Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[OH:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>CO>[NH2:26]/[C:6](/[C:5]1[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1
Reactant: N
Reactant: O=C(c1ccc(F)cc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccc(F)cc1
Yield: 63 %

Procedure:
Prepared as in Example 1 from 2-(4-fluorobenzoyl)-benzo[b]thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 63% of theory. Yellow, felt-like crystals; M.p. 158° C. (methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:48])[NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)[CH:7]=1.[CH2:49]([N:51]1[CH2:56][CH2:55]C(NC)[CH2:53][CH2:52]1)[CH3:50].[CH3:59][N:60]([CH3:63])[CH:61]=[O:62]>>[CH2:49]([N:51]1[CH2:56][CH2:55][CH:59]([N:60]([CH3:63])[C:61]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:48])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:62])[CH2:53][CH2:52]1)[CH3:50]
Reactant: CN(C)C=O
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CCN1CCC(NC)CC1
Product: CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 58 %

Procedure:
To phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) was added a solution of N-(1-ethylpiperidin-4-yl)-N-methylamine (66 mg) in N,N-dimethylformamide (1.0 ml), followed by stirring at room temperature for 9 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated. A solid was precipitated by addition of diethyl ether:hexane=1:2 to the residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (25.8 mg, 58%).
Reaction SMILES: [C:1]([Si:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:37][C:36]=1[Cl:50]>CN(C=O)C.C(OCC)C>[CH2:43]([O:42][C:38]1[CH:37]=[C:36]([Cl:50])[C:35]([CH2:34][N:15]2[CH2:16][CH2:17][CH:13]([CH:10]3[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:8][CH2:9]3)[C:14]2=[O:18])=[C:40]([Cl:41])[CH:39]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: CC(C)(C)[Si](OC1CCC(C2CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
Treat a solution of 3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (0.75 g, 1.78 mmol) in DMF (25 mL) with 60% sodium hydride (0.11 g, 2.67 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene (0.74 g, 2.13 mmol), and stir for 30 minutes at 0° C. Warm to room temperature and stir for 30 minutes under N2. Quench the reaction with water and dilute with diethyl ether. Wash the organic layer with water three times, dry (Na2SO4), and remove the solvent in vacuo to afford crude product. Purify with a 0 to 30% ethyl acetate in hexanes gradient to afford 1.2 g (99%) of the titled product. MS (m/z): 686 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[O:24])=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CSC(=O)N1CC(C)(C)SCc1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 40.9 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]-L-cysteine methyl ester (0.5 g) in dimethylformamide (10 ml), carbonyldiimidazole (0.28 g) was added and the mixture was stirred for 2.5 hours at 100°-110° C. 1N hydrochloric acid was added into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and then saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography and recrystallized from n-hexane--isopropanol to give 0.22 g (40%) of the titled compound.
Reaction SMILES: O1CCOCC1.O.[C:8]12([NH:18][S:19]([C:22]3[CH:23]=[C:24]([C:32](O)=[O:33])[C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=3)(=[O:21])=[O:20])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>C(N(CC)CC)C>[CH2:35]([NH:39][C:32]([C:24]1[C:25]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=[C:22]([S:19](=[O:21])(=[O:20])[NH:18][C:8]23[CH2:15][CH:14]4[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]4)[CH2:9]2)[CH2:17]3)[CH:23]=1)=[O:33])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(O)c1cc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc2c1OCCO2
Reactant: CCCCN
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1cc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc2c1OCCO2
Temperature: 25 °C
Yield: 46.5 %

Procedure:
500 ml of dioxane, 50 ml of water, 49 g of 7-[(1-adamantyl)-sulfamoyl]-1,4-benzodioxane-5-carboxylic acid and 12.5 g of triethylamine were introduced into a 2-liter balloon flask provided with an agitator and a thermometer. The solution was agitated at ambient temperature and then 17 g of isobutyl chloroformiate was added. The mixture was agitated and then 10 g of butylamine was introduced. After agitation of the mixture dioxane was removed. The residue was dissolved in 200 ml of hot water. The crystals formed by cooling were washed with water, dried and redissolved in 250 ml of acetone at boiling temperature. The solution was filtered hot. The crystals formed by cooling were dried off, washed and dried. 26 g of N-(butyl)-7-[(1-adamantyl)-sulfamoyl]-1,4-benzodioxane-5-carboxamide was produced (M.P. 147° C.; yield: 46.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10](=O)[NH:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10](=[S:29])[NH:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCCC(c2ccccc2F)(C(F)(F)F)N1
Solvent: C1CCOC1
Product: Fc1ccccc1C1(C(F)(F)F)CCOCC(=S)N1
Temperature: 25 °C
Yield: 180.6 %

