Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>>[Br:19][C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Br
Product: C[C@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20.5 °C
Reaction time: 0.5 h
Yield: 181.4 %

Procedure:
Under an argon atmosphere, (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1.0 g, 3.87 mmol, >99.5% ee) was added dropwise with phosphorus tribromide (0.52 g, 1.94 mmol) on a water bath at a temperature lower than 20° C., and the mixture was stirred at 19 to 22° C. for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 0.76 mL, 3.87 mmol) at a temperature lower than 0° C., and the mixture was stirred at 13 to 15° C. for 18 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (15 mL×2). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL×1) and then with saturated brine (15 mL×1), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 8 g; developing solvent, n-hexane) to obtain 1.13 g of (S)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:27]=1.C(O)(=O)C>C(O)CCC>[NH2:19][C:17](=[O:18])[CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([Cl:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:27]=2)[N:7]=1)[CH3:20]
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1Cl

Procedure:
A stirred solution of 2-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)propanamide (A30) (0.120 g, 0.370 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.177 g, 0.666 mmol) in n-butanol (3 mL) and glacial acetic acid (0.004 mL, 0.074 mmol) was stirred at 150° C. in the microwave for 30 minutes. After cooling, the solvent was removed to afford a crude purple oil which was purified by silica gel column chromatography (Combiflash Rf, 0-30% MeOH in DCM) to give the title compound A32 as a red oil (0.090 g, 44% yield). LCMS-C: rt 5.44 min; m/z 554 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH2:26]Cl)[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH2:26][N:38]4[C:34](=[O:40])[CH2:35][CH2:36][C:37]4=[O:39])[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CN2C(=O)CCC2=O)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 16.92 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(chloromethyl)oxazole-4-carboxamide (0.132 g, 0.327 mmol) and potassium carbonate (0.068 g, 0.490 mmol) were dissolved in dry DMF under nitrogen atmosphere. Succinimide (0.036 g, 0.359 mmol) was added and the mixture was stirred in RT for 4.5 h. DCM was added and the organic phase was washed with water. The product was triturated using diethyl ether, DCM and finally by Flash-chromatography. Yield 16.92%. %. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.83 (s, 4H), 4.29 (dd, 1H), 4.39 (dd, 1H), 4.51-4.59 (m, 1H), 4.83 (s, 2H), 6.63 (d, 1H), 7.47 (d, 1H), 7.52 (d, 1H), 7.74 (d, 1H), 7.87 (dd, 1H), 7.98 (d, 1H), 8.11 (s, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: OCCO
Reactant: CCOC(=O)C(=NOC)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC)C1(C)OCCO1
Yield: 70 %

Procedure:
A solution of ethyl 2-methoxyimino-3-oxobutyrate (syn isomer 17.3 g), ethylene glycol (12.4 g) and p-toluenesulfonic acid (0.5 g) in benzene (260 ml) was heated under reflux while removing water. The resultant solution was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn and dried over magnesium sulfate. After evaporating the solvent from the solution, the residue was distilled under reduced pressure to give ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 15.2 g), bp 97° to 102° C./4 mmHg.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCOc1nc(-c2ccccn2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 100 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with ethanesulfonylchloride to give 83 mg 5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.28 min, [M+1]+=629.63, [M−1]−=627.73.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[CH3:23][NH:24][C:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=1.[H-].[Na+]>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([N:24]([CH3:23])[C:25]2[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: CNC1=CC(=O)CC1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C1=CC(=O)CC1)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
4.02 g of the epoxide of example 1 are reacted analogously to example 5 with 2.44 g N-methyl-3-amino-cyclopent-2-en-1-on and 660 mg of sodium hydride (80%) in dimethylsulfoxide. Usual working up yields crystalls of the title compound having a m.p. of 271°-74° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:12])[NH:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:20]([CH3:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[CH3:30])=[O:22].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:12][CH:20]([CH3:31])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])=[O:22])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH][nH]c1=O
Reactant: Cc1ccc(C(=O)C(C)Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC(C)C(=O)c2ccc(C)cc2C)n[nH]c1C

