Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C:19]4[O:18][CH:22]=[CH:21][N:20]=4)=[CH:30][CH:29]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cc2ncco2)cc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: Clc1cccc(-c2nc3c(c(Nc4ccc(Cc5ncco5)cc4)n2)CCC3)c1
Yield: 38.1 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.075 g, 0.28 mmol) was reacted with 4-(oxazol-2-ylmethyl)aniline (0.074 g, 0.42 mmol) to afford the title compound (0.043 g, 58%) as an off-white solid. MW=402.88. 1H NMR (DMSO-d6, 300 MHz) δ 8.88 (s, 1H), 8.30-8.19 (m, 2H), 8.03 (d, J=0.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.56-7.50 (m, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.15 (d, J=0.8 Hz, 1H), 4.13 (s, 2H), 2.90 (q, J=7.6 Hz, 4H), 2.20-2.04 (m, 2H); APCI MS m/z 403 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([CH:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([CH:8]([OH:9])[C:2]2([NH:1][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:15]=[C:14]([Cl:16])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC2(C(O)c3cc(Cl)cc(Cl)c3)CCCCC2)cc1
Temperature: 35 °C

Procedure:
To a stirred solution of (1-amino-cyclohexyl)-(3,5-dichloro-phenyl)-methanol and pyridine (100 μL, 1.24 mmol) in CH2Cl2 (4 mL) was added p-toluenesulfonyl chloride. The mixture was heated at ca. 35° C. for 8 hours. The mixture was applied to a 10 mL Chem Elut cartridge pre-wetted with 5% aqueous HCl (5 mL) and eluted with CH2Cl2 (25 mL). The eluate was applied to a second Chem Elut cartridge pre-wetted with saturated aqueous NaHCO3. The eluate from the second cartridge was evaporated to leave N-{1-[(3,5-dichloro-phenyl)-hydroxy-methyl]-cyclohexyl}-4-methyl-benzenesulfonamide (139 mg) as an oil. 1H NMR (500 MHz, CDCl3) δ(ppm): 7.7 (d, 2H), 7.2 (s, 2H), 7.15 (d, 2H), 7.1 (s, 1H), 4.82 (s, 1H), 4.16 (s, 1H), 2.33 (s, 3H), 0.9-1.9 (m, 10H).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[S:3].[N-:15]=[N+:16]=[N-:17].[Na+].Cl>O>[C:8]([C:7]1[CH:13]=[CH:14][C:4]([N:1]2[C:2]([SH:3])=[N:17][N:16]=[N:15]2)=[CH:5][CH:6]=1)([OH:10])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(-n2nnnc2S)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.3 %

Procedure:
Then, 31 g of ethyl p-isothiocyanatobenzoate and 11.7 g of sodium azide were dispersed in 300 ml of water and the dispersion was refluxed for 5 hours. The reaction mixture was cooled to room temperature and acidified (pH about 2) by the addition of concentrated hydrochloric acid. Crystals of 1-(4-ethoxycarbonylphenyl)-5-mercaptotetrazole thus deposited were collected by filtration and after adding thereto 25 g of sodium hydroxide and 500 ml of water, the mixture was stirred for 30 minutes at 70° C. The reaction mixture was cooled to room temperature, neutralized by the addition of concentrated hydrochloric acid, and crystals thus deposited were collected by filtration and recrystallized from methanol to provide 40 g of 1-(4-carboxyphenyl)-5-mercaptotetrazole. The yield was 48% and the melting point was 198° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[O:32][C:33]=1[CH3:34]>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[O:32][C:33]=2[CH3:34])=[C:3]([O:14][CH3:15])[CH:4]=1)[CH3:13]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1

