Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:9]=1[CH2:8][CH2:7]3.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3
Reactant: CN1CC2CCC3c4ccc(OS(=O)(=O)C(F)(F)F)cc4CCC23C1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CC2CCC3c4ccc(-c5ccc(C#N)cc5)cc4CCC23C1
Temperature: 90 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
Trifluoro-methanesulfonic acid 8-methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-2-yl ester (Example 1D) (23.0 mg, 0.061 mmol) and 4-cyanophenylboronic acid (18 mg, 0.122 mmol) were dissolved in toluene (2 mL) and ethanol (0.5 mL). 0.15 mL of 1M Na2CO3 solution was added. Nitrogen was bubbled through the reaction mixture for 10 min. Tetrakis(triphenylphosphine)palladium (7.1 mg, 0.006 mmol) was then added. The mixture was stirred at 90° C. for 20 h. The reaction mixture was quenched with water (2 mL), extracted with CH2Cl2 (5 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel twice using 10% methanol in dichloromethane and 0.5% ammonium hydroxide and 5% methanol in dichloromethane, providing 6.2 mg (30.8%) of the title compound 1E.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)/[C:8](NC2SC=CN=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:28])C>>[CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)/[C:8]([OH:9])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
A solution of the isomeric mixture of 3-cyclopentyl-2-(4-meth-anesulfonyl-phenyl)-acrylic acid ethyl ester [65.02 g, 0.202 mol, (E):(Z)=1.63:1] in methanol (504 mL) was treated with a 1N aqueous sodium hydroxide solution (423 mL, 0.423 mol). The reaction mixture was stirred at 25° C. for 20 h, at which time, thin layer chromatography indicated the presence of starting material. The reaction mixture was then concentrated in vacuo to remove some of the methanol (300 mL). The resulting reaction mixture was heated under reflux for 1 h, at which time, thin layer indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×1 L). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid (62.58 g) as a cream solid consisting of a 16.2:1 mixture of (E):(Z) isomers. The cream solid was treated with ethyl acetate (200 mL), and the resulting slurry was heated to a boil. The resulting white solid surrounded by a light yellow liquid of ethyl acetate was allowed to cool to 25° C. The solid was filtered to afford pure (E)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid (41.18 g, 69%) as a white solid: mp 200-202° C.; EL-HRMS m/e calcd for C15H18O4S (M+) 294.0926, found 294.0921.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:46](O)(=[S:48])[CH3:47]>C1COCC1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([O:12][C:46](=[S:48])[CH3:47])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (from Example 51 above) (2.6 g, 12.02 mmol) and triphenyl phosphine (Aldrich, 7.9 g, 30.12 mmol) in dry THF (100 mL) at 0° C. was added dropwise diethyl azodicarboxylate (Aldrich, 4.8 mL, 30.48 mmol). After stirring for 15 minutes thioacetic acid (Aldrich, 2.2 mL, 30.78 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature slowly and stirred overnight. Then, the reaction mixture was concentrated and the residue was purified by flash chromatography (silica gel, 0-5% ether in hexanes gradient) to give (±)-trans-thioacetic acid-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl] ester as a light yellow liquid. (Yield 2.36 g, 72%).
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][C:15]1[C:20](Br)=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[C:26](=[O:27])[N:25]([CH3:28])[N:24]=[N:23]1>O>[CH3:14][C:15]1[C:20]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[C:26](=[O:27])[N:25]([CH3:28])[N:24]=[N:23]1
Reactant: Cc1c(Br)cccc1-n1nnn(C)c1=O
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1c(S[Si](C(C)C)(C(C)C)C(C)C)cccc1-n1nnn(C)c1=O
Temperature: 90 °C
Yield: 91.7 %

