Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Si:23]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([CH:48]=[O:49])[CH:43]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Si:23]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48](=[O:49])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:43]=1)([C:36]([CH3:38])([CH3:39])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](OCc1ccnc(C=O)c1)(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1ccnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g) in ethanol (15 mL) were added 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)pyridine-2-carbaldehyde (1.40 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (95.0 mg) and triethylamine (190 μL), and the mixture was stirred with heating under reflux for 4 hr under argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.90 g, yield 88%) was obtained as a brown oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 698 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[Cl:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(Cl)s1
Reaction time: 3 h

Procedure:
2-Amino-5-chlorothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled and filtered to recover the desired product 5-chlorothiazol-2-yl isocyanate dimer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:23])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Fc1cccc(F)c1C1=NCC(=S)Nc2ccc(Cl)cc21

Procedure:
A solution of 7.65 g. (0.025 mole) of 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-2-one in 500 ml. of pyridine is treated with 5.55 g. (0.025 mole) of phosphorus pentasulfide and heated under reflux in a nitrogen atmosphere for two hours. The pyridine (350 ml.) is removed in vacuo and the thus-produced residue is poured onto crushed ice. The aqueous phase is extracted with methylene chloride and then discarded. The extract is washed successively with three 200-ml. portions of water and 100 ml. of brine, and dried over anhydrous sodium sulfate. Removal of the solvent gives 7.0 g. of solid which is recrystallized from ethanol-water, to give in 2 crops, 6.8 g. of crude material which, after recrystallization from ethanolwater, gives pure 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepine-2-thione, m.p. 222.5°-224° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[CH2:12][CH2:11][N:10](C(O)=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][N:6]=[C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=C1CCN(C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)ON=C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 34 ml of dichloromethane containing 0.9 g of tert-butyl ester of 4-tert-butoxyimino-piperidine-1-carboxylic acid is cooled to 0° C. 25 ml of a 4M solution of hydrochloric acid in dioxane (30 eq) is added. The reaction mixture is stirred at room temperature for 3 hours and then diluted by adding dichloromethane. A saturated solution of sodium hydrogen carbonate is then added until pH=8 is obtained. The aqueous phase is extracted three times with dichloromethane. The organic phases are then combined, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. 0.49 g of piperidin-4-one O-tert-butyl-oxime is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[OH:53])[CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)#[N:24]>C(#N)C>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[O:53][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: ClCc1ccc(CCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(CCc3ccccc3)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 70 %

Procedure:
460 mg (2 mmol) of 1-(chloromethyl)-4-(2-phenylethyl)benzene [preparation according to M. Carrara et al., Arzneim. Forsch. 47 (7), 803-809 (1997)] and 414 mg (3 mmol) of anhydrous potassium carbonate are added to a solution of 411 mg (1 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then evaporated to dryness. The residue is taken up in ethyl acetate, washed with water and with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the organic phase is evaporated and the resulting crude product is purified by preparative HPLC. 431 mg (0.7 mmol, 65% yield) of a solid are obtained.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow oil, MS: m/e=372.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C).
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH3:14]I>>[CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][O:7][CH3:14])[CH2:8][OH:9])[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCC(CO)(CO)CCCC
Product: CCCCC(CO)(CCCC)COC

Procedure:
2,2-Di-n-butyl-3-methoxy-propanol was prepared from 2,2-di-n-butyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=399.1 (M+H)+
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([O:16][CH3:17])[C:9]=1[Cl:18])(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:18][C:9]1[C:10]([O:16][CH3:17])=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=1[CH:7]=[CH2:6]
Reactant: COc1c(C#N)ccc(CCOS(C)(=O)=O)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=Cc1ccc(C#N)c(OC)c1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-chloro-4-cyano-3-methoxyphenyl)ethyl methanesulfonate (207 mg, 0.714 mmol) in DCM (4 mL) was treated with DBU (0.538 mL, 3.57 mmol) and stirred overnight at 40° C. TLC (50% ethyl acetate/hexanes) showed complete conversion to a faster intense UV band for product. The reaction was then diluted with DCM and aq. citric acid and the mixture was extracted twice with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (5-20% ethyl acetate/hexanes) afforded the title intermediate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])(C)(C)C.CCCCC.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:30](OCC)=[O:31])[N:21]=1.[Cl-].[NH4+]>C(OCC)C.C(OCC)C.C(Cl)Cl>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:30]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)=[O:31])[N:21]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Fc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccc(F)cn1)c1nc(Cl)c2ccccc2n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
To a stirred solution of 2-bromo-5-fluoropyridine (237 mg, 2.11 mmol) in anhydrous diethyl ether (7 mL) at −78° C. was added dropwise 1.7 M tert-butyl lithium/pentane (4 mL, 6.8 mmol). The brown mixture was stirred at −78° C. for 20 min, then ethyl 4-chloroquinazoline-2-carboxylate (500 mg, 2.11 mmol) in 3:1 diethyl ether/DCM (4 mL) was added to the mixture over 40 min. The resulting mixture was stirred at −78° C. for 1 h and then at −40° C. for 4 h. Then 10% aq ammonium chloride was added and the mixture was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexane to afford (4-chloroquinazolin-2-yl)(5-fluoropyridin-2-yl)methanone (150 mg, 25%). 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=3 Hz, 1H), 8.37-8.28 (m, 2H), 8.17 (d, J=8.4 Hz, 1H), 8.04 (t, J=8.4 Hz, 1H), 7.83 (t, J=8.4 Hz, 1H), 7.63 (td, J=3 Hz, J=8.4 Hz, 1H); LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(S(C)(=O)=O)C5)n4)n3Cc3ccccc3)n12
Reaction time: 0.07 h
Yield: 84.2 %