Procedure:
To a mixture of ethyl (4-hydroxy-3-methoxyphenyl)acetate (7.00 g), potassium carbonate (5.43 g) and N,N-dimethylformamide (100 mL) was added 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (7.77 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)acetate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave white crystal (8.22 g, yield 56%) melting point: 106-107° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (5.0 g, 43.0 mmol) in CH2Cl2 (40 mL) and pyridine (30 mL) was added 4-(dimethylamino)pyridine (0.26 g, 2.2 mmol) followed by p-toluenesulfonyl chloride (8.2 g, 43.0 mmol). The mixture was allowed to stir at ambient temperature for 16 hours then was quenched with 5% aqueous HCl (15 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (9.1 g, 33.7 mmol, 78% yield). MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[OH-].[Na+]>O>[CH2:14]([O:13][C:11]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
D-Aspartic acid (25.0 g, 0.188 mol) and benzyl chloroformate (34.3 ml, 0.282 mol) were added to sodium hydroxide (22.9 g, 0.564 mol) in water (600 ml). The resulting mixture was stirred at room temperature for 3 days. The mixture was then acidified with 6MHCl to pH1 and extracted with ethyl acetate (3×250 ml). The extracts were combined, dried (MgSO4) and evaporated to a clear oil, wt 50.2 g. 1H NMR (90 MHz, CDCl3): δ 3.05 (2,bm), 4.65 (1,bm), 5.25 (2,s), 6.2 (1,bs), 7.4 (5,s), 10 (1,bs).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[Br:18]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([Br:18])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CN1c2ccccc2CC(Br)c2ccccc21
Temperature: 2.5 °C
Reaction time: 0.92 h
Yield: 91.4 %

Procedure:
6.60 g (0.030 mols) of 5-cyano-10,11-dihydro-5H-dibenz[b,f]-azepine (I) are stirred at 50° C. with 50 ml of CCl4. The fluid suspension is added under stirring with 5.6 g (0.0315 mols) of N-bromosuccinimide of purity above 98%, then with 0.37 g (0.0015 mols) of dibenzoylperoxide. Temperature is raised to mild reflux and the mixture is stirred for a further 55 minutes controlling the formed foam, then cooled and solvent is evaporated off. The residue is suspended in toluene (15 ml) at 80° C. for 20 minutes, filtered, the solution is cooled at 0-5° C. for 1 hour, to obtain 8.2 g (83%) of 5-cyano-10-bromo-10,11-dihydro-5H-dibenz[b,f]azepine (II), m.p. 132-9 (with decomposition).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[N:8]([CH2:26][CH3:27])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[C:17]#[N:18])=[CH:13][CH:12]=[C:11]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH:10]=2.S(=O)(=O)(O)[OH:29].[OH-].[NH4+]>>[NH2:6][C:7]1[N:8]([CH2:26][CH3:27])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[C:17]([NH2:18])=[O:29])=[CH:13][CH:12]=[C:11]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH:10]=2
Reactant: CCn1c(N)c(C#N)c(=O)c2ccc(-c3ccncc3)cc21
Reactant: O=S(=O)(O)O
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1c(N)c(C(N)=O)c(=O)c2ccc(-c3ccncc3)cc21
Temperature: 100 °C

Procedure:
A mixture of 2.70 g 2-amino-3-cyano-1,4-dihy- dro-1-ethyl-4-oxo-7-(4-pyridinyl)quinoline methanesulfonate and 25 ml sulfuric acid was heated at 100° C. for 4 hrs. The reaction mixture was cooled, poured onto ice and made basic with ammonium hydroxide. The solid product was collected and recrystallized twice from DMF to give 2.45 g 2-amino-1,4-dihydro-1-ethyl-4-oxo-7-(4-pyridinyl)-3quinolinecarboxamide, m.p. above 300° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)cc2)cc1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
4-(4-Methanesulfonyl-phenoxy)nitrobenzene (28 g, 95 mmol) prepared in Step B was dissolved in methanol (500 mL) and ethyl acetate (500 mL). 10% Pd/C (1.0 g) was added thereto, and the mixture was stirred under hydrogen gas of atmospheric pressure for 3 h. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, concentrated under reduced pressure, and dried over anhydrous magnesium sulfate to give the title compound (25 g, Yield 100%).
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].CN(C=O)C.C(NC(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])=[C:3]([O:27][CH2:28][C:29]3([CH3:33])[CH2:32][O:31][CH2:30]3)[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: C#CC(C)(C)O
Reactant: CC1(COc2ccc3c(c2Br)[C@]2(COC(N)=N2)c2cc(-c4cccnc4)ccc2O3)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1c(OCC2(C)COC2)ccc2c1[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 90 °C