Procedure:
Under ice-cooling, to a mixture of triisopropylsilanethiol 4.99 g and tolune 30 ml was added 60% sodium hydride 0.63 g, and the resulting mixture was stirred for thirty minutes. To the reaction mixture was added 1-(2-methyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 10) 2.82 g and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct 0.856 g. The reaction mixture was heated to 90° C. and was stirred for four hours. After cooling the reaction mixture, thereto was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methyl-3-triisopropylsilanylsulfanylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 3.64 g.
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34](O)=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)CCl.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][N:50]([CH3:55])[S:51]([NH2:54])(=[O:53])=[O:52]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH2:2]([N:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([NH:54][S:51]([N:50]([CH2:49][CH:48]([O:47][CH3:46])[O:56][CH3:57])[CH3:55])(=[O:53])=[O:52])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)Cc1ccccc1)COc1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 14 h

Procedure:
A solution (0.06 M) of N-benzyl-2-{[(7S)-11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]oxy}-N-methylethanaminium chloride and DMAP (3 eq) in anhydrous DCM, was treated with EDC (1.5 eq) and N-(2,2-dimethoxyethyl)-N-methylsulfamide (prepared as described in Example 1, Step 1). The mixture was stirred at 40° C. for 14 h, and then diluted with EtOAc, washed with aqueous sat. aq. NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. The product was used in the next step without further purification. (ES+) m/z 719 (M+H)+.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(N4C5=NC=CC=C5C=C4)CCCC3)N=2)=O)CC1.[Si]([O:47][CH2:48][CH2:49][N:50]([CH:83]1[CH2:86][CH2:85][CH2:84]1)[C:51]([C:53]1[C:58]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:57]([OH:67])[N:56]=[C:55]([CH2:68][C:69]2([N:74]3[C:78]4=[N:79][CH:80]=[CH:81][CH:82]=[C:77]4[CH:76]=[CH:75]3)[CH2:73][CH2:72][CH2:71][CH2:70]2)[N:54]=1)=[O:52])(C(C)(C)C)(C)C>>[CH:83]1([N:50]([CH2:49][CH2:48][OH:47])[C:51]([C:53]2[C:58]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[C:57]([OH:67])[N:56]=[C:55]([CH2:68][C:69]3([N:74]4[C:78]5=[N:79][CH:80]=[CH:81][CH:82]=[C:77]5[CH:76]=[CH:75]4)[CH2:73][CH2:72][CH2:71][CH2:70]3)[N:54]=2)=[O:52])[CH2:86][CH2:85][CH2:84]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1CCC1
Agent: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclobutyl-(2-hydroxyethyl)-amide (426) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (418) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amide (425) (200 mg, 0.30 mmol) and was obtained as white solid (100 mg, 59%).
