Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH2:20]C3C4C(=CC=CC=4)C=CC=3)[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(C#N)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC([C@H]1N2C(=O)C(C#N)=C(C)C(C3C=CC=CC=3)=C2SC1)=O>>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH3:20])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(C#N)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(CN)c(=O)n21
Yield: 67 %

Procedure:
By following the procedure described for the preparation of 7a from 6a, 6c (36 mg, 0.11 mmol) gave 7c as a yellow solid (27 mg, 67%): [α]D−110 (c 0.13, CHCl3); IR λ 2956, 1747, 1631, 1575, 1490, 1442, 1216 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.49-7+(m, 3H), 7.25-7.15 (m, 2H), 5.64 (dd, J=8.5, 2.4, 1H), 3.92-3.69 (m, 7H), 3.62 (dd, J=11.5, 8.6, 1H), 3.41 (dd, J=11.6, 2.3, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) 6168.8, 161.1, 152.0, 147.8, 136.4, 130.0, 129.9, 129.0, 128.9, 128.5, 118.0, 115.3, 64.0, 53.6, 37.9, 31.7, 18.0; MS (ES+) calcd 331 for C17H20N2O3S, obsd 331.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:19]=[CH2:20]
Reactant: Cc1csc2c(NC(CO)CO)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC(CO)CO)c2scc(C)c2n1
Yield: 82.9 %

Procedure:
In a sealed tube were heated 328 mg (1.2 mmol) of 2-chloro-4-(1,3-dihydroxypropan-2-yl)amino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1/1) to give 293 mg (yield: 83.2%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C@H:8]([CH3:31])[C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].O(C1C=CC(C(CCC2C=CC=CC=2)C(O)C)=CC=1)C1C=CC=CC=1.[CH2:57]([O:64]C1C=C(C(CCC2C=CC=CC=2)C(O)C)C=CC=1OC1C=CC=CC=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>>[CH2:1]([O:3][C:4]([CH2:6][NH:7][CH:8]([CH3:31])[CH:9]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:22]([O:64][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:23]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCOC(=O)CN[C@H](C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)CNC(C)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(OCc2ccccc2)c1

Procedure:
The above identified compound was obtained by carrying out the same reaction as in Example 49(5) and (6) except that instead of (2RS,3SR)-3-(4-phenoxyphenyl)-5-phenylpentan-2-ol used as the starting material in Example 49(2), (2RS,3SR)-3-(3-benzyloxy-4-phenoxyphenyl)-5-phenylpentan-2-ol was used.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].Cl[C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[N:25]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 2-chloro-1-methyl-1H-benzimidazole (67.1 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (104 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1.I[CH3:20].O>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:20])[CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C2CCC(=O)C2)c2cc(F)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 0.335 g, 8.2 mmol) in dimethylformamide (20 mL) was stirred at room temperature. A solution of 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.5 g, 6.9 mmol) in 10 mL of DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for an additional 30 min, then iodomethane (3.1 g, 21.8 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.6 g of crude product. Flash chromatography on silica gel (50% ethyl acetate/hexane) afforded 1.2 g (81%) of the title compound as a thick oil which solidified on standing. An analytical sample was recrystallized from ethyl acetate/hexane: mp 104–105° C.; MS (ESI) m/z 232 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(CC#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[K+].[CH3:16][CH2:17][OH:18]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][C:17]([OH:14])=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CCC1(c2ccc(Br)cc2)CC1
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)CC1(c2ccc(Br)cc2)CC1

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-acetonitrile (from previous step) was dissolved in EtOH (50 mL) and H2O (6 mL). Potassium hydroxide (5.4 g, 96 mmol) was added and the reaction was heated to reflux overnight. After cooling the reaction was submitted to standard aqueous workup and purified on silica gel to yield the title compound.
Reaction SMILES: [SH-:1].[C+4:2].[SH-:3].[SH-].[SH-].[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([NH:13][NH2:14])=O)([O-:8])=[O:7].[OH-].[K+]>CO>[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]1[S:1][C:2]([SH:3])=[N:14][N:13]=1)([O-:8])=[O:7]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: [C+4]
Reactant: [SH-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1nnc(S)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
Carbon bisulfide (4 ml) was added to a solution of 1.81 g (10 mmol) of 2-nitrobenzohydrazide in 8 ml of methanol. A solution of 616 mg (11 mmol) of potassium hydroxide in methanol (10 ml) was added thereto, and the mixture was stirred at room temperature for 6 hr. The precipitated crystal was collected by filtration and was dried. The dried crystal was added dropwise to 5 ml of concentrated sulfuric acid, and the mixture was stirred at room temperature for 3 hr. The reaction solution was added dropwise to 100 ml of ice water, and the resultant precipitate was collected by filtration and was dried to give 1.21 g (51%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH2:20][OH:21])[CH:5]=[CH:4][C:3]1=2>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:20]=[O:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3=C(CO)CCCC3)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C3=C(C=O)CCCC3)ccc21

