Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)O)c2)cc1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.2 mL, 0.39 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 147-(1); 33.9 mg, 0.066 mmol) in methanol (0.6 mL), and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (dichloromethane:methanol=9:1) to give the title compound (26.5 mg, 80%).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1>O1CCCC1.C(OCC)C>[CH3:1][Si:2]([CH3:7])([C:3]([CH3:6])([CH3:5])[CH3:4])[O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: OCCCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Reaction time: 3 h

Procedure:
A solution of dimethyl-t-butylsilyl chloride (18 g.) in tetrahydrofuran (50 ml.) was added dropwise to a stirred solution of 8-bromooctanol (20 g.) and imidazole (14.2 g.) in tetrahydrofuran (100 ml.) and the mixture was stirred at laboratory temperature for 3 hours, diluted with diethyl ether (200 ml.) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using petroleum ether (b.p. 60°-80° C.) as eluant. A solution of the 8-(dimethyl-t-butylsilyloxy)octyl bromide thus obtained (6.46 g.) in dimethyl sulphoxide (2 ml.) was added to a stirred suspension of lithium acetylide-ethylenediamine complex (2.02 g.) in dimethylsulphoxide (30 ml ) which was cooled to 10° C.; and the mixture was stirred for 18 hours and then poured into ice-water (150 ml.). The mixture was extracted three times with petroleum ether (b.p. 60°-80° C.; 30 ml. each time) and the combined extracts were washed with water (10 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 5:1 v/v mixture of cyclohexane and diethyl ether as eluant. There was thus obtained 10-(dimethyl-t-butylsilyloxy)dec-1-yne.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:16]Br>>[Br:16][CH2:14][C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)CBr)cc(OC)c1OC

Procedure:
In a manner similar to Preparation 30 react 1-(3,4,5-trimethoxyphenyl)ethanone with bromine to obtain the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:32][C:33]1[CH:38]=[CH:37][C:36](CO)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([S:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:20][Cl:24])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(SCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
Triphenylphosphine (14.9 g, 56.8 mmol), carbon tetrachloride (35 mL, 360 mmol), (4-benzylsulfanyl-phenyl)-methanol (6.33 g, 27.5 mmol), and tetrahydrofuran (120 mL) were combined and stirred at reflux temperature overnight. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water (750 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product. Flash chromatography (Analogix SuperFlash™ column, 100% hexanes -25% ethyl acetate in hexanes) afforded 4.57 g (67%) of 4-(benzylsulfanyl)benzyl chloride as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.16-7.44 (m, 9 H), 4.72 (s, 2 H), 4.26 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:39]4[CH2:44][CH2:43][S:42][CH2:41][CH2:40]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: C1CSCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCSCC3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.300 g) from Example No. 35 in DMF (16 mL) are added DMAP (16 mg), 2,4,6-collidine (0.27 mL), and methanesulfonyl chloride (0.16 mL). The reaction mixture is stirred at room temperature for 2 h and then thiomorpholine (0.83 mL) is added. The mixture is stirred at room temperature for 3 d and is then poured into water (50 mL). The resulting off-white solid is filtered off and recrystallized from ethanol to yield 0.222 g (60%) of the title compound as an off-white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Intermediate 1B, 1-(4-(benzyloxy)phenyl)-2-(pyridin-4-yl)ethanone (5.22 g, 17.21 mmol) and solvent THF (60 mL) were added to 20% Pd(OH)2—C, wet (1.044 g, 7.43 mmol) in a 250 mL stainless steel pressure bottle. The reaction mixture was stirred for 3 hr at 30 psi and ambient temperature. HPLC indicated that both starting material and product were present, so MeOH (10 mL) was added and the reaction was run for an additional 1 h. The reaction mixture was filtered through a nylon membrane and the filtrate was concentrated under reduced pressure to give a pale yellow solid (3.13 g, 85% yield). Much of the yellow color was removed by rinsing with MeOH. After the MeOH rinses, the solid was rinsed with Et2O, then dried in a vacuum oven at 50° C. for 4 hours. This vacuum-dried sample weighed 2.071 g (56.4%). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (br s, 1H), 8.52-8.45 (m, 2H), 7.96-7.89 (m, 2H), 7.29-7.24 (m, 2H), 6.90-6.83 (m, 2H), 4.35 (s, 2H). MS (DCI—NH3) m/z=214 (M+H)+, m/z=231 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])#[N:2].[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])#[N:2]
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@@H]1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoate (4.25 g, 10.6 mmol) in ethanol (40 ml) and THF (30 ml) was added a 1 N aqueous sodium hydroxide solution (21 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the objective product as a solid material. The resultant material was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].C(N(CC)CC)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:34]([NH2:36])=[O:35])=[CH:31][NH:32][CH:33]=2)=[CH:25][CH:24]=1>O1CCCC1.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:34]([NH2:36])=[O:35])=[CH:31][NH:32][CH:33]=2)=[CH:25][CH:24]=1
Reactant: NC(=O)c1c[nH]cc1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1c[nH]cc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
0.012 cm3 of 2-fluoro-5-trifluoromethylphenyl isocyanate and 0.012 cm3 of triethylamine are added at a temperature in the region of 20° C., under an argon atmosphere, to 0.017 g (84.48 mmol) of 4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in suspension in 27 cm3 of tetrahydrofuran. After stirring for 20 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: ethyl acetate/dichloromethane (95/5 by volume)]. After concentrating the fractions under reduced pressure, a yellow residue is obtained which is stirred in 5 cm3 of dichloromethane and then filtered and dried under reduced pressure (2.7 kPa) to give 22 mg of 4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-3-carboxamide, in the form of a beige solid; 1H NMR (300 MHz, (CD3)2SO, —δ in ppm): from 6.57 to 7.02 (very broad m: 2H); 6.85 (broad t, J=2.5 Hz: 1H); 7.29 (broad t, J=2.5 Hz: 1H); from 7.33 to 7.43 (m; 5H); 7.49 (dd, J=10.5 and 8.5 Hz: 1H); 8.60 (dd, J=7.5 and 2.5 Hz: 1H); 9.31 (broad s: 1H); 9.58 (broad s: 1H); 11.2 (broad s: 1H); EI: m/z=406 (M+), m/z=205 (C8H3NOF4+), m/z=179 (C7H4NF4+) base peak, ES+: m/z=407 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A solution of the compound of Example 67, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.47 g, 5.14 mmol) in 40 mL 1-methyl-2-pyrrolidinone was treated with triethylamine (1.43 mL, 10.3 mmol). With vigorous stirring, the solution was treated dropwise with benzoyl chloride (0.597 mL, 5.14 mmol). After 18 h, the reaction was concentrated. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave a clear, colorless oil. The oil was triturated in ether and filtered to yield 531 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}benzamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([OH:12])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[C:13](Br)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CSc1sc(C(=O)O)cc1C#N
Reactant: CC(C)(C)Br
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1sc(C(=O)OC(C)(C)C)cc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
A mixture of 4-cyano-5-(methylthio)thiophene-2-carboxylic acid (2.0 g, 10 mmol), benzyltrimethylamonium chloride (2.25 g, 10 mmol), tertbutyl bromide (54 mL, 480 mmol) and anhydrous potassium carbonate (36 g, 260 mmol) in dimethylacetamide (100 mL) was stirred at 60° C. for 6 hours. After cooling, the mixture was diluted with ethyl acetate (400 mL) and washed with water. Organic layer was dried and evaporated under reduced pressure to give a residue which was purified by chromatography (eluent ethyl acetate/n-hexane 3:1) thus yielding 1.5 g of the title compound.
