CH3:12])[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH2:22][O:23][CH3:24]>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][CH2:11][CH3:12])[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH2:22][O:23][CH3:24])=[O:1]
Reactant: CCCOc1ncnc(CO)c1-c1ccc(OC)cc1OCOC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCOc1ncnc(C=O)c1-c1ccc(OC)cc1OCOC
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 6-hydroxymethyl-5-(2-methoxymethoxy-4-methoxyphenyl)4-propoxy-pyrimidine in CH2Cl2 was treated with MnO2 and stirred vigorously for 24 h. The mixture was filtered through celite and concentrated to afford the tide compound (1.48 g, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:19])=[N-]>C1COCC1>[OH:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 96.1 %

Procedure:
To a solution of compound 235 (5.2 g, 22.49 mmol) in THF (50 mL) was added diazomethane (38.5 mL, 27.0 mmol, 0.7M) dropwise until yellow color persists. The mixture was concentrated to afford title compound 236 (5.3 g, 96%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 4.50-4.47 (m, 1H), 4.44 (t, J=7.7 Hz, 1H), 3.76-3.43 (m, 2H), 3.73 (s, 3H), 2.33-2.22 (m, 1H), 2.11-2.03 (m, 1H), 1.91 (m, 1H), 1.45-1.41 (m, 9H). LRMS (ESI): (calc.) 245.13. (found) 146.0 (M-Boc+H)+.