Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:15])=[O:14])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.O[C:43]1[CH:48]=[CH:47][C:46]([C:49](=[O:51])[CH3:50])=[CH:45][CH:44]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([O:15][C:43]2[CH:48]=[CH:47][C:46]([C:49](=[O:51])[CH3:50])=[CH:45][CH:44]=2)=[O:14])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)COC1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OC(=O)[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 63.4 %

Procedure:
At 0° C., 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylic acid (1.0 g) is dissolved in ethyl acetate (25 ml), dicyclohexylcarbodiimide (DCC; 1.26 g) is then added and the reaction mixture is subjected to agitation for 45 minutes at 0° C. Dimethylaminopyridine (DMAP; 100 mg) and 4′-hydroxyacetophenone (565 mg) are successively added, the reaction mixture is then left to return to room temperature. After 5 hours of agitation, the mixture is filtered and the filtrate is washed with a sodium hydrogen carbonate saturated solution, then with a sodium chloride saturated solution. The organic phase is dried on MgSO4, filtered and concentrated. The obtained orange oil is purified by chromatography on silica to obtain the desired product as a transparent oil (940 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13](F)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][OH:28]>>[CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2c(NC3CCCC3)c(C#N)cnc2cc1F
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2ncc(C#N)c(NC3CCCC3)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of 4-cyclopentylamino-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.53 mmol) and sodium hydride (53 mg, 2.21 mmol) in 1.6 mL of 2-methoxyethanol is heated at reflux for 30 minutes, then cooled to room temperature. The reaction mixture is partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative thin layer chromatography, eluting with 5% methanol in dichloromethane, followed by trituration with methanol and diethyl ether, provides 95 mg of 4-cyclopentylamino-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 87-90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[O:14])[O:12][C:11]([C:19]3[N:23](COCC[Si](C)(C)C)[C:22]4[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:21]=4[N:20]=3)([C:15]([F:18])([F:17])[F:16])[C:5]2=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.CC1C=C2C(=O)OC(C3N(COCC[Si](C)(C)C)C4C=C(C#N)C=CC=4N=3)(C(F)(F)F)C2=C2C=1NC=C2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[O:14])[O:12][C:11]([C:19]3[NH:23][C:22]4[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:21]=4[N:20]=3)([C:15]([F:18])([F:17])[F:16])[C:5]2=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1cc2c(c3cc[nH]c13)C(c1nc3cc(C#N)ccc3n1COCC[Si](C)(C)C)(C(F)(F)F)OC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc2c(c3cc[nH]c13)C(c1nc3ccc(C#N)cc3n1COCC[Si](C)(C)C)(C(F)(F)F)OC2=O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(c3cc[nH]c13)C(c1nc3cc(C#N)ccc3[nH]1)(C(F)(F)F)OC2=O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a solution of a mixture of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (36 mg, 0.068 mmol) in THF (0.5 mL), TBAF (1M in THF, 1.37 mL, 1.37 mmol) was added. The reaction was stirred at 75° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with brine, and the layers were separated. The aqueous layer was extracted with ethyl acetate and dried over Na2SO4. After concentration, the residue was purified via silica gel flash chromatography (heptanes/((30% EtOAc in CH2Cl2)=0 to 100%) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 10.09 (br. s., 1H), 8.06 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.5, 1.5 Hz, 1H), 7.54-7.57 (m, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.00-7.04 (m, 1H), 2.63 (d, J=0.8 Hz, 3H). HRMS calcd. for C20H11F3N4O2 (M+H)+ 397.0907. found 397.0902.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C@@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]2)[CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: COC(=O)C1CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1C[C@H](N[C@@H](C)c2ccc(OC)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 1 g of methyl 3-oxoindane-1-carboxylate in 10 ml of toluene were added 0.78 ml of (1S)-1-(4-methoxyphenyl)ethanamine and 100 mg of p-toluenesulfonic acid monohydrate, followed by heating to reflux for 5 hours using a Dean-Stark type reflux device. Then, 634 mg of magnesium sulfate was added thereto, followed by heating to reflux for 5 hours using a Dean-Stark type reflux device. Further, 634 mg of magnesium sulfate was added thereto, followed by heating to reflux for 5 hours using a Dean-Stark type reflux device. The insoluble material was removed by filtration and the solvent was then evaporated under reduced pressure to obtain an intermediate product. To a solution of the obtained intermediate product in 17 ml of ethanol was added 209 mg of sodium borohydride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The solvent was evaporated under reduced pressure, and to the obtained residue were added water, a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.195 g of methyl (3S)-3-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-1-carboxylate.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:37]([O:39][CH2:40][O:41][C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:38])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][CH2:29][O:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[O:27])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:23].[NH2:8][C@@:9]1([C:37]([O:39][CH2:40][O:41][C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:38])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][CH2:29][O:30][C:31]([O:33][CH:34]([CH3:35])[CH3:36])=[O:32])=[O:27]
Reactant: CC(C)OC(=O)OCOC(=O)[C@H]1[C@@H]2[C@H](O)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCOC(=O)OC(C)C)[C@H]12
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)OCOC(=O)[C@H]1[C@@H]2[C@H](O)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)OCOC(=O)OC(C)C)[C@H]12
Reaction time: 0.75 h
Yield: 95 %

