Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.Cl[C:11]1([C:17]([O:19][CH3:20])=[O:18])[C:15](=[O:16])[CH:14]=[CH:13][S:12]1>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17]([C:11]1[S:12][C:13]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=[CH:2]2)=[CH:14][C:15]=1[OH:16])=[O:18]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: c1cnc2nc[nH]c2c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cccnc32)cc1O

Procedure:
In a similar manner as described for example C6, 30.0 g of 1H-imidazo[4,5-b]pyridine and 19.26 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 2 l chloroform give 3-hydroxy-5-imidazo[4,5-b]pyridin-3-yl-thiophene-2-carboxylic acid methyl ester (compound C8b) and the crude title compounds as an isomeric mixture which was used for the next step without further purification (example B5). The structural assignment of compound C8b was unequivocally established by two-dimensional 1H NMR experiment (NOESY, COSY).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3([C:13]4[N:14]([N:15]=[N:16][N:17]=4)[C:6]=2[CH:5]=1)[CH2:12][O:11]3)([O-])=O>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]([CH3:12])([OH:11])[C:13]3[N:14]([N:15]=[N:16][N:17]=3)[C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)-n1nnnc1C1(CO2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1(O)COc2ccc(N)cc2-n2nnnc21

Procedure:
The general hydrogenation procedure described herein was used with 9-nitro-5H-spiro[benzo[b]tetrazolo[1,5-d][1,4]oxazepine-4,2′-oxirane] (16 mg, 0.06 mmol) and Pd(OH)2 on carbon (3 mg), at 1 atm H2 (Balloon) in EtOH (15 mL) to give the product (yield assumed quantitative=14 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:11]2[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=[C:10]2[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:35][N:36]([CH3:38])[CH3:37])=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (50 mg, 0.11 mmol) and N,N-dimethylformamide dimethyl acetal (1 mL) is heated at 80° C. for 14 h. After cooling down to room temperature, excess N,N-dimethylformamide dimethyl acetal is removed under vacuum to provide 5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as yellow solid (56 mg, 100%). HPLC-MS calculated for C28H22ClN5O2 (M+H+): 496.2. Found: 496.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.S([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)(O)(=O)=O.C(O)C>O>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[CH3:25])[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CN(c1ccc(O)cc1)c1ccc2cc(Cl)ccc2n1

Procedure:
A mixture of 2,6-dichloroquinoline (1.1 g; prepared according to the method of O Fischer, Chem. Ber., 35, 3683 (1902), 4-(N-methylamino)phenol sulfate (1.5 g), ethanol (5 ml) and water (20 ml) was heated under reflux for a period of 24 hours. Water (50 ml) was added to the mixture and the aqueous mixture was extracted with chloroform (2×100 ml). The chloroform extracts were dried (anhydrous MgSO4) and the solvent was evaporated to give 4-[N-(6-chloro-2-quinolinyl)-N-methylamino]phenol (1.1 g) as a dark oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.0-6.6 and 7.2 (10H, m and d of d, quinoline, hydroxy and phenyl protons); 3.6 (3H, s, N--CH3).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13]COC)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>Cl.O1CCOCC1>[F:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1noc(-c2ccccc2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Oc1noc(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
4-Fluoro-3-methoxymethoxy-5-phenylisoxazole (0.44 g) was dissolved in a solution of 4N hydrochloric acid/dioxane (5.0 ml), and the solution was stirred at room temperature for one hour. After the reaction, the solvent was evaporated under reduced pressure and the crystal thus obtained was washed with dichloromethane (10 ml) to obtain the title compound (0.30 g, 83%) as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]1[O:22][CH:20]1[CH3:21]>>[O:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1CO1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Yield: 83 %