Procedure:
To a solution of 5-(2-fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepan-3-one (1.19 g, 4.29 mmol) in 15 mL THF was added Lawesson's reagent (955 mg, 2.36 mmol). The reaction mixture was stirred at room temperature over night. The mixture was then partitioned between aqueous Na2CO3 solution (2 mol/L) and TBME. The layers were separated, washed with aqueous Na2CO3 solution (2 mol/L), brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 95/5→90/10 to give 1.25 g of the title compound as a yellow resin.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][CH3:34])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:43](Cl)(Cl)=[S:44].O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:33]([CH3:34])[C:43]2=[S:44])[CH2:19][CH2:18]1
Reactant: S=C(Cl)Cl
Reactant: CNc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=S)n(CCN2CCC(Nc3nc4ccccc4n3Cc3ccco3)CC2)c(=O)c2ccccc21
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred mixture of 4.7 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-(methylamino)benzamide, 2.02 parts of N,N-diethylethanamine and 195 parts of dichloromethane was added dropwise a solution of 1.14 parts of carbonothioic dichloride in dichloromethane. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into water. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.4 parts (27.5%) of 3-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2,3-dihydro-1-methyl-2-thioxo-4(1H)-quinazolinone; mp. 188.4° C. (compound 129).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][C:12]([OH:14])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:11][C:12]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:14]
Reactant: COc1cccc(OC)c1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OC)c1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.58 h
Yield: 59.2 %

Procedure:
N,N'-Carbonyldiimidazole (0.52 g) is added to a solution of 2-(2,6-dimethoxyphenyl)acetic acid (0.63 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 35 minutes at +5° C. The mixture is stirred for 35 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.05 g) and triethylamine (0.44 cc) in dichloromethane (25 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (16 cc) and isopropyl ether (15 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-dimethoxyphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (0.89 g) melting at 224° C. is obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:15][C:16]1[N:17]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][CH:36]=2)[C:18](=[O:33])[C:19]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH:29]([CH3:31])[CH2:28][C:27]=3[CH:32]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]>O>[CH2:13]([O:15][C:16]1[N:17]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:3][C:4](=[O:7])[O:5][N:48]=3)=[CH:39][CH:40]=2)[C:18](=[O:33])[C:19]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH:29]([CH3:31])[CH2:28][C:27]=3[CH:32]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: CCOc1nc(C)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1nc(C)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogen carbonate (1.35 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethoxy-4-methyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.77 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.39 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.58 g, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C([O:40][C:41](=O)[C:42]1[C:47]([CH2:48]Br)=[CH:46][CH:45]=[CH:44][C:43]=1[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][N:27]3[CH2:48][C:47]4[C:42](=[C:43]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:52])[CH3:53])[CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:40])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN2Cc3cccc(O[Si](C)(C)C(C)(C)C)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
To a solution of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (80 mg, 0.20 mmol) and diisopropyl ethylamine (35 μl, 0.40 mmol) in acetonitrile (10 ml) at room temperature as added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (69 mg, 0.2 mmol). The solution was stirred for 12 hours at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with 20% ethyl acetate/hexane to yield 42 mg (33%) of 2-amino-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].CC(=C)C[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].[C:23]1([CH3:33])[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1>>[C:23]([C:9]1[C:10]([OH:12])=[CH:11][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:6]([OH:7])[CH:8]=1)([CH3:33])([CH3:28])[CH3:24]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)CCCC(=O)OC
Product: COC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O