Procedure:
Add bis({[(1-methylethoxy)carbonyl]oxy}methyl) (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate in a 4.0M solution of hydrogen chloride in dioxane (14.47 mL, 57.87 mmol) and stir for 45 minutes. Add ethyl acetate, and concentrate the reaction mixture to a foam. Triturate the foam with ethyl acetate to produce a solid. Concentrate and dry under vacuum at 40° C. overnight to provide the title compound as an off-white solid (1.77 g, 2.75 mmol, 95%): MS (m/z): 608 (M+H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CC[C@@H](F)C1
Yield: 77.2 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 0.79 g, 7.96 mmol) was slowly added (R)-(−)-3-fluoropyrrolidine hydrochloride (1.0 g, 7.96 mmol), triethylamine (1.11 mL, 7.96 mmol) and MeOH (2.5 mL). The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((R)-3-fluoropyrrolidin-1-yl)-2-isocyanoethanone BLE 04170 as a brown oil (0.96 g, 77% yield) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15](OCC)=[O:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2
Product: CN(C)CCNC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2

Procedure:
The product of Example 13 and N,N-dimethylethylenediamine were processed as in Examples 29A, 29B and 5B to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.16-1.57 (m, 5H), 1.68-1.77 (m, 1H), 1.78-1.89 (m, 6H), 1.90-2.00 (m, 2H), 2.34-2.45 (m, 1H), 2.36 (s, 3H), 2.61-2.79 (m, 4H), 3.00 (s, 6H), 3.38 (t, J=5.9 Hz, 2H), 3.75 (t, J=5.9 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 7.66-7.72 (m, 2H); MS (DCI/NH3) m/z 378 (M+H)+; anal. calculated for C20H31N3O2S.C7H8O3S.1.2H2O: C, 56.76; H, 7.30; N, 7.35. Found: C, 56.86; H, 7.45; N, 7.05.
Reaction SMILES: [CH3:1][C:2](O)([C@H:4](/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]2O)=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])C)[CH3:3].C[C@@H]([C@@H]1[C@@]2(C)CCC/C(=C\C=C3\C[C@@H](O)C[C@H](O)C\3=C)/[C@@H]2CC1)/C=C/[C@@H](C(O)(C)C)C>O1CCCC1.CCOCC>[CH3:23][C:22]1[CH2:21][CH2:20][C@H:19]([OH:30])[CH2:18][C:17]=1/[CH:16]=[CH:15]\[C:14]1[C@@H:13]2[CH2:12][CH2:11][C@H:10]([C@@H:8]([CH2:7][CH2:6][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:9])[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH:24]=1
Reactant: C[C@H](/C=C/[C@H](C)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1

