Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.CC(=O)OCC>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
1-Benzhydrylazetane-3-carboxylic acid (101 mg) was dissolved in THF (2 mL) and lithium aluminium hydride (27 mg) was added. The mixture was stirred overnight at RT. Water, sodium potassium tartrate solution and EA were added. The phases were separated, the org. phase was dried (Na2SO4) and evaporated off to afford 93 mg of the desired product.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>C1COCC1.O1CCOCC1>[CH:19]1([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([CH:2]3[CH2:15][CH2:16][CH2:5][CH2:4][CH2:3]3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: c1cc2ccc3c(C4CCCCC4)ccc4ccc(c1C1CCCCC1)c2c43
Temperature: 90 °C
Yield: 71 %

Procedure:
Under an atmospheric argon gas flow, 1,6-dibromopyrene in an amount of 20 g (55.6 millimole), cyclohexylmagnesiumbromide in an amount of 117 milliliter [117 millimole, 1 mole/liter (THF: tetrahydrofuran)], (diphenylphosphinoferrocene)palladium(II)dichloride in an amount of 2.27 g (5% by mole), dried dioxane in an amount of 80 milliliter and THF in an amount of 70 milliliter were placed into a three-neck flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was stirred with heating at a temperature of 90° C. for 8 hours. After the completion of the reaction, adding 100 milliliter of dilute hydrochloric acid, an organic layer was separated and concentrated under a reduced pressure. Then, the organic layer was passed through a silicagel short column, and after concentrating under the reduced pressure again, a precipitated crystal was separated by filtration and as a result, 7.0 g of 1,6-dicyclohexylpyrene (pale yellow powder) was obtained (the yield: 71%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[C:18]1(C)C=CC=C[CH:19]=1>>[CH2:18]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([CH2:4][CH2:3][CH2:2][Br:1])=[CH:6][CH:7]=1)[CH3:19]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(CCCBr)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(CCCBr)cc1

Procedure:
100 g 4-(3-Bromo-propyl)-benzoic acid (JACS 65, 2281 (1943)), 400 ml of toluene and 80 ml of thionyl chloride were refluxed for 4 hours. The solvent and the thionyl chloride in excess were removed under reduced pressure and after addition of 400 ml of absolute ethanol to the residue the mixture was heated for 1 hour to the boiling point. It was evaporated under reduced pressure, the residue was taken up in benzene and washed neutral with a saturated NaHCO3 -solution. The organic phase was distilled off after drying with MgSO4.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:37]C1N(C2N=C(N)NC(=O)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[C:27]2[Br:37])[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1nc2c(nc(Br)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2c(Br)nc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for Palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of 8-bromoguanosine for 2'-deoxyguanosine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O>C1COCC1.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)([OH:15])[CH2:12][O:11][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)OC
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: COCC(O)(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
A solution of 1,1-bis(3-chlorophenyl)-2-methoxyethanol (47 g) (obtained by the reaction of 3-chlorophenylmagnesium bromide with methyl 2-methoxyacetate in THF) in formic acid (44 cc) is heated to reflux for 5 hours, cooled and poured into a mixture of saturated sodium carbonate solution (500 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×250 cc) and with saturated sodium chloride solution (200 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-chlorophenyl)acetaldehyde (36.9 g) in the form of a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[N:26]([CH2:32][C:33]([OH:35])=[O:34])[C:25]3=[O:36])[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:11][CH2:10]1.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)[O:34][C:33](=[O:35])[CH2:32][N:26]1[C:25](=[O:36])[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]3)[S:18]([CH3:21])(=[O:20])=[O:19])[CH:23]=2)[C:27]1=[O:31]
Reactant: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)C3=O)S(C)(=O)=O)CC1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC4CC4)c2)C3=O)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.76 %

Procedure:
A mixture of 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (128 mg, 0.237 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (83 mg, 0.198 mmol), EDC (53.0 mg, 0.277 mmol) and DMAP (48.3 mg, 0.395 mmol) in DCM (4 ml) was stirred at room temperature overnight. Additional EDC (18.93 mg, 0.099 mmol) was added, and the reaction was stirred at the same temperature for further 4 hours. The mixture was diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 96/4, then DCM/MeOH 92/8) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)-ethyl)pyridine 1-oxide as a white solid (29 mg, 0.035 mmol, 17.76% yield, MS/ESI+ 826.03 [MH]+, [αD]=−23.91, c=0.466, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.92-7.99 (m, 2H), 7.88 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.95 (dd, 2H), 3.80-3.92 (m, 2H), 3.32-3.45 (m, 1H), 3.17-3.24 (m, 1H), 3.15 (s, 3H), 2.39 (t, 2H), 2.25-2.34 (m, 4H), 2.12-2.22 (m, 4H), 2.07 (s, 3H), 1.15-1.32 (m, 1H), 0.53-0.67 (m, 2H), 0.31-0.45 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:20]=[C:19](I)[C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23].C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([NH:25][C:26]1[CH:31]=[C:30]([C:19]2[C:9]3[N:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:11]=[N:12][C:8]=3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: OCCCO
Solvent: O
Product: CCOC(=O)c1cc(-c2cccc(NC(C)=O)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (0.70 g, 1.8 mmol), 3-acetamidophenylboronic acid (0.48 g, 2.7 mmol), 1,3-propanediol (0.65 ml, 8.9 mmol), potassium carbonate (1.23 g, 8.9 mmol) and bis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in a mixture of dimethoxyethane (10 ml) and water (5 ml) was stirred at reflux for 1 hour. The cooled reaction mixture was concentrated under reduced pressure, and the concentrate was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure, and the concentrate was triturated in ethyl acetate leaving the product as an off-white solid (0.48 g, 67%) m/z, 400.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9].[CH3:20][NH:21][CH3:22]>O1CCCC1.C(OCC)(=O)C.C(OCC)C>[CH3:20][N:21]([CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9])[CH3:22]
Reactant: CNC
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(CCl)c2)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 70 °C
Yield: 58 %