Procedure:
16.6 Parts of 2-t-butylhydroquinone, 14.2 parts of methyl 5-methyl-hex-5-enoate and 0.5 parts of p-toluene sulphonic acid are reacted and worked up as described for Example 25. Distillation gives methyl 5-(4'-t-butyl-2',5'-dihydroxyphenyl)-5-methylhexanoate, b0.3 186°-210° C. This fraction, after crystallisation from 40°-60° petroleum ether, has m.p. 136°-9° C. and the following percentage composition by weight.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[C@@H:41]([CH2:45]O)[CH:42]([CH3:44])[CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[CH:41]([CH2:45][I:1])[CH:42]([CH3:44])[CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: CC(C)[C@H](CO)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(CI)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
Iodine (42 g), triphenylphosphine (47 g) and imidazole (12 g) were added to a solution of 4-(R)-benzyl-3-(2-(R)-hydroxymethyl-3-methylbutyryl)oxazolidin-2-one (45 g) in toluene (400 ml) and the mixture was heated to 80° C. for 1 h, then cooled and washed with water and saturated brine. The solvent was dried (Na2SO4) and evaporated and the residue filtered through silica (200 g) eluting with diethyl ether-hexane 1:1 to give the title compound as a yellow viscous oil (56.4 g).
Reaction SMILES: C(OP([CH:9]([Cl:11])[Cl:10])(=O)OCC)C.[C:12]([CH:15]1[C:17]([CH3:19])([CH3:18])[CH:16]1[CH:20]=O)(=[O:14])[CH3:13].O>CN(C)C=O.O1CCCC1>[Cl:11][C:9]([Cl:10])=[CH:20][CH:16]1[C:17]([CH3:19])([CH3:18])[CH:15]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)C1C(C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
A solution of 12.3 g (0.11 mol) of potassium tert.-butylate in 30 ml of dimethylformamide was added dropwise, under an inert gas atmosphere (nitrogen or argon) at -20° to -25° C., to a solution of 24 g (0.180 mol) of dichloromethane-phosphonic acid diethyl ester and 14 g (0.1 mol) of 2-acetyl-3,3-dimethylcyclopropanecarboxaldehyde in 100 ml of tetrahydrofuran. The mixture was subsequently stirred for 3 hours without cooling, 200 ml of water were added and extraction was carried out twice with 100 ml of methylene chloride. The organic phase was washed with 50 ml of 10% strength sodium hydroxide solution and then with 3 times 50 ml of water, dried over sodium sulphate and evaporated in vacuo. 14.8 g (71% of theory) of 1-(2,2-dichlorovinyl)-2-acetyl-3,3-dimethylcyclopropane were obtained from the residue, by vacuum distillation, in the form of a pale yellow oil having a boiling point of 55°-57° C./0.3 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:54]=[N+:55]=[N-:56].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][N:54]=[N+:55]=[N-:56])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCN=[N+]=[N-])CCC3)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
A solution of 0.200 g (0.266 mmol) of crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in 1.8 ml of absolute N,N-dimethylformamide was treated with 0.025 g (0.398 mmol, 1.5 equiv.) of anhydrous sodium azide, and stirred for 45 min. at 50° C. The reaction mixture was then poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent and yielded 0.162 g (0.231 mmol, 86.8% of theory) of (3R,4R)-3-[1-(3-azido-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 700 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[Br:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[N:59]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:62][CH:61]=3)[CH:58]([C:70]3[CH:71]=[C:72]([NH2:88])[C:73]([NH:76][CH2:77][C:78]4[CH:83]=[CH:82][C:81]([O:84][CH3:85])=[CH:80][C:79]=4[O:86][CH3:87])=[CH:74][CH:75]=3)[CH2:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[Br:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[N:59]([C:60]3[CH:61]=[CH:62][C:63]([C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:64][CH:65]=3)[CH:58]([C:70]3[CH:75]=[CH:74][C:73]([NH:76][CH2:77][C:78]4[CH:83]=[CH:82][C:81]([O:84][CH3:85])=[CH:80][C:79]=4[O:86][CH3:87])=[C:72]([NH:88][C:14]([C@@H:10]4[CH2:11][CH2:12][CH2:13][N:9]4[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:17]([CH3:19])[CH3:18])=[O:16])[CH:71]=3)[CH2:57][CH2:56]2)=[CH:51][CH:50]=1
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(Br)cc4)N3c3ccc(C(C)(C)C)cc3)cc2N)c(OC)c1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1NCc1ccc(OC)cc1OC)C(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (0.339 g, 1.245 mmole) and HOBt (0.191 g, 1.245 mmole) were dissolved in DMF (4 mL) cooled in an ice bath and treated with EDAC (0.245 g, 1.245 mmole) and N-Methylmorpholine (NMM) (0.55 mL, 4.98 mmole). The resulting solution was stirred 5 minutes in the ice bath, treated dropwise with the product from Example 191F in DMF (4 mL) and the resulting dark mixture was stirred in the ice bath for 1 hr then at room temperature for 18 hr. The next day, the reaction mixture was diluted with EtOAc (50 mL) and the organic layer was washed with 10% NaHCO3 and 10% NaCl, dried over anhydrous Na2SO4(s), filtered and the solvent was removed in vacuo leaving an oily residue as the title compound as a mixture of isomers (0.65 g). ESI+(m/z): 868.2.