Procedure:
In Example 2, 16 mg of tri-tert-ethoxy aluminum was used in place of anhydrous aluminum chloride, and the color of the catalyst solution changed from brown to slightly greenish brown by the addition of tri-tert-ethoxy aluminum. Then 4-phenoxyphenol and propylene oxide were added to the slightly greenish brown catalyst solution to achieve the reaction in the same manner as described in Example 2. Thus (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was obtained in 83% yield and the optical purity was 90% e.e.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[CH2:36]([O:35][CH2:34][CH2:33][N:32]1[C:31]2[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=2[N:29]=[C:28]1[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][C:10]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:22][CH2:23]1)[CH3:37]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reaction time: 24 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (10 mmol) and a solution of hydrochloric acid in dioxane (10 mL. 4 M, 40 mmol) in dichloromethane (150 mL). After 24 hours, evaporate in vacuo to give a residue. Partition the residue between with dichloromethane (300 mL) and a saturated aqueous solution of sodium bicarbonate. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: CN1C=CN=C1.[Br:7][C:8]1[N:13]=[C:12]([C:14](=[O:17])[NH:15][CH3:16])[C:11]([NH:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([CH2:34][P:35](=[O:40])([OH:39])[O:36][CH2:37][CH3:38])=[CH:32][C:31]=3[O:43][CH3:44])[N:20]=2)=[CH:10][CH:9]=1.[CH3:45][C:46]1([CH3:63])[C:50]([CH3:52])([CH3:51])[O:49][B:48]([C:53]2[CH:54]=[N:55][N:56]([CH2:58][CH2:59][C@H:60](O)[CH3:61])[CH:57]=2)[O:47]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:7][C:8]1[N:13]=[C:12]([C:14](=[O:17])[NH:15][CH3:16])[C:11]([NH:18][C:19]2[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([CH2:34][P:35](=[O:39])([O:40][C@@H:60]([CH2:59][CH2:58][N:56]4[CH:57]=[C:53]([B:48]5[O:47][C:46]([CH3:63])([CH3:45])[C:50]([CH3:51])([CH3:52])[O:49]5)[CH:54]=[N:55]4)[CH3:61])[O:36][CH2:37][CH3:38])=[CH:32][C:31]=3[O:43][CH3:44])[N:20]=2)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: Cn1ccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)O[C@H](C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 60 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
1-Methylimidazole (1.91 mL, 24 mmol) was added to a stirring suspension of ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 1 g, 2 mmol), (2R)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-2-ol (Compound 69B, 430 mg, 1.6 mmol) and (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (5.04 g, 9.69 mmol) in 1,2-dichloroethane (49.5 mL). The reaction was allowed to stir at 60° C. for 24 hrs, after which, it was concentrated in vacuo to a solid and purified using a Teledyne ISCO Combiflash® RF system [0-5% MeOH in 1:1 EtOAc/DCM] to afford 442 mg of the desired product as mixture of diastereomers (32%). MS (ESI): m/z=867.78/869.81 [M+H]+. UPLC: tR=1.69 min (UPLC-TOF: polar—2 min)
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[F:7][C:8]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20]#[N:21])=[N:12]1.CO>C1(C)C=CC=CC=1>[F:26][C:8]([F:7])([C:22]([F:23])([F:24])[F:25])[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20](=[NH:6])[NH2:21])=[N:12]1
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Trimethylaluminum (2.0M in toluene, 60 mL, 120 mmol) was added dropwise to a suspension of ammonium chloride (6.42 g, 120 mmol) in 180 mL toluene cooled to 0° C. The solution was then stirred at room temperature for 3.5 hours. This solution (0.5M, 146 mL, 72.9 mmol) was then added to the intermediate from Step D above (4.6 g, 15.9 mmol) and then heated at 110° C. for 2.5 hours. The solution was then cooled to room temperature and carefully poured to silica gel (70 g) and methanol (750 mL). After stirring overnight the suspension was filtered and the filtered solid washed with methanol. The filtrate was concentrated in vacuo to give the title compound which was used in the next step without further purification. m/z=308.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH:33]=[O:34])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[H][H]>[Pd].C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][C:10]=1[CH2:33][OH:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO

Procedure:
A 500 mL Parr hydrogenation bottle was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-formylphenyl]acrylic acid tert-butyl ester (18.3 g, 37.6 mmol), THF (60 mL), and methanol (120 mL). Triethylamine (2 mL) and then 5% Pd/C (5.9 g) were added. The mixture was shaken with hydrogen at 60 psi pressure for 48 h. The mixture was filtered through Celite and concentrated to an oil. This oil was purified using the Biotage medium pressure chromatography (EtOAc:hexanes 15:85) to a pale yellow oil (12.8 g, 69%). 1H NMR (400 MHz, CDCl3) δ 1.09 (s, 9H), 1.35 (s, 9H), 2.49 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 4.55 (s, 2H), 6.56 (dd, J=8.3, 2.4 Hz, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 7.33-7.44 (m, 6H), 7.70 (dd, J=7.8, 1.5 Hz, 4H). MS (ES) m/e 508 (M+NH4).
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[C:3]([CH:8]3[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:25][CH:24]=1
Reactant: CC(=O)N1CCC(c2nccnc2F)C1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 80 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(3-(3-fluoropyrazin-2-yl)pyrrolidin-1-yl)ethanone (78 mg, 0.37 mmol), 4-(pyridin-2-ylamino)phenol (139 mg, 0.746 mmol), cesium carbonate (243 mg, 0.746 mmol), and DMSO (1.2 mL). The reaction mixture was degassed and flushed with N2 and heated in an oil bath at 80° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH in EtOAc, to provide 1-(3-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-1-yl)ethanone as an off-white solid. MS (ESI, pos. ion) m/z: 376.1 (M+1). IC50 (uM) 0.0164.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[ClH:10].[Cl:11]N1C(=O)CCC1=O>C(OCC)C>[ClH:11].[Cl:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CCOCC
Product: O=C(CCl)c1cccnc1
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 12 g (11 mL, 100 mmol) of 3-acetylpyridine in 100 mL of ethylether was added 100 mL of 1M ethereal hydrogen chloride. The resultant precipitate was filtered and 15.0 g (95.2 mmol) was collected and placed in a 500-mL round bottom flask equipped with a magnetic stir bar. To this was added 95 mL of 1M hydrogen chloride in acetic acid. After the mixture was stirred until is all the solid had dissolved, 12.7 g (95.2 mmol) of N-chlorosuccinimide (NCS) was added in one portion. The solution turned yellow and the NCS gradually dissolved. After 4 h, a white precipitate had formed. The mixture was allowed to stir for 2.5 days. It was then filtered. The solid collected was washed with 10 mL of acetic acid and 200 mL of ethylether to give 15.2 g (83%) of the title compound as a white solid: 1H NMR (200 MHz, d6 -DMSO) δ9.22 (t, 1H, J=1 Hz), 8.29 (dd, 1H, J=1.6, 5.1 Hz), 8.55 (td, 1H, J=2, 8.1 Hz), 7.82 (ddd, 1H, J=0.8, 5.1, 8.1 Hz), 5.27 (s, 2H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C=O>[CH:1]1([O:7][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To 3.9 g of cyclohexanol (1.1 equivalents) put into the presence of 2.12 g of sodium hydride (1.5 equivalents) under stirring for 10 min, is added a solution of 5 g of 4-fluoronitrobenzene in 75 mL of dimethylformamide. The whole is heated to 60° C. for 5 hrs. After returning to room temperature, the medium is hydrolyzed and the reaction crude product is extracted with ethyl acetate several times. The organic phases are dried on magnesium sulfate, filtered and evaporated under reduced pressure. With a silica gel chromatography of the residue (cyclohexane and then cyclohexane/ethyl acetate: 98/2 and 90/10) 6.06 g of the desired product are able to be isolated.
Reaction SMILES: [Na][Na].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].Cl[CH2:10][C:11]1([CH2:15][Cl:16])[CH2:14][O:13][CH2:12]1>>[Cl:16][CH2:15][C:11]1([CH2:10][O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:8][CH2:10][C:11]2([CH2:15][Cl:16])[CH2:14][O:13][CH2:12]2)[CH2:14][O:13][CH2:12]1
Reactant: OCCCCO
Reactant: ClCC1(CCl)COC1
Agent: [Na][Na]
Product: ClCC1(COCCCCOCC2(CCl)COC2)COC1

