Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C@H:14]([Cl:29])[C@H:13]3O)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC.O>ClCCl>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14]([Cl:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
5.0 g of 17α-acetoxy-6β-chloro-7α-hydroxy-1α,2α-methylene-4-pregnene-3,20-dione is mixed in 25 ml of dichloromethane with 0.1 g of p-toluenesulfonic acid and 3.0 ml of trimethyl orthoformate. The mixture is allowed to stand for 4 hours at 0° C., mixed with 20 ml of water and stirred for 15 minutes. Then the organic phase is separated, dried with sodium sulfate and concentrated in vacuo. Thus, 4.8 g of 17α-acetoxy-6-chloro-1α,2α-methylene-4,6-pregnadiene-3,20-dione with a melting point of 202° to 205° C. (80% purity) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]2[NH:7][C:8](=[O:44])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([C:26]5[CH:27]=[C:28]6[C:32](=[C:33]([CH3:35])[CH:34]=5)[N:31](COCC[Si](C)(C)C)[N:30]=[CH:29]6)=[O:25])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl.N.O>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]2[NH:7][C:8](=[O:44])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([C:26]5[CH:27]=[C:28]6[C:32](=[C:33]([CH3:35])[CH:34]=5)[NH:31][N:30]=[CH:29]6)=[O:25])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(cnn5COCC[Si](C)(C)C)c4)ncn3)CC1)C(=O)N2
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]ncc5c4)ncn3)CC1)C(=O)N2

Procedure:
65 mg (0.10 mmol) 7-methoxy-3-(1-{6-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-5-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 0.4 mL MeOH and 0.6 mL (2.4 mmol) of a 4 molar HCl solution in dioxane was stirred overnight at RT. The mixture was neutralised with 0.4 mL of a 6 molar methanolic ammonia solution, mixed with some water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]=12.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][C:4]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)=[C:5]3[C:9](=[O:10])[CH2:8][CH2:7][C:6]=23)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1CCc2c(Cl)sc(Cl)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CCc2c(-c3ccncc3)sc(-c3ccncc3)c21
Yield: 49.6 %

Procedure:
To a stirred solution of 1,3-dichloro-5,6-dihydro-4H-cyclopenta(c)thiophen-4-one (923 mg, 4.45 mmol) in dimethoxyethane (23 mL) was added 4-pyridineboronic acid (1.3 g, 10.6 mmol), saturated aqueous NaHCO3 solution (7.5 mL), and bis(triphenylphosphine)palladium chloride (350 mg, 0.49 mmol) under nitrogen. The mixture was heated at reflux temperature for 36 hours. The reaction mixture wvas filtered through celite and the filtrate was extracted with ethyl acetate (100 mL×5). The combined organic layer was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. Chromatographic purification eluting with dichloromethane/methanol (25:1) and the subsequent recrystallization from ethyl acetate/hexane gave the title compound (645 mg, 50% yield) as yellow solids.
Reaction SMILES: [C:1]([N:4]([CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:35][I:36]>>[I-:36].[C:1]([N:4]([CH2:28][C:29]1[CH:30]=[N+:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)[C:5](=[O:27])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccnc2)C(C)=O)cc1
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccc[n+](C)c2)C(C)=O)cc1
Product: [I-]
Temperature: 110 °C