Procedure:
The above alcohol is stirred with excess active manganese dioxide in methylene chloride for 5 hours. The reaction mixture is filtered and evaporated to give 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexenecarboxaldehyde.
Reaction SMILES: Br.C(O)(=O)C.CS(C)=O.[C:10]([NH:15][CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=2)[CH2:18]1)(=[O:14])[CH2:11][CH2:12][CH3:13].C(OC(C)C)(C)C>C(O)(=O)C>[C:10]([NH:15][CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=2)[CH2:18]1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
25 ml of 30% hydrogen bromide-acetic acid and 1 ml of dimethyl sulfoxide were added to 20 ml of a suspension containing 3.13 g of 2-(butyrylamino)methyl-5-[4,5-di-hydropyridazin-3(2H)-on-6-yl]indane suspended in acetic acid. The mixture was stirred at room temperature for 3 hours. Diisopropyl ether was added to the mixture, and crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 2.80 g of 2-(butyrylamino)methyl-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C>[OH:5][C:4]1[CH:3]=[C:2]([O:10][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:21])=[O:20])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Yield: 53.4 %

Procedure:
A solution of orcinol monohydrate (0.71 g, 5.0 mmol) and 2,3-dichlorobenzenesulfonyl chloride (1.23 g, 5.0 mmol) in saturated NaHCO3 (20 mL) and diethyl ether (20 mL was stirred at room temperature for 2 days. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (methylene chloride to 2% ethyl acetate in methylene chloride) to give the title compound as a pale yellow oil (0.89 g, 55%). 1H-NMR (300 MHz, CDCl3) δ 2.24 (s, 3 H), 5.23 (s, 1 H), 6.43 (t, 1 H, J=2.2 Hz), 6.54 (d, 2 H, J=1.1 Hz), 7.34 (t, 1 H, J=8.1 Hz), 7.75 (dd, 1 H, J=0.8, 4.0 Hz), and 7.91 (dd, 1 H, J=0.8, 4.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][Br:12])[C:6]=2[CH:11]=1
Reactant: Cc1csc2ccc(Br)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1csc2ccc(Br)cc12
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 4.30 gm (18.9 mMol) 5-bromo-3-methylbenzothiophene, 0.25 gm (1.03 mMol) benzoylperoxide, and 3.37 gm (18.9 mMol) N-bromosuccinimide in 50 mL carbon tetrachloride was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 4.28 gm (74%) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 43 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (457 mg, 3.0 mmol, prepared generally according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) and 2-fluoro-4-nitrophenol (706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in 1-methyl-2-prolidinone (NMP) (3 mL) was heated at 200° C. under microwave irradiation for 1 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), and dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluting with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford the desired compound (350 mg, 43%) as a brown solid. MS(ESI+) m/z 274 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([O:43][C:44]([S:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([OH:10])=[O:9])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCS)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)SCCN(CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 69 %

Procedure:
(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]-3-phenylpropionic acid (Compound No. 11-1, 108 mg) is dissolved in anhydrous methylene chloride (1.5 ml) under a nitrogen atmosphere, and the solution is stirred. To the solution are added N,N-diisopropylethylamine (0.07 ml) and benzyloxycarbonyl chloride (0.05 ml) successively under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous citric acid solution, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 102 mg (69%) of the titled compound (Compound No. 12-1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][NH:3]1.O.Cl[CH2:28]Cl.[C:30](=[O:33])([O-])[O-].[Na+].[Na+]>C(OC(=O)C)(=O)C>[C:30]([N:3]1[CH:2]([CH3:1])[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4]1)(=[O:33])[CH3:28]
Reactant: O=C([O-])[O-]
Reactant: ClCCl
Reactant: Cc1cc(C2=NNC(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1C)OCO3
Yield: 87 %

Procedure:
1.70 g (5.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are stirred in 10 ml of acetic anhydride at room temperature for a day. The reaction mixture is poured into a mixture of 100 ml of water and 75 ml of dichloro methane, stirred for an hour and the pH is adjusted to 8 by adding sodium carbonate in portions. The layers are separated, the aqueous phase is extracted twice with 25 ml of dichloro methane each. The united organic phases are washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product obtained is recrystallized from 15 ml of ethanol. Thus 1.65 g of the desired product are obtained, yield 87%, mp.: 178–181° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][NH:5]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CN1CC2CC1CN2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Yield: 65.9 %