Procedure:
To {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (6.0 mg, 0.014 mmol, from Example 90) was added methanesulfonyl chloride (1.3 μL, 0.017 mmol, Aldrich) in DCM (0.50 mL), followed by triethylamine (4.0 μL, 0.028 mmol). The reaction was complete in 4 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product (5.9 mg, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2CCc3ccccc3O2)CC1
Reaction time: 16 h
Yield: 74.8 %

Procedure:
First 1.57 g (10 mmol) of piperidine-4-carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and then, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.17 g (85.7%) of crude product are obtained and are chromatographed on 110 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.90 g (75.1%) of 1-[2 -(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are thus obtained in the form of a yellow oil. The 1-[2-(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 190°-192°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C#N
Reaction time: 1 h

Procedure:
(3R,4S)-1-Benzyl-3-hydroxy-4-methylpyrrolidine (4.00 g) was dissolved in dichloromethane (40 mL). While this solution was cooled on a dry ice/acetone bath, triethylamine (3.06 mL) was added. Methanesulfonyl chloride (1.70 mL) was then added dropwise and the mixture was further stirred for 1 hour. Following addition of water (40 mL), the temperature of the mixture was allowed to rise to room temperature and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (40 mL) and the extract was combined with the dichloromethane layer. The combined dichloromethane layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (120 mL). To this solution, tetrabutylammonium cyanide (5.53 g) and sodium cyanide (2.05 g) were added and the mixture was stirred at 80° C. for 13 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and water (50 mL) was added to the resulting residue. The mixture was extracted with diethyl ether (2×200 mL). The diethyl ether extracts were combined and the combined extract was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (hexane: ethyl acetate=4:1) to give 3.32 g of (3R,4S)-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH2:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:33]#[CH:34].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCC3CCCCC3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.59 mmol) and 4-prop-2-ynyl-morpholine (222.0 mg; 1.77 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (30%). HPLC-MS: m/z: 551.8 (M)+; Rt: 2.35 min
Reaction SMILES: [OH:1][CH:2]([CH:7]([CH3:9])[CH3:8])[C:3](=[CH2:6])[C:4]#[N:5].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>O.C(Cl)Cl>[C:4]([C:3](=[CH2:6])[CH:2]([O:1][C:16](=[O:18])[CH3:17])[CH:7]([CH3:9])[CH3:8])#[N:5]
Reactant: CC(=O)Cl
Reactant: C=C(C#N)C(O)C(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=C(C#N)C(OC(C)=O)C(C)C
Yield: 98.7 %

Procedure:
A nitrogen-purged 5 L, three-necked, round-bottom flask with overhead stirring is charged with 50 g (0.4 mol) of 3-hydroxy-4-methyl-2-methylenepentanenitrile, 0.4 L of methylene chloride, and 80 mL (1 mol) of pyridine. The solution is cooled at 10° C. to 15° C. in an ice bath. Using a 500 mL graduated addition funnel, a mixture of 100 mL of methylene chloride and 43 mL (0.6 mol) of acetyl chloride is added slowly while maintaining the reaction temperature at 25° C.±5° C. The reaction is stirred at 22° C.±3° C. for about one additional hour. The reaction solution is poured into a 4 L separators funnel containing 85 mL (1.0 mol) of hydrochloric acid and 750 mL of water. The lower organic layer is washed again with a solution of 20 mL (0.2 mol) of HCl and 250 mL of water. The organic layer is dried over anhydrous magnesium sulfate (20 g), filtered, and concentrated by rotary evaporation to provide 66 g of acetic acid 2-cyano-1-isopropyl-allyl ester as a yellow oil which may be used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].O>[OH-].[Na+].C(O)C.C1C=CC=CC=1>[C:17]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:21])/[CH:18]=[CH:19]/[CH3:20]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: C/C=C/C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: C/C=C/C(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl crotonate was prepared by dissolving 22.2 grams of 2,6-di tert.butyl hydroquinone in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol and adding drop wise to this solution a solution of 11.5 grams of crotonyl chloride in 50 milliliters of benzene. The addition was completed in 45 minutes. The reaction mixture was stirred for 4 hours at room temperature and then at 50° C. for 1 hour. After adding 100 milliliters of water to the reaction mixture, the layers were separated. The organic layer was evaporated to dryness and the residue dissolved in hexane. The hexane solution was washed three times with 10 percent sodium hydroxide solution, once with water, dried over sodium sulfate, and cooled to yield 10.5 grams of product which after recrystallization from hexane melted at 80° C. to 81.5° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=1)=[O:6]>CO>[CH2:19]([O:18][C:16]1[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:17]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2c(OCc3ccccc3)cc(C(=O)O)cc2O1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
NaOH (23 mL, 69 mmol, 3N aqueous solution) was added to a solution of 4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (77a) (7.18 g, 23 mmol) in MeOH (80 mL). The reaction mixture was heated to 60° C. for 3 hr, and concentrated in vacuo. The residue was diluted with H2O (100 mL) and washed with EtOAc (100 mL). The aqueous phase was acidified with 3N aqueous HCl to Ph ˜2 to form a white precipitate, which was filtered and dried to give a white solid (6.05 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1 H) 7.38-7.48 (m, 4 H) 7.33 (t, J=7.07 Hz, 1 H) 7.14 (s, 1 H) 6.88 (s, 1H) 5.17 (s, 2 H) 2.98 (s, 2 H) 1.42 (s, 6 H); LCMS for C18H18O5 m/z 299.10 (M+H)+.