Procedure:
A mixture of 0.281 g of product from Example 27 and 1.88 ml of methyl iodide is heated in a sealed tube at 110° C. for 20 hours. The cooled solution is concentrated in vacuo and the residue recrystallized from methyl alcohol to give 0.367 g of the desired product as cream crystals.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([Br:70])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][C:67]([Br:70])=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: N=C(OCC=Cc1ccc(Br)cc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(Br)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-bromocinnamyl trichloroacetimidate (135 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (19 mg).
Reaction SMILES: C(O)CCC.C(O)CCCCCCC.S(=O)(=O)(O)O.[OH:20][C@H:21]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]1[OH:23]>O>[O:20]=[CH:21][C@@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: O
Solvent: CCCCCCCCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A maleic acid ester of an APG was prepared as follows. To a 1 L erlenmeyer flask, containing a magnetic stir bar, was added 185.1 g anhydrous n-butanol (Aldrich, 99.8%), 36.1 g n-octanol (Aldrich, 99+%), and 2.0 g deionized water. To the stirred mixture, 0.184 g (100 mL) of concentrated sulfuric acid (J. T. Baker, 96.6%) was added using a 1 mL glass syringe. This mixture was added to a 500 mL three necked round bottom flask containing 50.0 g of anhydrous α-D-glucose (Aldrich, 96%) and a concave magnetic stir bar. The flask was fitted with a thermocouple probe, a dry air intake, and a 25 mL Barrett receiver on which two glass condensers were mounted, which were connected to a gas bubbler. The condensate collection side of the Barrett receiver was filled with n-heptane, and the gas flow-through side was wrapped in cotton wool for the purpose of insulation. Dry air, passed over a 10 inch column filled with dry molecular sieves and Drierite, was passed through the liquid phase in the round bottom flask. The flask was heated for 4 hours at about 95° to 100° C. using a temperature controlled oil bath. Approximately 12 mL of condensate water was collected in the Barrett receiver as a result of glucose oligomerization reaction and the aldol condensation reaction to give alkylation at the C1 position. The white suspension of sugar particles disappeared as the reaction from glucose to APG proceeded until a clear solution was obtained. This demonstrated that the APG is soluble in the alcohol. The resulting APG solution was colorless, indicating that byproduct formation of colored bodies, such as furfurals, was minimized.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:17]([CH3:19])[CH3:18])([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+]>CO>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:17]([CH3:19])[CH3:18])([C:13]([OH:15])=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@]1(C(C)C)C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)O)(C(C)C)C1

Procedure:
reacting said methyl (1S,4S)-4-(2,5dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylate with NaOH and MeOH to form (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20].[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[C:19]([C:18]([CH3:22])([CH3:21])[CH2:17][C:11]1[CH:12]=[C:13]([O:16][CH2:39][C:35]2[CH:34]=[C:33]([CH:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][CH:36]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])#[N:20]
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C#N)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)-2,2-dimethylpropanenitrile (136 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (136 mg) and tributylphosphine (0.22 mL) in toluene (5.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (225 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=1[NH2:19].CCO.C([O-])([O-])=O.[Na+].[Na+].[C:29]1(B(O)O)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]1([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=2[NH2:19])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1Br
Reactant: OB(O)C1=CCCCC1
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 80 °C
Yield: 98.9 %

Procedure:
A solution of 133 mg (0.381 mmol) of 2-bromo-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in toluene (6 mL) and EtOH (3 mL) was treated with 1.52 mL (3.05 mmol) of 2.0 M aqueous Na2CO3 and 60.0 mg (0.476 mmol) of cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 30.8 mg (0.027 mmol) of Pd(PPh3)4, and heated to 80° C. for 2.5 h. The mixture was cooled to RT, diluted with EtOAc (20 mL), and washed with saturated aqueous NaHCO3 (1×15 mL) and brine (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 132 mg (99%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C18H26N2O3S, 351.2 (M+H). found 351.1.
Reaction SMILES: [SH2:1].[O-]CC.[Na+].[Si:6]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][CH2:23][CH2:24]Cl)=[O:21])([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C(O)C>[Si:6]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][CH2:23][CH2:24][SH:1])=[O:21])([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCO[Si](CCCNC(=O)NCCCl)(OCC)OCC
Reactant: S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCS)(OCC)OCC
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of NaSH in ethanol [prepared by introducing H2S (15.21 g, 0.45 mol, 1.07 eq) into a sodium ethoxide solution (prepared from Na (10.55 g, 0.46 mol, 1.10 eq) in EtOH (300 mL))] is added, by metered addition at 52° C., (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—Cl (138.90 g, 0.42 mol, 1.00 eq) in ethanol (300 ml), and the mixture is heated to 78° C. After a reaction time of 5 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—SH product (134.96 g, 97.9% of theory) is obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](C(F)(F)F)[CH:11]=2)[N:5]=[C:4]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=CC=CC=3)C2)[CH:3]=1.[Cl:30]C1C=C(C)N=C(C=CC2C=CC=C(Cl)C=2)N=1.N1CCCC1>C(Cl)Cl.CCOC(C)=O>[Cl:30][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:6]2[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N:20]3[CH2:29][CH2:28][CH2:27][CH2:22]3)[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(N2CCc3ccccc3C2)nc(/C=C/c2cccc(C(F)(F)F)c2)n1
Reactant: Cc1cc(Cl)nc(C=Cc2cccc(Cl)c2)n1
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(Cl)c2)n1
Temperature: 60 °C
Yield: 80 %