Procedure:
A solution of 2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (0.4402 g, 1.6 mmol), p-fluoro-nitrobenzene (0.56 mL, 5.4 mmol), N,N-diisopropylethylamine (0.84 mL, 4.82 mmol) in 5 mL of acetonitrile is heated at 100° C. overnight. After the solvent is removed, the residue is treated with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane to yield 0.246 g (65% yield) of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Cl:11])[CH:2]=[CH2:3].[C:13](Cl)([Cl:15])=[S:14]>[OH-].[Na+].O.C(Cl)(Cl)Cl>[Cl:15][C:13]([O:12][C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=1)=[S:14]
Reactant: S=C(Cl)Cl
Reactant: C=CCOc1cc(O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCOc1cc(OC(=S)Cl)ccc1Cl

Procedure:
3-Allyloxy-4-chlorophenol (35.0 g) was dissolved in a solution of 7.7 g of sodium hydroxide in 30 ml of water. To the solution, there was added with stirring a solution of 14.6 ml of thiophosgene in 55.0 ml of chloroform. The reaction mixture was allowed to stand for phase separation. The chloroform layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Reduced pressure distillation of the residue gave 33.0 g of O-(3-allyloxy-4-chlorophenyl) chlorothioformate as a fraction boiling at 128°-129° C./0.4 mmHg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20]Br>>[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CC(C)CCCCBr
Reactant: OCCCCCCCCCCCCBr
Product: CC(C)CCCCCCCCCCCCCCCCO
Yield: 44 %

Procedure:
17-methyloctadecan-1-ol was prepared from 12-bromo-1-dodecanol and 5-methylhexylbromide in 44% yield. 1H NMR δ 0.86 (6H), 1.10-1.40 (32H), 3.64 (2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#N)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:22].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH:9]=[O:22])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ncc(F)cc1F
Temperature: 78 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3,5-difluoro-pyridine-2-carbonitrile (0.440 g, 3.14 mmol) (Niewoehner, U. et al. PCT Int. Appl. (2001), WO 2001068647) in dry CH2Cl2 (20 mL) cooled at −78° C., was added DIBAL-H (1.0 M in CH2Cl2, 3.2 mL, 3.2 mmol). After the mixture was stirred a t−78° C. for 1 h, aqueous HCl (3 N, 10 mL) was added, and the mixture was warmed to room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording afford 3,5-difluoro-pyridine-2-carbaldehyde as a colorless crystalline solid (0.0880 g, 20%). 1H NMR (CDCl3) δ 7.32-7.39 (m, 1H), 8.53 (d, 1H, J=2.4 Hz), 10.16 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1>>[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[C:12]=2[CH:11]=1
Reactant: COCCOCCBr
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Product: COCCOCCC1(CCOCCOC)c2ccccc2-c2ccc(Br)cc21

Procedure:
2-Bromo-9,9-bis(3,6-dioxaheptyl)-fluorene was synthesized from bromo-2-(2-methoxyethoxy)ethane and 2-bromofluorene by methods described in Part A of Example 5.
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10].[BH4-].[Na+].C(OCC)(=O)C.Cl>C(O)(C)C.O>[CH3:21][C:18]([CH3:22])([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])[CH2:19][OH:20]
Reactant: CC(C)(CO)CCCCCC(=O)CCCCCC(C)(C)CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(CO)CCCCCC(O)CCCCCC(C)(C)CO
Yield: 44.2 %

Procedure:
Under nitrogen atmosphere, a solution of 8-oxo-2,2,14,14-tetramethylpentadecane-1,15-diol (0.9 g, 2.5 mmol) in iso-propanol (10 mL) was added dropwise to a stirred suspension of sodium borohydride (0.1 g, 2.7 mmol) in iso-propanol (10 mL) at room temperature. The reaction progress was monitored by thin layer chromatography (silica, hexanes:ethyl acetate=1:1). Additional sodium borohydride was added after each hour (0.36 g, 10 mmol, six times). The reaction mixture was stirred for additional 20 h, hydrolyzed with water (10 mL), acidified with 1 N hydrochloric acid (25 mL) to pH 1, and extracted with dichloromethane (4×15 mL). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over magnesium sulfate, and concentrated in vacuo to furnish the crude product (1.0 g) as a white solid in oil, which was purified by column chromatography (silica; hexanes, then hexanes:ethyl acetate=2:1 to 1:2) to give the pure product (0.35 g, 43%) as nice white crystals. M.p.: 71-75° C. 1H NMR (300 MHz, CD3COCD3/CD3OD/TMS): δ (ppm): 4.32-4.03 (m, 3H), 3.52 (s, 1H), 3.22 (s, 4H), 1.63-1.20 (m, 20H), 0.83 (s, 12H). 13C NMR (75 MHz, CD3COCD3/CD3OD/TMS): δ (ppm): 72.0, 71.7, 39.8, 38.4, 35.8, 31.8, 26.7, 24.8, 24.6. HRMS (LSIMS, gly): Calcd. for C19H41O3 (MH+): 317.3056. found: 317.3026. HPLC: 97.1% purity.