Procedure:
Reaction of the disodium salt of butane 1,4-diol with excess 3,3-bis-(chloromethyl)oxetane gives 1,4-bis-[(3-chloromethyl-3-oxetanyl)methyloxy]butane (10). This difunctional oxetane can be further substituted to give multioxetane compounds having various pendant groups. Substitution of the difunctional oxetane can be tailored so that the multioxetane compound can react with oxetane monomers having widely varying reactivity ratios. Reaction of 1,4-bis-[(3-chloromethyl-3-oxetanyl)methyloxy]butane with sodium iodide gives 1,4-bis-[3-iodomethyl-3-oxetanyl)methyloxy]butane (11). Reaction of this diiodide with silver nitrate gives 1,4-bis-[(3-nitratomethyl-3-oxetanyl)methyloxy]butane (12), and with sodium azide it gives 1,4-bis-[(3-azidomethyl-3-oxetanyl)methyloxy]butane (13). ##STR10##
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[Cl:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[CH:21]=2)[C:11]([O:12][CH2:13][C:14]#[N:15])=[C:10]([CH3:38])[CH:9]=1.[OH-].[Na+]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH3:38])[C:11]([O:12][CH2:13][C:14]2[NH:15][N:3]=[N:2][N:1]=2)=[C:16]([CH:17]=1)[CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)cc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1OCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1OCc1nnn[nH]1
Temperature: 110 °C

Procedure:
Sodium azide (395 mg, 6.1 mmol) and ammonium chloride (325 mg, 6.1 mmol) are added to a solution of {4-chloro-2-methyl-6-[3-(quinolin-2-ylmethoxy)-phenoxymethyl]-phenoxy}-acetonitrile (300 mg, 0.68 mmol, example 36c) in DMF (2 mL) and heated at 110° C. for 2 h. The reaction is then cooled and poured into a 1 N sodium hydroxide solution (20 mL) with the formation of a solid. This mixture is then washed with ether (4×) and the ether is discarded. The remaining aqueous solution contains a solid which is filtered. This solid is dissolved in 10% ethanol water (250 mL) and the pH is lowered to about 5 with 2N HCl. A solid precipitates which is filtered to provide the title compound. m.p. 181–184° C.; 1H NMR (300 MHz, DMSO-d6) d 8.40 (d, 1H), 8.01–7.97 (m, 2H), 7.77 (dd, 1H), 7.66–7.60 (m, 2H), 7.33 (d, 2H), 7.18 (dd, 1H), 6.72 (dd, 1H), 6.65 (dd, 1H), 6.59 (dd, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 5.07 (s, 2H), 2.24 (s, 3H); MS (EST) 488, 490 (M+H;Cl)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[CH2:20]([N:22](CC)[CH2:23]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:20][N:22]([CH3:23])[C:17]([C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8]1)=[O:19]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2N1
Reaction time: 0.25 h

Procedure:
A mixture of 5 g of (2S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (commercial) and of 5.8 g of triethylamine in 100 ml of DCM is cooled in an ice bath, 8.4 g of BOP are added and the mixture is left stirring for 15 minutes. Dimethylamine gas is then added by sparging for 10 minutes and the mixture is left stirring for 3 hours at AT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with a 5% Na2CO3 solution and with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (85/15, v/v) mixture. 4.1, g of the expected product are obtained.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:52])=O>ClCCl>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([Cl:52])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)Cl)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (20.6 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 100 ml of dichloromethane were introduced into a round-bottomed flask and 4.3 ml (21.6 mmol) of dicyclohexylamine were added dropwise. The reaction mixture was stirred at room temperature for one hour and 2.2 ml (21.6 mmol) of thionyl chloride were added dropwise. The reaction mixture was stirred for one hour and was evaporated to dryness, the residue was taken up in ethyl ether, the dicyclohexylamine salt was filtered off and the filtrate was evaporated. 10.4 g (100%) of the crude acid chloride were collected, which acid chloride was used as is in the synthesis to follow.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:12]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:12][C:13]=1[O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(CC1CC1)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(CC1CC1)c1ccc(N)c(OCC2CC2)c1
Reaction time: 6 h
Yield: 96.1 %

Procedure:
To a stirred solution of ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4.0 g), in dry MeOH (100 mL), Pd(OH)2 (2 g) was added and the mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.5 g) as a thick liquid.