Procedure:
A mixture of 66 mg (0.25 mmol) of (E) 4-chloro-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidine and 0.89 g (12.5 mmol) pyrrolidine was heated at 60° C. for 1.5 h after which time the reaction was completed according to TLC analysis (CH2Cl2/EtOAc: 4/1). The excess pyrrolidine was removed in vacuo and the residue was purified on a silica gel chromatography column (eluted with CH2Cl2/EtOAc: 4/1). The purified fractions were combined, evacuated in vacuo, the solid residue was triturated with ether and filtered off by suction to give (E)-2-[2-(3-Chloro-phenyl)-vinyl]-4-methyl-6-pyrrolidin-1-yl-pyrimidine (61 mg, 80%) as an off-white crystalline solid. ISP mass spectrum, m/e: 300.3 (M+1 calculated for C17H18ClN3: 300).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:17])[O:12][CH2:11][C:10]([CH2:15][CH3:16])([CH2:13][OH:14])[CH2:9][O:8]1.O>N1C=CC=CC=1>[CH3:1][S:2]([OH:4])(=[O:8])=[O:3].[CH3:6][C:7]1([CH3:17])[O:8][CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][OH:14])[CH2:11][O:12]1
Reactant: CS(=O)(=O)Cl
Agent: CCC1(CO)COC(C)(C)OC1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (15 ml.) was added dropwise to a stirred solution of 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane 1 (33.0 g) in dry pyridine (100 ml.) at 0°. The mixture was stirred for two hours at room temperature and then poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 2,2-Dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane methane sulphonate was obtained as a colourless oil (39 g.) which solidified on standing. The compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:10][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH3:24])=[C:4]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:5]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)[CH3:9])(=[O:37])=[O:36]
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1-c1cc(F)cc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)OS(C)(=O)=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-chloro-N-ethyl-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxamide (185 mg, 0.523 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol), followed by methanesulfonyl chloride (0.061 mL, 0.78 mmol). The reaction was stirred at rt for 10 min, quenched by pouring onto iced water, and extracted with dichloromethane. The combined organic layers were washed with aq. sodium bicarbonate, dried over magnesium sulfate, and evaporated to dry. The residue was used directly in next step (0.226 g, 100%). LCMS calculated for C19H21ClF2NO4S (M+H)+: m/z=432.1; Found: 432.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.O[N:15]1C2C=CC=CC=2N=[N:16]1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:15][NH2:16])=[O:10])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C(=O)NN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.8 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methylpropanoic acid (10.0 g, 50.5 mmol) in dry acetonitrile (100 ml) and dry N,N-dimethylformamide (25 ml) at room temperature was added 1-hydroxybenzotriazole (HOBt, 8.2 g, 61 mmol), followed by ethyl dimethylaminopropylcarbodimide hydrochloride (EDC, 11.65 g, 61 mmol). The mixture was stirred at room temperature for 12 hours, at which time all the starting acid had been consumed as shown by TLC (30% ethyl acetae:hexanes) analysis. The reaction mixture was cooled to 0° C., and slowly added to a solution of hydrazine hydrate at 0° C. (4.8 ml, 100 mmol) in acetonitrile (50 ml). The mixture was stirred at 0° C. for 1 hour, then warmed to room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue diluted with ethyl acetate, which was washed with water (2×), then brine. The organic phase was separated, and solvent removed under reduced pressure to provide 2-(4-chlorophenyl)-2-methylpropanehydrazide (9.64 g, 90%) as a white solid. LCMS (CI) shows M+H 213.
Reaction SMILES: C(O[C@@:5]([CH3:21])([C:19]#[CH:20])[CH2:6][CH2:7][C:8]1[C:9](=[O:18])[C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14])(=O)C.C(O)(=O)C>C(Cl)Cl.[Zn]>[C:19]([C@:5]1([CH3:21])[CH2:6][CH2:7][C:8]2[C:13]([CH3:14])=[C:12]([OH:15])[C:11]([CH3:16])=[C:10]([CH3:17])[C:9]=2[O:18]1)#[CH:20]
Reactant: C#C[C@@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OC(C)=O
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 4 °C
Reaction time: 0.83 h
Yield: 25 %