Procedure:
A resealable tube was charged with (S)-1′-bromo-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (300 mg, 0.590 mmol), 2-methyl-3-butyn-2-ol (248 mg, 2.95 mmol), tetrakis(triphenylphosphine)palladium (68.2 mg, 0.059 mmol) and copper(i) iodide (22.48 mg, 0.118 mmol). To this were added DMF (1180 μL, 0.590 mmol) and diisopropylamine (1241 μL, 8.85 mmol). The reaction was flushed with argon, sealed and heated at 90° C. for 1.5 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% CH2Cl2 to 10:1 methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-4-(2-amino-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-yl)-2-methylbut-3-yn-2-ol as a light yellow solid. MS m/z=512.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].C(N(CC)CC)C.Cl.[NH2:22][CH2:23][C:24]#[N:25]>C1C=CC=CC=1>[C:23]([CH2:24][NH:25][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])#[N:22]
Reactant: N#CCN
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: N#CCNC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 11.95 g. (0.05 mole) of 2,4 dichlorophenoxyacetyl chloride in 50 ml. of benzene was added slowly to a stirred mixture of 10.1 g. (0.10 mole) of triethylamine and 4.2 g. (0.05 mole) aminoacetonitrile hydrochloride in 200 ml. of benzene. The mixture was stirred for 2 hours at room temperature and then washed successively with water, 5% sodium hydroxide solution, water, 5% hydrochloric acid solution, and water and then dried over magnesium sulfate. The resultant filtrate was concentrated under vacuum to give a solid which was crystallized from dilute ethanol to give 8.6 g. (66% yield) of product having a melting point of 107°-108° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:43][C@@H:44]([CH2:54][CH3:55])[C@H:45]([NH:52][CH3:53])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([N:52]([C@@H:45]([C@@H:44]([CH3:43])[CH2:54][CH3:55])[CH2:46][N:47]1[CH2:48][CH:49]([OH:51])[CH2:50]1)[CH3:53])=[O:16]
Reactant: CC[C@H](C)[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
DIPEA (0.224 mL, 1.29 mmol) was added to 3,4-difluorobenzoic acid (0.068 g, 0.43 mmol) and TBTU (0.138 g, 0.43 mmol) in DCM (2 mL). The mixture was stirred at rt for 30 min. 1-((2S,3S)-3-Methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound G2.1) (0.1 g, 0.43 mmol) in DCM (1 mL) was added and the resultant mixture was stirred at rt overnight. The mixture was washed with NaHCO3, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (95 mg, 68%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.61-0.74, 0.75-0.92, 0.97-1.09, 1.20-1.63, 2.33-2.45, 2.48-2.83, 3.11-3.23, 3.32-3.38, 3.39-3.53, 4.04-4.23, 5.14-5.31, 7.10-7.22, 7.28-7.41, 7.42-7.56, 7.56-7.70. Total number of protons: 24. HRMS (M+H)+: calculated 327.1884. found 327.1878. The compounds according to Examples 29.2-29.9 were prepared, from appropriate intermediates, by analogy with the method described for Example 29.1 hereinbefore.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Br[C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][N:25]=1.Cl>CC#N>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][N:25]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: CCOC(=O)C(C)C1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1nnc(Br)s1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask were placed a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate (800 mg, 2.73 mmol, 1.00 equiv, 90%) in CH3CN (30 mL), KHCO3 (1.5 g, 15.00 mmol, 5.00 equiv) and 2-bromo-5-nitro-1,3,4-thiadiazole (890 mg, 3.80 mmol, 1.40 equiv, 90%). The resulting mixture was stirred overnight at room temperature. The pH value of the solution was adjusted to 4 with HCl (2 mol/L), then extracted with 4×50 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 0.4 g (22%) of ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate as a brown oil.
Reaction SMILES: CN(C)[C:3]1[CH2:10][CH2:9][C:8]2[C:4]=1[CH:5]=[CH:6][CH:7]=2.[CH:12]1([Li])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.O>O1CCCC1>[CH:12]1([C:3]2[CH2:10][CH2:9][C:8]3[C:4]=2[CH:5]=[CH:6][CH:7]=3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: CN(C)C1=C2C=CC=C2CC1
Reactant: [Li]C1C=Cc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C1=CC2=C(C3C=Cc4ccccc43)CCC2=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A solution of 12.5 g (85 mmol) of 4-(dimethylamino)-5,6-dihydropentalene in 50 ml of tetrahydrofuran are admixed with a solution of 10.4 g (85 mmol) of indenyllithium in 20 ml of tetrahydrofuran. The reaction solution is stirred for 24 hours at room temperature and the reaction is stopped by addition of water. Extraction with diethyl ether, drying of the organic phases over MgSO4 and removal of the solvent under reduced pressure and subsequent recrystallization of the crude product from diethyl ether gives 13.9 g (75%) of 4-indenyl-5,6-dihydropentalene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[OH-].[NH4+:16].II>C1COCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:16])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(O)ccc(C#N)c1[N+](=O)[O-]
Reaction time: 48 h
Yield: 84 %

