Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:36]=[C:5]2[N:6]([CH:29]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CO.[BH4-].[Na+]>O1CCCC1>[OH:35][CH:32]1[CH2:33][CH2:34][CH:29]([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:36]=[C:5]23)[CH2:30][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2 g), methanol (15 mL) and tetrahydrofuran (15 mL) was added sodium borohydride (0.24 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.8 g, 90%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:37])[NH:9][C@@H:10]1[C@@H:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]([CH2:34]Cl)[CH2:32][F:33])[CH2:26][N:13]2[CH2:14][CH2:15][C:16]3[C:21]([C@@H:12]2[CH2:11]1)=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)([CH3:6])([CH3:5])[CH3:4]>CN(C)C=O>[C:3]([O:7][C:8](=[O:37])[NH:9][C@@H:10]1[C@@H:27]([N:28]2[CH2:34][C@@H:31]([CH2:32][F:33])[CH2:30][C:29]2=[O:36])[CH2:26][N:13]2[CH2:14][CH2:15][C:16]3[C:21]([C@@H:12]2[CH2:11]1)=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1cc2c(cc1OC)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)CC(CF)CCl)CN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](N3C[C@@H](CF)CC3=O)CN1CC2
Yield: 38.4 %

Procedure:
Sodium hydride (55–65% dispersion in oil, 1.14 g, 28.5 mmol) was added to a suspension of [(S,S,S)-3-(3-chloromethyl-4-fluoro-butyrylamino)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (6.72 g, 13.1 mmol) in N,N-dimethylformamide (95 mL) at r.t., then after 1 h the reaction mixture was poured onto ice and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, cyclohexane/2-propanol 4:1) afforded [(S,S,S)-3-((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.40 g, 38%) and the epimer, [(S,S,S)-3-((R)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.73 g, 44%).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K]>CN(C)C=O>[Br:1][CH2:2][CH2:3][N:9]1[C:5](=[O:15])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]1=[O:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCBr
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 1,2-dibromoethane (30 g, 159.57 mmol, 2.95 equiv) in N,N-dimethylformamide (200 mL). This was followed by the addition of potassium phthalimide (10 g, 54.05 mmol, 1.00 equiv) in several batches. The resulting solution was stirred for 24 h at 60° C. The reaction was then quenched by the addition of 500 mL of water. The resulting solution was extracted with 2×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 8 g (57%) of 2-(2-bromoethyl)isoindoline-1,3-dione as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C

Procedure:
A mixture of 2.5 grams (13.5 mmol) of 2-chloro-5-nitrobenzaldehyde (Aldrich Chem. Co.) in 250 mL of CH3OH was treated with 2.92 grams (54.1 mmol) of sodium methoxide, refluxed for 16 hours and allowed to cool to room temperature. After removal of the solvent in vacuo, the residue was suspended in water, treated with 2N HCl (adjusting to pH<5) and extracted into methylene chloride. After drying over MgSO4, the solvent was removed in vacuo to give a yellow solid, 2.02 grams (83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccc(C)cc1
Yield: 14 %

Procedure:
The procedure described in Example 26 is repeated, but using 4.28 g (25 mmols) of 4-bromotoluene and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 23 hours at 130° C., 0.67 g (3.5 mmols) of ethyl 4-methylcinnamate is obtained, corresponding to a yield of 14% of theory (conversion figure 1400; Pd content 0.01 mol %).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11](=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].COC1C=CC(P2SP(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>C1(C)C=CC=CC=1>[C:16]1([C:13]2[O:14][C:15]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=3[C:11](=[S:32])[CH:12]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(P2SP(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3ccccc3)oc12
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2c(=S)cc(-c3ccccc3)oc12
Temperature: 25 °C
Yield: 123.2 %