Procedure:
(22E)-5,7,22-Ergostatriene-1α,3β,25-triol and its 24-epimer of formula (I) can be converted into 1α,25-dihydroxyvitamin D2 and its 24-epimer of formula (II) by a general procedure for the synthesis of vitamin D from the 5,7-diene. More particularly, (22E)-5,7,22-ergostatriene-1α,3β,25-triol and its 24-epimer of formula (I) in tetrahydrofuran/ether were respectively irradiated to afford a previtamin D. The previtamin D was isomerized by heating in a suitable solvent, e.g. ethanol. Purification of the resulting products by chromatography and recrystallization affords 1α,25-dihydroxyvitamin D2 and the 24-epimer thereof.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[OH:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:17](=[O:16])[C:18]([CH3:23])([CH3:22])[CH2:19][OH:20])=[CH:13][CH:12]=1
Reactant: CC(C)(CO)C(=O)O
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CO)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-2, step-1, 800 mg, 3.45 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (591 mg, 5.00 mmol) in DMF (5 mL) were added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.29 g, 5.18 mmol) and DIPEA (1.29 g, 10.0 mmol). Then reaction mixture was stirred at rt for 12 h and it was diluted with EtOAc, washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO d6): δ 8.09-8.06 (t, J=8.0 Hz, 1H), 7.45-7.38 (m, 2H), 4.91-4.88 (t, J=5.2 Hz, 1H), 4.42-4.37 (q, J=8.0 Hz, 2H), 4.29-4.28 (d, J=5.6 Hz, 2H), 3.48 (m, 2H), 1.33-1.29 (t, J=8.0 Hz, 3H), 1.05 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:4][C:5]([NH:8][CH:9]=[C:10]([C:16](OCC)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[NH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]2=[O:17]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(-c2ccncc2)n1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(-c3ccncc3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A suspension of diethyl N-[3-fluoro-2-(4-pyridyl)-6-pyridyl]aminomethylenemalonate (11.5 g) in 120 ml of Dowtherm A was heated to reflux for 10 minutes and then cooled to room temperature. The resulting solid was filtered off. The filtrate was heated to reflux for 10 minutes and the solid was collected. The combined solid was washed successively with ethanol and ether to give ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate (7.2 g, m.p. 280°-285° C.).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:21][CH2:20][N:19](CC5C=CC=CC=5)[CH2:18][CH2:17]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.N>>[N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1)N1CCC1
Agent: N
Solvent: CC(=O)O
Product: O=C(c1cc2cccc(N3CCNCC3)c2o1)N1CCC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 39d starting from azetidin-1-yl(7-(4-benzylpiperazin-1-yl)benzofuran-2-yl)methanone (0.52 g, 1.38 mmol) and acetic acid (0.63 mL, 11.1 mmol). A solution of ammonia (3 mL, 7N in MeOH) was added to the mixture after the reaction was complete. The solvent was removed by rotary evaporation. The crude product was purified by flash chromatography (SiO2; gradient 0-10% ammonia (7N in MeOH) in DCM). Yield: 0.36 g (91%).
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C=CC=CC=1N)CC2.C(OC(=O)C)(=O)C.[OH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][C:45](=O)[CH3:46])[CH2:32][CH2:31]2>N1C=CC=CC=1>[CH2:45]([NH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH:33]1[CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([OH:27])[CH:37]=[CH:36][C:35]=2[CH2:34]1)[CH3:46]
Reactant: CC(=O)Nc1ccccc1C1CCc2cc(O)ccc2C1
Agent: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCNc1ccccc1C1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (3.7 g), acetic anhydride (19 ml) and pyridine (19 ml) was stirred for 1 hour at room temperature. The reaction solution was concentrated in vacuo, then ethyl acetate (20 ml) and chloroform (5 ml) were added thereto, the crystal that was precipitated was filtered and dried. Synthesized from the total amount of the resulting N-[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide according to an analogous synthetic method to Example 364 described below, the total amount of N-[2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide was used according to an analogous synthetic method to Example 337 described below to provide the title compound (2.3 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:20][Br:21])[CH2:9][C:10]([O:12]CC1C=CC=CC=1)=[O:11]>O1CCCC1.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:20][Br:21])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(CC(CBr)OC1CCCCO1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CC(CBr)OC1CCCCO1
Reaction time: 0.75 h