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(=O)NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)=CC=2C(O)=O)C=1C.[CH2:44]([N:48]([CH2:94][C:95]1[CH:100]=[CH:99][C:98]([Cl:101])=[C:97]([Cl:102])[CH:96]=1)[C:49]([C:51]1[C:55]([Cl:56])=[C:54]([CH3:57])[N:53]([C:58]2[CH:68]=[CH:67][C:66]([C:69](=[O:93])[NH:70][S:71]([C:74]3[CH:83]=[CH:82][C:81]4[C:76](=[C:77]([O:84][CH2:85][CH2:86][N:87]5[CH2:92][CH2:91][O:90][CH2:89][CH2:88]5)[CH:78]=[CH:79][CH:80]=4)[CH:75]=3)(=[O:73])=[O:72])=[CH:65][C:59]=2[C:60]([O:62]CC)=[O:61])[N:52]=1)=[O:50])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]([CH2:94][C:95]1[CH:100]=[CH:99][C:98]([Cl:101])=[C:97]([Cl:102])[CH:96]=1)[C:49]([C:51]1[C:55]([Cl:56])=[C:54]([CH3:57])[N:53]([C:58]2[CH:68]=[CH:67][C:66]([C:69](=[O:93])[NH:70][S:71]([C:74]3[CH:83]=[CH:82][C:81]4[C:76](=[C:77]([O:84][CH2:85][CH2:86][N:87]5[CH2:88][CH2:89][O:90][CH2:91][CH2:92]5)[CH:78]=[CH:79][CH:80]=4)[CH:75]=3)(=[O:72])=[O:73])=[CH:65][C:59]=2[C:60]([OH:62])=[O:61])[N:52]=1)=[O:50])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)OCC)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Yield: 76.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 91F, ethyl 2-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)benzoate (75 mg, 0.085 mmol) was converted to the title compound (56 mg, 77%). MS(ESI+) m/z 858.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20](OCC)=[O:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([CH2:20][OH:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(Sc2cc(Cl)cc(Cl)c2)c(CO)nn1CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of Example 46 (65 mg, 0.17 mmol) in tetrahydrofuran (2.5 ml) was cooled to −78° C. and treated with lithiumaluminium hydride (1M in THF) (170 μL, 0.17 mmol). After stirring at −78° C. for 2 hours the reaction mixture was allowed to warm to 0° C. for 1 hour and was then allowed to warm to room temperature. After stirring at this temperature for 18 hours, water (1 ml) was added. The reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (42 mg) as a colourless oil, which solidified on standing, m.p. 89–90° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CP(C)(=O)OCC(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COP(C)(=O)C[C@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 4.3 g of isobutyl P-[2(R)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.5 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(R)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =-15.8 (0.51% in ethanol).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:30]([C:31]([NH2:33])=[O:32])[C:29]=1[OH:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:31]([C:30]1[C:29]([OH:37])=[C:28]([CH:36]=[CH:35][CH:34]=1)[O:27][CH2:26][CH2:25][N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1)(=[O:32])[NH2:33]
Reactant: COCCOc1ccc(OCC2CO2)cc1
Reactant: NC(=O)c1cccc(OCCNCc2ccccc2)c1O
Product: COCCOc1ccc(OCC(O)CN(CCOc2cccc(C(N)=O)c2O)Cc2ccccc2)cc1