Procedure:
A solution of 4.0g of 8-ethoxycarbonyl-2-phenyl-4-oxo-4H-1-benzopyran (prepared as described in Da Re et al., Ber. 1962, 99 (1966)) and 3.55 g of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane (Lawesson's reagent) in 68 ml of toluene was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The crude residue was rinsed with petroleum ether and filtered to give a solid. The material was purified by flash chromatography on silica gel, eluting with a petroleum ether - ethyl acetate gradient (9:1 to 7:3). Evaporation in vacuo of the collected fractions yielded 3.99 g of pure title compound, melting at 161°-163° C. after recrystallization from cyclohexane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:18]=[C:17]3[C:13]([N:14]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:18]=[C:17]3[C:13]([N:14]([C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(-c3cccc([N+](=O)[O-])c3)nc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(-c3cccc(N)c3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-nitrophenyl)-9-methyl-7-(pyrrolidin-1-ylcarbonyl)-7,9-dihydro-8H-purine-8-one <the compound of Example 203> (41 mg) in methanol (10 ml) was added 10% palladium on carbon (10 mg) and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. After removing the catalyst from the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound 35 mg.
Reaction SMILES: C(OC[C@H]1O[C@@]([SiH](C)C)(N2C=C(C)C(=O)NC2=O)C[C@@H]1O)(C)(C)C.[C:25]([NH:33][C:34]1[C:35]2[N:36]=[CH:37][N:38]([C:47]=2[N:48]=[CH:49][N:50]=1)[C@@H:39]1[O:46][C@H:43]([CH2:44][OH:45])[C@@H:41]([OH:42])[CH2:40]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.[C:58]([Si:62]([CH3:65])([CH3:64])Cl)([CH3:61])([CH3:60])[CH3:59]>CN(C)C=O.ClCCl.C(O)C>[C:25]([NH:33][C:34]1[C:35]2[N:36]=[CH:37][N:38]([C:47]=2[N:48]=[CH:49][N:50]=1)[C@@H:39]1[O:46][C@H:43]([CH2:44][O:45][Si:62]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:65])[CH3:64])[C@@H:41]([OH:42])[CH2:40]1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Agent: Cc1cn([C@@]2([SiH](C)C)C[C@H](O)[C@@H](COC(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Reaction time: 2 h
Yield: 76 %

Procedure:
N6 -Benzoyl-5'-O-tert-butyldimethylsilyl-2'-deoxyadenosine (Compound 5, Table I) was prepared by a procedure similar to that used to prepare the 5'-O-tertbutyldimethylsilylthymidine, as described in Example 1, except that N6 -benzoyl-2'-deoxyadenosine (10 g, 26.9 mmole), 4-N,N-dimethylaminopyridine (0.86 g, 7.0 mmole), triethylamine (3.6 g, 4.96 ml, 35.4 mmole) and tert-butyldimethylchlorosilane (5.33 g, 35.4 mmole) were dissolved in 100 ml dry N,N-dimethylformamide. The reaction was allowed to stir for 2 hours before being worked up as described in Example 1. Chromatography was performed using dichloromethane/ethanol (20/1) as eluent to yield 9.6 g N6 -benzoyl-5'-O-tert-butyldimethylsilyl-2'-deoxyadenosine as a white foam (73% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=O)[C:15](Cl)=[O:16])=[CH:3]1.Cl.C([O:23][C:24](=[NH:39])[CH2:25][C:26]1[C:34]2[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:38])[CH:27]=1)(C)C>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]2[C:15](=[O:16])[NH:39][C:24](=[O:23])[C:25]=2[C:26]2[C:34]3[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:38])[CH:27]=2)=[CH:3]1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Reactant: CC(C)OC(=N)Cc1cn(C)c2c([N+](=O)[O-])cccc12
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4c([N+](=O)[O-])cccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21

Procedure:
ll) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-7-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-7-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[C:6]([NH2:18])[CH:5]=1.[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=3)[CH:20]=[N:18][C:6]=2[CH:5]=1)=[O:19]
Reactant: COC(=O)c1ccc(Nc2ccnc(Br)c2)c(N)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccnc(Br)c1
Temperature: 60 °C

Procedure:
3-Amino-4-(2-bromo-pyridin-4-ylamino)-benzoic acid methyl ester 4 (3 g; 9.3 mmol) was dissolved in 50 ml dry THF and added trimethyl orthoformate (1.4 ml; 13.9 mmol) and p-toluenesulphonic acid (1 g), the reaction mixture was heated to 60° C. for 6 h. LCMS showed almost complete conversion and the reaction was quenched with sodium bicarbonate and extracted with EtOAc (500 ml*3). The organic layer was washed with water and brine. Finally it was dried over sodium sulphate and concentrated in vacuo to give the expected product 5. The compound was pure enough for progress into the next step as seen by NMR and HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:19][C:20](=[O:35])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([CH3:34])[CH:22]=3)[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[NH:7][C:6]=2[CH:36]=1.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+].ClCl>CN(C)C=O.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:19][C:20](=[O:35])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([CH3:34])[CH:22]=3)[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:7]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:6]=2[CH:36]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(C(=O)NC(Cc2ccc(O)cc2)c2nc3ccc(Cl)cc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C(Cc2ccc(O)cc2)NC(=O)c2ccc(C(=O)N3CCCC3)c(C)c2)nc2ccc(Cl)cc21
Yield: 30 %