Procedure:
Treat 5-(3-chloromethyl-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in PREPARATION 32), (100 mg, 0.37 mmol) with a 2.0 M solution of dimethylamine in tetrahydrofuran (3 mL) and heat at 70° C. in a sealed tube for 2 h. Cool to room temperature, dilute with ethyl acetate, and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with a gradient from 50:50 hexanes:dichloromethane to 90:10 (50:50 hexanes:dichloromethane):methanol, to give a yellow oil. Dissolve the oil in diethyl ether and extract twice with 1 N hydrochloric acid. Combine the aqueous layers and make basic with a 1 N sodium hydroxide. Extract the resultant purple aqueous layer three times with ethyl acetate. Combine the organic extracts, wash with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate to an oil. Concentration of the oil from diethyl ether provides the title compound as a crystalline solid (60 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:19]([CH3:21])[C:18]=1[C:17]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) (21.63 g, 100.0 mmol) and ethyl acetoacetate (12.6 mL, 100.0 mmol) in anhydrous toluene (300 mL) was added SnCl4 (23.1 mL, 200.0 mmol) over a period of 25 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3.5 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜130 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a pale yellow solid (24.6 g, 75%). 1H NR (400 MHz, DMSO-d6) δ 1.30-1.36 (m, 5H), 1.53-1.65 (m, 4H), 1.81-1.86 (m, 2H), 2.42-2.45 (m, 1H), 2.54 (s, 3H), 4.05 (d, J=7.2 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.21-7.23 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 329 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][F:19])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[F:19][CH2:18][C@@H:17]1[CH2:16][O:15][C:14](=[O:20])[N:13]1[C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CN(C)C=O
Reactant: O=C1OC[C@@H](CF)N1c1nc(-c2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2csc(N3C(=O)OC[C@H]3CF)n2)cc1
Temperature: 120 °C
Yield: 81 %

Procedure:
(4S)-3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(fluoromethyl)-1,3-oxazolidin-2-one (0.21 g, 0.59 mmol), prepared in Example 73, and zinc cyanide (41 mg, 0.35 mmol) were dissolved in 8 mL of dimethylformamide. The mixture was purged with nitrogen for 15 min, tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol) was added and the mixture was heated to 120° C. for 2 h. The mixture was cooled and diluted with ethyl acetate, and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (100% CH2Cl2) afforded the title compound (146 mg, 81%) as a white solid. mp 195-196° C. HRMS: calcd for C14H10FN3O2S+H+, 304.05505; found (ESI, [M+H]+), 304.0555. Analytical HPLC: retention time 8.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)=[N+:2]=[N-:3].[Cl:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.CCN(CC)CC>CC#N>[N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:36][CH:35]=2)[CH2:30][CH2:31]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 8.6 %

Procedure:
A murky solution of (±)-trans-4-nitro-benzenesulfonic acid 2-azido-cyclohexyl ester (1.77 g, 5.41 mmol), 4-(4-chlorobenzyl)-piperidine (1.14 g, 5.43 mmol), and Et3N (0.75 mL, 5.4 mmol) in CH3CN (11.2 mL) was stirred at room temperature for 17 hours, 65° C. for 31 hours, and 80° C. for 5 d, allowed to cool to room temperature, and concentrated. The residue was partitioned between CH2Cl2 and 1 N NaOH, the aqueous phase was extracted with CH2Cl2 and the extracts were dried and concentrated. Chromatography of the residue with 98:1.9:0.1–95:4.75:0.25 CH2Cl2:MeOH:NH4OH to 100% MeOH and subsequent chromatography with 10:1 hexanes:EtOAc to 100% EtOAc followed by 95:5 EtOAc:MeOH gave, in order of elution, starting (±)-trans-4-nitro-benzenesulfonic acid 2-azidocyclohexyl ester (1.2 g, 68%), desired product (155 mg, 9%), and starting 4-(4-chlorobenzyl)-piperidine (810 mg, 71%). Product: 1H NMR δ 1.19–1.81 (m, 12H), 1.92–2.08 (m, 3H), 2.22 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 3.02 (m, 2H), 4.05 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 333.2 (M+H)+.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-])=[O:5].Cl.C(N=C=NCCCN(C)C)C.[N:22]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:5]
Reactant: OCCCN1CCOCC1
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCCCN1CCOCC1