Procedure:
4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol) was dissolved in THF (2.5 L) and then ammonium hydroxide (2.5 L) was added followed by iodine (464 g, 1.8 mol). The resulting mixture was allowed to stir for 2 days at which time it was concentrated under reduced pressure. The residue was acidified with HCl (2 N) and extracted into diethyl ether. The organic layer was washed with brine and dried (sodium sulfate) and concentrated under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to provide the title compound (166 g, 84%): 1H NMR (DMSO-d6) δ: 11.91 (1H, s), 7.67 (1H, d), 7.20 (1H, d), 3.88 (3H, s)
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].CS([Cl:34])(=O)=O.Cl>ClCCl.C(N(CC)CC)C>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(CO)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-[4-(hydroxymethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (566 mg), lithium chloride (135 mg), triethylamine (446 μl) and dichloromethane (50 ml) was added methanesulfonyl chloride (172 μl), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added dilute hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(chloromethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (494 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+]>Br>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(C2CCCN2Cc2ccccn2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(C2CCCN2Cc2ccccn2)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.0 g) in dry acetonitrile (70 ml) was added milled potassium carbonate (6.1 g) followed by 2-picolyl chloride hydrochloride (3.1 g) at ambient temperature, under nitrogen, with stirring for 65 hrs. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and the residue was purified by flash column chromatography (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to give 4.1 g (91%) of 2-(3-methoxyphenyl)-1-(2-pyridinylmethyl)pyrrolidine. 2-(3-Methoxyphenyl)-1-(2-pyridinylmethyl)pyrrolidine and 48% hydrobromic acid (40 ml) were warmed to 100° C. for 7 hrs, cooled to ambient temperature, and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to give 2.7 g (69%) of product, mp 96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][Cl:19])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:17][CH2:18][Cl:19])=[CH:14][CH:15]=1
Reactant: Oc1cccc(Cl)c1
Reactant: OC(CCCl)c1ccc(Br)cc1
Product: ClCCC(Oc1cccc(Cl)c1)c1ccc(Br)cc1

Procedure:
3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol following the procedure set out in Example 48B to give the title compound, which was used in the next step without further purification.