Reaction SMILES: C(OC(=O)[CH:7]([C:16]#[N:17])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][S:14][C:10]1[N:9]=[C:8]([CH2:7][C:16]#[N:17])[CH:13]=[CH:12][N:11]=1
Reactant: CSc1nccc(C(C#N)C(=O)OC(C)(C)C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(CC#N)n1
Temperature: 25 °C

Procedure:
To a solution of Intermediate cyano-(2-methylthio-pyrimidin-4-yl)-acetic acid tert-butyl ester (5.3 g, 20 mmol) in anhydrous toluene (100 mL) was added p-toluenesulfonic acid (800 mg). The mixture was heated to reflux for 8 h, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (3:1 hexanes/ethyl acetate eluant) to afford the title compound: 1H NMR 400 MHz (CDCl3) δ 8.56 (d, 1H), 7.12 (d, 1H), 3.84 (s, 2H), 2.57 (s, 3H); MS m/z: 166.0 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 24.6 mg (0.74 mmol, 60% dispersion in mineral oil) NaH in 5 mL THF at 0° C. was added 0.115 g (0.61 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared using route 15 step a) in 1 mL THF dropwise over 10 minutes, and the reaction was stirred at 0° C. for 30 minutes. 46 μL (0.74 mmol) methyl iodide was added and the reaction was stirred at room temperature for 2 hours. 20 mg (0.61 mmol, 60% dispersion in mineral oil) of NaH followed by 38 μL (0.61 mmol) of methyl iodide were added and the reaction mixture was stirred at room temperature for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration, the solvent was evaporated to give the desired product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[N:10]1([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3([CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([N:35]1[CH2:36][CH2:37][N:32]([CH2:31][C:25]2([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]4[CH2:11][CH2:12][CH2:13][CH2:14]4)=[CH:24][CH:23]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:33][CH2:34]1)(=[O:5])=[O:3]
Reactant: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
Methanesulphonic acid anhydride (49 mg, 0.28 mmol) was added at 0° C. to a solution of 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine (90 mg, 0.23 mmol) and pyridine (47 μl, 0.58 mmol) in dichloromethane (1 ml). The reaction was stirred at 0° C. for 10 minutes, then allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20 ml) and aqueous sodium carbonate (20 ml). The layers were separated. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 by volume) to provide the title compound (61 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 1.29-1.36 (m, 3H), 1.45-1.52 (m, 5H), 1.85-1.90 (m, 4H), 2.08-2.15 (m, 4H), 2.22 (t, 4H), 2.32 (s, 2H), 2.67-2.79 (m, 9H), 3.00-3.03 (m, 4H), 4.02 (t, 2H), 6.83 (d, 2H), 7.24 (d, 2H). HRMS ESI+ m/z 464.2931 [MH]+.
Reaction SMILES: [CH3:1][Mg]I.[CH:4]1([C:10]2([CH:18]=[O:19])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>CCOCC>[CH:4]1([C:10]2([CH:18]([OH:19])[CH3:1])[CH2:15][O:14][C:13]([CH3:16])([CH3:17])[O:12][CH2:11]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: C[Mg]I
Reactant: CC1(C)OCC(C=O)(C2CCCCC2)CO1
Agent: Cl
Solvent: CCOCC
Product: CC(O)C1(C2CCCCC2)COC(C)(C)OC1
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (3.0 ml, 3M solution in ether) was added to a solution of 5-cyclohexyl-2,2-dimethyl-5- formyl-1,3-dioxane (1.8 g.) in dry ether (50 ml.) The mixture was refluxed, with stirring, for two hours, cooled and poured into a mixture of 2N hydrochloric acid solution in ice. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 5-Cyclohexyl-2,2-dimethyl-5-(1-hydroxyethyl)-1,3-dioxane was obtained as a cream solid (1.5 g.)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C@@H:25]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:24]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:23]1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)C=C.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)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>[Cl:11][C:9]1[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]([C@H:22]2[C@H:23]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@@H:24]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:26]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[O:27]2)=[C:5]([OH:4])[CH:10]=1
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCCCCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCCCCCO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 5-(((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)pentan-1-ol (29, 479 mg, 0.584 mmol) from Step 2 in tetrahydrofuran (6 mL) were added sodium borohydride (177 mg, 4.668 mmol) and tetrakis(triphenylphosphine)palladium (67.5 mg, 0.058 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® apparatus (silica gel, 10 to 50% tetrahydrofuran in hexanes gradient) gave the title compound (30, 459 mg, 0.58 mmol, 100%) as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 67.3 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-cyano phenoxy)-nicotinic acid 0.335 g (0.94 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.94 mmol) were used to afford 0.35 g of the required product. Percentage purity (LCMS): 86.8%, (M+1)=553.6 (with BOC). 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (9H, s), 1.82 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 6.74 (1H, d), 6.95 (1H, d), 7.28 (4H, dd), 7.82 (4H, dd), 8.08 (1H, d), 8.21 (1H, d).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:31][C:27]1[CH:26]=[C:25]([CH2:24][CH:7]([OH:6])[CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][C:12](=[O:15])[N:11]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Following the procedure described for Example 5, Step B, 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (261.7 mg, 0.551 mmol) was deprotected with TBAF (1M in THF, 0.83 mL, 0.83 mmol). The addition was performed at 0° C. and the reaction mixture was stirred at room temperature for 24 h. Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 7-{2-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (141 mg). 1H NMR (CDCl3) δ7.32 (m, 1H), 6.98 (m, 3H), 3.86 (m, 1H), 3.64 (m, 2H), 2.99-2.80 (m, 2H), 2.71 (m, 1H), 2.38 (m, 4H), 2.16 (m, 1H), 1.74-1.29 (m, 14H); MS 361.3 (M+1).