Procedure:
A solution of 285 mg (0.99 mmol) of (R)-2-[3-(acetyloxy) -3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione in 4 mL of CH2Cl2 was stirred with 250 mg of Zn dust, and 250 mg of glacial acetic acid. The reaction mixture was stirred at 4° C. under argon for 50 min., then filtered. It was worked up with CH2Cl2 as described above. The crude hydroquinone acetate was taken into 6 mL of CH2Cl2 and treated with 20 mg of AgClO4 ·H2O as described above to give 124 mg of crude product after workup, and purification by flash chromatography. Crystallization of this material from toluene-hexane (1:1) at -15° C. gave 57 mg of (S)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol: [α]D25 +20.20°, (c 1.3, CHCl3).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]>>[Br-:24].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: C=CCCCBr
Product: C=CCCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 58.5 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0495 g, 0.164 mmol) and 5-bromo-1-pentene (0.035 mL, 0.295 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0433 g, 59.3%). EI-MS m/z 371(M+) Rt (2.03 min).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][CH2:16][O:17][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)[CH:28]([C:26]2[CH:25]=[CH:24][C:23]3[O:18][CH2:19][CH2:20][O:21][C:22]=3[CH:27]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCCO3)c2cc3c(cc21)OCCO3
Yield: 14 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(ethylenedioxy)-phenyl]urea (132 mg) and 1,4-benzodioxan-6-carboxaldehyde (113 mg) by the procedure described in example 10 in 14% yield, mp: 92-95° C. 1H NMR (CDCl3): 6.85-6.76 (m, 3H), 6.62 (s, 1H), 6.32 (s, 1H), 5.20 (s, 1H), 4.99 (s, 1H), 4.46 (m, 1H), 4.24 (s, 4H), 4.23-4.17 (m, 4H), 1.56 (d, J=6.9, 3H), 1.54 (d, J=6.9, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[S:14][C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=1[C:18]#[N:19].[C:22]1([CH:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:18]([C:17]1[C:16]([CH3:20])=[C:15]([CH3:21])[S:14][C:13]=1[NH:12][C:29](=[O:30])[CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)#[N:19]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: Cc1sc(NC(=O)C(Cc2ccccc2)c2ccccc2)c(C#N)c1C
Reaction time: 19 h

Procedure:
EDCI (61 mg; 0.32 mmol) was added to a solution of 2-Amino-3-cyano-4,5-dimethylthiophene (prepared in Example 1, Step 1; 24 mg; 0.148 mmol) and 2,3-diphenylpropionic acid (72 mg; 0.32 mmol). After stirring for 19 h, the reaction mixture was applied directly to a silica gel column (Merck Silica gel 60, 230–400 mesh, eluent: 10%–33% ethylacetate/hexanes) to provide N-(3-Cyano-4,5-dimethyl-thiophen-2-yl)-2,3-diphenyl-propionamas a white solid (17.0 mg; 39%).