Procedure:
Prepared analogously to Example 6b from N-[1-(6-chloro-1H-benzimidazol-2-yl)-2-(4-hydroxyphenyl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, methyl bromoacetate, and potassium carbonate in dimethylformamide. Yield: 30%; Rf value: 0.33 (silica gel; dichloromethane/ethanol=19:1); C31H31ClN4O5 (575.06); mass spectrum: (M+H)+=575/577 (chlorine isotope) and (M−H)−=573/575 (chlorine isotope).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:29](=[O:30])[C:26]2[C:27]3[C:28]4[C:23](=[CH:24][CH:25]=2)[C:22]2[C:31]5[C:18]([CH:19]=[CH:20][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=5[C:13]=4[CH:12]=[CH:11][C:10]=3[C:8]1=[O:9].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>N1C=CC=CC=1.O1CCOCC1.C(Cl)Cl>[C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:9])[C:10]2[C:27]3[C:28]4[C:13](=[CH:12][CH:11]=2)[C:14]2[C:31]5[C:18]([CH:17]=[CH:16][CH:15]=2)=[CH:19][CH:20]=[CH:21][C:22]=5[C:23]=4[CH:24]=[CH:25][C:26]=3[C:29]1=[O:30])(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1CCCCCO)c54
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
2 g (5 mmol) of N-(5-hydroxypentyl)perylene-3,4-dicarboximide from 1. were dissolved under nitrogen in 60 ml of pyridine, with heating at 80° C., cooled to 65° C. and admixed dropwise at this temperature with a solution of 0.81 ml (10 mmol) of acryloyl chloride in 30 ml of anhydrous dioxane. The mixture was stirred at 65° C. for a further 1.5 h, the solvent was removed by distillation, the residue was taken up in 20 ml of chloroform, a filtration was conducted, the filtrate was admixed with 100 ml of hexane, and the precipitated product was isolated by filtration. Chromatography on a short silica gel column using methylene chloride as eluent gave 1.5 g (65%) of the desired product as a brownish red powder with a strong tendency to polymerize on heating.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[CH2:18])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccccc2COc2cc(F)ccc21
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2ccccc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Cool a solution of 3-fluoro-6H-dibenzo[b,e]oxepin-11-one (prepared according to the procedure reported by M Kurokawa, F Sato, Y Masuda, T Yoshida and Y Ochi, Chem. Pharm. Bull., 1991, 39(10), 2564-5273; 11.5 g, 50.5 mmol) and THF (100 mL) to 0° C. under N2. Add dropwise MeMgBr (3.0M in Et2O, 33.7 mL, 101 mmol) this mixture. Warm to room temperature and stir overnight. Cool to 0° C. and quench very carefully (exotherm) with HCl (4.00 M in dioxane, 30 mL). Warm to room temperature and stir for 30 min. Dilute reaction mixture with water (70 mL) and extract into ethyl acetate (three 100 mL portions). Dry (MgSO4), filter, and concentrate organics to a brown solid. Purify crude product on a 100 g plug of silica gel, eluting with hexanes to afford 9.26 g (81%) of the title compound as a yellow solid. MS [EI] 226; HPLC shows 90% purity.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[C:20]([CH2:26][OH:27])[CH:19]=1)=[N+:12]=[N-:13].C(N(CC)CC)C>C(Cl)Cl>[N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[C:20]([CH:26]=[O:27])[CH:19]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=NCCCOc1cc(CO)nc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCCOc1cc(C=O)nc(C=O)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (1.21 mL, 17.1 mmol) was diluted with CH2Cl2 (approximately 25 mL) and cooled to −78° C. Oxalyl chloride (0.745 mL, 8.45 mmol) was added dropwise and the reaction mixture was stirred for 15 minutes. 4-(3-azidopropoxy)-2,6-dihydroxymethylpyridine (1 g, 4.27 mmol) dissolved in CH2Cl2 (10 mL) was added slowly to the cooled reaction mixture. After 0.5 hour triethylamine (2.77 mL, 19.70 mmol) was added dropwise to the reaction mixture. The dry ice/acetone bath was removed and the reaction mixture was warmed to room temperature for approximately 40 minutes. The reaction mixture was partitioned between CH2Cl2 and water and extracted several times with CH2Cl2. The CH2Cl2 layers were combined, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography to give the title compound. 1H NMR (DMSO) δ2.02 (m, 2H, CH2), 3.52 (t, 2H, CH2), 4.31 (t, 2H, CH2), 7.64 (s, 2H, 2x Ar), 10.01 (s ,2H, CHO). 13C NMR (DMSO) δ27.61 (CH2), 47.40 (CH2), 66.22 (CH2), 111.58 (Ar), 154.40 (quaternary, Ar), 166,50 (quaternary, Ar), 192.44 (CHO).
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:6][CH2:5][C:4]2[CH:7]=[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=4)[C:12]=3[O:23][C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:9]=[CH:10][C:3]1=2.Cl.B(Br)(Br)Br.O>C(Cl)Cl>[O:39]=[S:2]1(=[O:1])[CH2:6][CH2:5][C:4]2[CH:7]=[C:8]([C:11]3[C:12]([O:23][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]5)=[CH:37][CH:38]=4)=[C:13]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]4)[CH:9]=[CH:10][C:3]1=2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4c(c3)CCS4(=O)=O)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=S1(=O)CCc2cc(-c3ccc4cc(O)ccc4c3Oc3ccc(OCCN4CCCCC4)cc3)ccc21
Temperature: -78 °C