Procedure:
Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0° C. 3-Morpholin-4-yl-propan-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous-oil.
Reaction SMILES: CO[C:3](=[O:37])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH2:8][CH:7]([NH:23][C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][N:27]=2)=[O:25])[C:6]1=[O:36].[Li+].[OH-].C(OC(=O)[NH:45][C:46]1[CH:47]([O:52][CH2:53][CH3:54])[O:48][C:49](=[O:51])[CH:50]=1)C=C.C1(S(NCC2CN(CC(O)=O)C(=O)C(NC(C3C4C(=CC=CC=4)C=CN=3)=O)CC=2)(=O)=O)C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.O.C(Cl)Cl.C(Cl)Cl.CN(C=O)C.CCOC(C)=O.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>[C:17]1([S:14]([NH:13][CH2:12][C:10]2[CH2:11][N:5]([CH2:4][C:3](=[O:37])[NH:45][CH:46]3[CH2:50][C:49](=[O:51])[O:48][CH:47]3[O:52][CH2:53][CH3:54])[C:6](=[O:36])[CH:7]([NH:23][C:24]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][N:27]=3)=[O:25])[CH2:8][CH:9]=2)(=[O:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CN1CC(CNS(=O)(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: C=CCOC(=O)NC1=CC(=O)OC1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC1OC(=O)CC1NC(=O)CN1CC(CNS(=O)(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {6-(Benzenesulfonylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester (34) (84 mg, 0.17 mmol) in 4 mL of 3:1 THF/H2O was treated with excess LiOH and stirred for 2.5 h at rt. The solution was acidified and extracted with EtOAc. The EtOAc layer was dried (Na2SO4) and concentrated to give the crude carboxylic acid. A catalytic amount of Pd(Ph3P)4 is added to a solution of (2-ethoxy-5-oxo-furan-3-yl)-carbamic acid allyl ester (0.24 g, 1.0 mmol) and N,N-dimethylbarbituric acid (0.38 g, 2.4 mmol) in CH2Cl2 (5 mL). The solution is stirred for 15 minutes at room temperature after which {6-(Benzenesulfonylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid (0.069 g) is added as a solution in CH2Cl2/DMF (2 mL, 1:1), followed by HOBt (0.126 g, 0.93 mmol) and EDCl (0.18 g, 0.93 mmol). The solution is stirred for 5 hours, diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The resulting residue us purified over silica (EtOAc/hexane) to afford the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15]>>[Cl:1][C:2]1[C:3]([I:11])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Cl)c(I)c1F
Reactant: CCC(N)CC
Product: CCC(CC)Nc1c(C#N)ncc(Cl)c1I
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-chloro-3-fluoro-4-iodopicolinonitrile (46 mg, 0.16 mmol) in 3-aminopentane (1 mL) was heated to 80° C. for 1 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo, and then diluted with EtOAc and water. The organic layer was washed with water and filtered through a silica gel plug to provide the title compound as a white powder (55 mg, 100%). m/z=350.1 [M+H]+ and 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13]CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][O:22]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[B-](CC)(CC)[CH2:29]C.Cl.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:21][O:22][CH3:29])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[B-](CC)CC
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1COS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC1CC(O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4-benzyloxy-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (234.14 mg, 0.65 mmol) was taken up in anhydrous THF under argon and cooled to 0° C. Super-Hydride (1.0M, 0.98 mmol, 0.98 mL) was added via a syringe over 10 min. The solution was stirred for 1 h at 0° C., the TLC indicated that no starting material remained. The reaction mixture was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane-ethyl acetate) Yield 168.57 mg. 1H NMR (CDCl3, 300 MHz): δ 1.22 (d, J=9.0 Hz, 3H), 1.44 (s, 9H), 1.65-1.77 (m, 1H), 2.13-2.24 (m, 1H), 3.45 (dd, J=7, 12 Hz, 1H), 3.61 (d, J=7 Hz, 1H), 3.94-4.04 (m, 1H), 4.50 (s, 2H), 7.27-7.39 (m, 5H).
Reaction SMILES: COC1C=CC(C2CCNC2)=C([N+]([O-])=O)C=1.BrC1C=C(OC)C=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)[CH2:35]2)=[C:30]([N+:47]([O-])=O)[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)[CH2:35]2)=[C:30]([NH2:47])[CH:29]=1
Reactant: COc1cccc(N2CCC(c3ccc(OC)cc3[N+](=O)[O-])C2)c1
Agent: COc1ccc(C2CCNC2)c([N+](=O)[O-])c1
Agent: COc1cccc(Br)c1
Product: COc1cccc(N2CCC(c3ccc(OC)cc3N)C2)c1
Yield: 102.3 %

Procedure:
Synthesized from 3-(4-methoxy-2-nitrophenyl)pyrrolidine and 3-bromoanisole according to an analogous synthetic method to Example 116 described below, 3-(4-methoxy-2-nitrophenyl)-1-(3-methoxyphenyl)pyrrolidine (156 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (145 mg).