Procedure:
By reacting 2.5 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene with 2.9 g of crude 3-(2-benzylaminoethoxy)salicylamide obtained according to Example (25c), analogously to Example (4a), 1-[N-[2-(3-carbamoyl-2-hydroxyphenoxy)ethyl]benzylamino]-3-[4-(2-methoxyethoxy)-phenoxy]propan-2-ol is obtained as an oil which is further processed in this state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(F)ccc1F

Procedure:
Following General Procedure BI above, and using 2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: ICI.[CH2:4]([C:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([CH:15]([OH:17])[CH3:16])[CH2:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6].[CH2:18]([Al](CC)CC)C.ClC1C=CC=C(C(OO)=O)C=1>CCCCCC.O>[CH2:4]([C:8]12[CH2:18][CH:9]1[CH2:10][CH:11]([CH:15]([OH:17])[CH3:16])[CH:12]([CH3:14])[CH2:13]2)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CC1=CCC(C(C)O)C(C)C1
Reactant: CC[Al](CC)CC
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ICI
Solvent: CCCCCC
Solvent: O
Product: CC(C)CC12CC(C)C(C(C)O)CC1C2
Reaction time: 16 h
Yield: 121.5 %

Procedure:
Diiodomethane (9.6 g, 36 mmol) was added at room temperature, with stirring and under nitrogen, to a solution of 1-(4-Isobutyl-6-methylcyclohex-3-enyl)ethanol 4b (3.5 g, 18 mmol) in hexane (50 ml). After cooling to 5° C. triethylaluminium (1M, 36 ml, 36 mmol) was added over 30 min while the temperature was kept below 5°. The reaction was allowed to return to room temperature and stirred for 16 h, then another portion of diiodomethane (9.6 g, 36 mmol) and triethylaluminium (1M, 36 ml, 36 mmol) were added. After a further 15 h yet more diiodomethane (4.8 g, 18 mmol) and triethylaluminium (1M, 18 ml, 18 mmol) were added. After 2 h stirring, the reaction being still incomplete, the reaction mixture was poured slowly, onto a stirred mixture of ice and water. The phases were separated and the aqueous one extracted twice with hexane. The combined organic layers were washed with water, twice with 2M HCl and again with water, dried (Na2SO4) and the solvent removed in vacuo. The crude oil (5.7 g) was dissolved in methylene chloride (50 ml) and solid 3-chloroperbenzoic acid (ca. 77%, 1.5 g, 6.7 mmol) was added in four portions under nitrogen. The mild exothermic effect was controlled with a cool water bath. The reaction was stirred till the unreacted 4b had been completely consumed (30 min). 2M NaOH was added and the mixture stirred until it became white. The phases were separated and the upper aqueous layer extracted twice with methylene chloride. The combined organic layers were washed twice with 2M NaOH and water, dried (MgSO4) and evaporated in vacuo to give 4.6 g of oil. The crude oil was purified by flash chromatography (MTBE/hex. 3:2) and combination of pure fractions gave 5b as a 1:1.1:1.8 mixture of diastereomers (3.4 g, 86% yield, colourless oil, 95% pure). Subsequent distillation provided an olfactory pure sample.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][CH2:18][CH2:19]O)[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[CH2:5][CH2:4][S:3]1.[N+:21]([C:24]1C=[CH:28][C:27](S([O-])(=O)=O)=[CH:26][CH:25]=1)([O-])=O.N1CCCCC1>C1COCC1>[CH3:1][C:2]1([CH2:16][O:17][CH2:18][CH2:19][N:21]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[CH2:5][CH2:4][S:3]1
Reactant: COc1cc2c(cc1OC)C(C)(COCCO)SCC2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OC)C(C)(COCCN1CCCCC1)SCC2

Procedure:
A mixture of 2-[[1-methyl-6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-1-yl]methoxy]ethanol-4-nitrobenzenesulfonate and piperidine is stirred at room temperature in THF. The mixture is then partitioned between methylene chloride and aqueous sodium carbonate. The title compound is isolated by chromatography and is crystallized.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.S(Cl)(C)(=O)=O.CNC>ClC(Cl)C.CO.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:13]([CH3:14])[CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)nc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(c1ccc(Br)nc1)N(C)C
Temperature: 4 °C
Yield: 12.1 %

Procedure:
1-(6-Bromopyridin-3-yl)ethanol (100 mg, 0.54 mmol) was dissolved in dichloroethane (4 ml), 200 mg of triethylamine was added thereto, and the mixture was stirred at 4° C. under ice cooling. Mesyl chloride (68 mg, 0.60 mmol) was added to the reaction solution. After the dropwise addition, the mixture was stirred at 4° C. under ice cooling and was further stirred at room temperature for 30 min. The reaction solution was poured into 10 ml of iced water and was extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure. The residue was dissolved in DMF (2 ml), and the solution was stirred at room temperature. A 2 M solution (1 ml) of dimethylamine (2 mmol) in methanol was added thereto, and the mixture was stirred at 50° C. for 4 hr. The reaction solution was poured into 10 ml of iced water and was extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give 15 mg (yield 33.1%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[Cl:11]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[N:3]=1
Reactant: C=C(C)c1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
A mixture of 3.60 g of 2-bromo-6-isopropenylpyridine, 2.91 g of N-chlorosuccinimide and 8 ml of benzene was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 1.50 g of the objective compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][F:26])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][F:26])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2ccc(OCCF)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2ccc(OCCF)cc2)c1
Yield: 62.7 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[4-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (20 mg, 30 μmol) in ethyl acetate (0.8 mL) and methanol (013 mL) was stirred for 4.45 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 19 mg). The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and purified by preparative HPLC to yield 13.9 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{2-[4-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.