Procedure:
Dissolve the compound of Example 22 (160 mg, 0.29 mmol) in CH2Cl2 (5 mL) and cool the solution to −78° C. Add HCl (0.2 mL, 2.0 M in diethyl ether (Et2O)) and stir the reaction mixture for 10 minutes. Remove the solvent under reduced pressure and then dissolve the solid in CH2Cl2 (5 mL) under N2. Cool the solution to 0° C. and add BBr3 (370 mg, 1.46 mmol). Stir the reaction for one hour and add water (20 mL). Extract the aqueous layer with CH2Cl2 (3×20 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 2-8% MeOH—NH4OH (10/1, v/v)/CH2Cl2) to give 6-(1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-5-yl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol. Dissolve the free base in CH2Cl2 (5 mL) and cool to −78° C. Add HCl (0.5 mL, 2.0 M in Et2O) and stir the solution for 10 minutes. Remove the solvent under reduced pressure to give a solid. Dry the solid at 40° C., overnight, in vacuo to give 42 mg of the title compound (27%): mass spectrum (ion spray): m/z=530.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:27][C@@H:28]1[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]1)(=O)=O>CN(C=O)C>[CH3:33][C:30]1([CH3:34])[O:29][C@H:28]([CH2:27][O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:32][O:31]1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CC1(C)OC[C@@H](COS(=O)(=O)C(F)(F)F)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)O1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A slurry of 3-nitro-5-(trifluoromethyl)phenol (0.658 g, 3.17 mmol), cesium carbonate (3.10, 9.52 mmol) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl trifluoromethanesulfonate (1.00 g, 3.49 mmol) in DMF (10 mL) was heated at 60° C. for 56 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate was diluted with EtOAc and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (4R)-2,2-dimethyl-4-{[3-nitro-5-(trifluoromethyl)-phenoxy]methyl}-1,3-dioxolane (770 mg, 75%) of as pale yellow oil. 1H NMR (400 MHz,CDCl3, HCl salt) δ: 8.10 (s, 1H), 7.94-7.97 (m, 1H), 7.51 (s, 1H), 4.49-4.56 (m, 1H), 4.09-4.23 (m, 3H), 3.92 (q, 1H), .1.45 (s, 3H), and 1.41 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH:16]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][C:7]=2[CH2:8][CH2:9]1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.96 g (5.00 mmol) 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 0.404 ml (5.50 mmol) acetone are dissolved in 20 ml THF, then 0.414 ml (7.50 mmol) acetic acid and 0.10 g p-toluenesulphonic acid are added and the mixture is stirred for 30 min at room temperature. At room temperature 1.378 g (6.50 mmol) sodium triacetoxyborohydride are added and stirred for 23 h. Then the mixture is made alkaline with sat. Sodium hydrogen carbonate solution and extracted with ethyl acetate, then the organic phase is dried with sodium sulphate and concentrated by evaporation i.vac.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:38]4[CH:37]=[CH:36][N:35]=[C:34]([Cl:33])[CH:39]=4)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(-c4ccnc(Cl)c4)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 188 step 4) and 2-chloropyridine-4-boronic acid. Light brown foam (58%). MS (EI): 563.1 (M+H)+.