Procedure:
The product of Step 3 (73 mg, 0.20 mmole) was dissolved in tetrahydrofuran (3 mL) and 10% palladium on charcoal (65 mg) was added. The mixture was flushed thrice with nitrogen, thrice with hydrogen, and then stirred under hydrogen for 45 min. The mixture was filtered through Celite, the Celite was rinsed with ethyl acetate (10 mL), and the combined filtrates were evaporated to give 3-[2-tetrahydropyranyloxy]4-bromobutanoic acid as a colourless oil, 54 mg (98%). IR (neat): 1715 cm−1. Mass spectrum (CI, m/z): 267, 269 (M+1, M+3).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([O:18][CH2:19][O:20][CH3:21])[C:12]=1[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CS(C)=O>[CH3:7][O:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([O:18][CH2:19][O:20][CH3:21])[C:12]=1[C:22]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:2][CH2:28]1
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)OCC)c1c(OCOC)ccc(C)c1OCOC
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OCOC)ccc(C)c2OCOC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (4.4 g, 20 mmol) in dry dimethyl sulfoxide (30 mL) sodium hydride (60% dispersion in mineral oil) (0.720 g, 18 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. A solution of ethyl 2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]prop-2-enoate (Intermediate 9, 3.5 g, 11.29 mmol) in dry dimethyl sulfoxide (15 mL) was slowly added and the reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (40 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water (2×50 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (3.1 g) as a colourless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([C:14]3[N:19]=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]([O:24]C(C)(C)C)=O)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1>O1CCOCC1>[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([C:14]3[N:19]=[CH:18][C:17]([C:20]4[CH:21]=[C:22]([OH:24])[NH:3][N:2]=4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(C2CCC3(CC2)OCCO3)nc1
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc(-c2ccc(C3CCC4(CC3)OCCO4)nc2)n[nH]1

Procedure:
Hydrazine hydrate (5 mL) was added to a solution of Example 93C (1.07 g, 2.96 mmol) in dioxane (10 mL). The resulting solution was refluxed for 3 hours before it was cooled and partitioned with tetrahydrofuran and brine. The aqueous phase was acidified with 6 N hydrochloric acid to pH 2 and extracted repeatedly with a tetrahydrofuran/ethyl acetate mixture. The combined organic phases were dried (magnesium sulfate), filtered, and concentrated. The crude product was recrystallized from ethyl acetate and hexane to provide a light brown solid.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCCl>[C:29]1([C:22]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:20][CH2:19][N:18]([CH2:35][C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.033 g, 0.162 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.162 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.046 g, 0.242 mmol) were stirred together in 1,2-dichloroethane (0.5 mL) at room temperature. After stirring for 1 hour, the reaction was heated to 85° C. and stirred overnight. The reaction was cooled, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% ethyl acetate/hexane to 100% ethyl acetate over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.22-8.26 (m, 2H), 7.76-7.80 (m, 2H), 7.21-7.35 (m, 10H), 4.93 (s, 2H), 3.64 (t, J=6.4 Hz, 2H), 2.69-2.74 (m, 2H), 1.88-1.97 (m, 2H); MS (ESI+) m/z 478 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](N)(=[NH:19])[CH3:18].C1(C)C(C)=CC=CC=1>>[CH3:18][C:17]1[NH:15][N:14]=[C:12]([C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]=2)[N:19]=1
Reactant: CC(=N)N
Reactant: NNC(=O)c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1nc(-c2nnc(-c3ccccc3)o2)n[nH]1
Temperature: 170 °C
Reaction time: 36 h
Yield: 22.5 %

Procedure:
To a solution of 5-phenyl-1,3,4-oxadiazole-2-carbohydrazide (400 mg, 1.96 mmol) and acetamidine hydrochloride (573 mg, 6.07 mmol) in xylene (20 mL) NaOH (243 mg, 6.07 mmol) was added. The mixture was stirred at 170° C. for 36 h, and then the reaction was cooled to RT, washed with H2O (20 mL), extracted with 4:1 CHCl3:i-PrOH (5×50 mL), dried with MgSO4 and concentrated. The crude product was purified on a Biotage pre-packed silica gel column (MeOH:DCM 2% to 20% MeOH) to afford 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (100 mg, 22%) as a white powder. MS (ES+) C11H9N5O requires: 227 found: 228 [M+H]+.