Procedure:
To a well stirred mixture of 5-methyl-3-oxo-2,3-dihydro-1H-pyrazole4-carboxylic acid ethyl ester (200 mg, 1.18 mmol, 1 eq.) and K2CO3 (179 mg, 1.29 mmol, 1.1 eq.) in DMF (5 ml) is added dropwise a solution of 2-bromo-1-(2,4-dimethyl-phenyl)-propan-1-one (Intermediate BA) (298 mg, 1.23 mmol, 1.05 eq.) in DMF (2.5 ml) at 50° C. After the addition, the reaction mixture is further stirred at 50° C. for 1 h then poured into water (50 ml) and extracted with EtOAc (2×25 ml). The combined organic fractions are dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [iso-hexane/DCM 1:1]/TBME 95:5→7:3) to yield the title compound as a white solid. TLC: RF=0.74 (iso-hexane/DCM/TBME 1:1:2); HPLC: AtRet=2.30; MS: m/z 331.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J 7.1, 3H), 1.43 (d, J 6.8, 3H), 2.31 (s, 6H), 2.33 (s, 3H), 4.15 (m, 2H), 5.75 (q, J 6.8, 1H), 7.13 (m, 2H), 7.83 (m, 1H), 12.24 (br. s., 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[OH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.Cl>CN(C=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([O:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(F)cc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
Potassium carbonate (3.19 g, 23.1 mmol) and 2,5-difluoronitrobenzene (7.34 g, 46.1 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (4.52 g, 46.1 mmol) in DMF (80 ml) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml×2). An organic layer was washed with water (100 ml×2), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole (5.33 g, yield: 48.8%). mp: 81-84° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (d, J=0.5 Hz, 3H), 5.71 (d, J=0.5 Hz, 1H), 7.26-7.38 (m, 2H), 7.69 (dd, J=2.8 and 7.9 Hz, 1H), 9.33 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])O)=[C:4]([CH3:19])[CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([CH:8]([Cl:22])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ncc1C(O)c1c(F)ccc(F)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ncc1C(Cl)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of (6-bromo-4-methylpyridin-3-yl)(2,3,6-trifluorophenyl)methanol (4.60 g, 13.9 mmol) in methylene chloride (70 ml), thionyl chloride (10.1 ml, 139 mmol) and N,N-dimethylformamide (0.60 ml) were added at 0° C., and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and subsequently water and then saturated aqueous sodium hydrogencarbonate were added thereto at 0° C. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain the title compound (4.65 g, 13.3 mmol, 96%) as a pale brown solid.
Reaction SMILES: Br[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[NH:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12].O>CS(C)=O>[CH2:7]([N:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCCC=CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.5 %

Procedure:
This example illustrates a synthesis for inventive compound no. 1591 (chemical name and structure above). To a mixture of bromohexene (10.7 g, 66 mmol, available from Aldrich) and sodium hydride (1.58 g, 66 mmol) in dimethylsulfoxide (100 mL) was added theobromine (11.9 g, 66 mmol, available from Sigma). The resulting reaction mixture was stirred for 43 hours. The reaction mixture was treated with water (200 mL) and then extracted with dichloromethane (3×80 mL). The combined extracts were washed with water (3×100 mL), dried over magnesium sulfate, and the solvent subsequently evaporated under vacuum, yielding 17 g of 1-(5-hexenyl)-3,7-dimethylxanthine (65 mmol, 98% yield) as a white powder.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:45]=1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:45]=3[O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Yield: 76.7 %

Procedure:
A mixture of 1.5 g (3 mmol) of 3-hydroxy-5-(octadecyloxy) benzoic acid phenylmethyl ester, 1.6 g (3.4 mmol) of 1-(6-bromo-hexyl)-2,3-bis(phenylmethoxy)benzene [M. Carson, R.-J. Han and R. A. LeMahieu, U.S. Pat. No. 5,025,036 (1991)], 0.45 g (3 mmol) of potassium iodide and 0.84 g (6 mmol) of potassium carbonate in 40 ml of acetone and 10 ml of DMF was stirred at reflux for 47 hours. The solvents were removed at reduced pressure and the residue was purified by HPLC using 5% ethyl acetate-hexane to give 2.0 g (77% yield) of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(octadecyloxy)benzoic acid phenylmethyl ester as an oil. The nmr spectrum served to confirm the structure.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1.[OH:31][C:32]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:33]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>>[N:23]1[N:22]([C:3]2[CH:4]=[C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH:6]=[C:7]([CH2:8][C:45]3[C:44]([O:46][CH3:47])=[CH:43][CH:42]=[C:33]([C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]=3[OH:31])[C:2]=2[OH:1])[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=12
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 2 and 2-hydroxy-4-methoxybenzophenone, the title compound is obtained as a yellow crystalline solid melting at 137°-139° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][C@H:7]([CH2:9][OH:10])[CH2:6][O:5]1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>C1(C)C=CC=CC=1.O>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:10][CH2:9][C@@H:7]2[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]2)[N:14]=1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@@H](COc2cccc(Br)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.62 g, 60% dispersion in mineral oil, 40.5 mmol) was added portionwise to an ice-cooled solution of (R)-(−)-1,2-O-isopropylideneglycerol (4.86 g, 36.8 mmol) in toluene (100 ml), and once addition was complete, the solution was allowed to warm to room temperature and stirred for 30 minutes. 2,6-Dibromopyridine (8.72 g, 36.8 mmol) was added, and the reaction heated under reflux for 5 hours. The cooled mixture was diluted with water, the layers separated, and the aqueous phase extracted with ether. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to afford the title compound as a yellow oil (quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[S:4][CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl(O)(=O)(=O)=O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([NH:1][C:2]1[CH:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[S:4][CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:30])[CH3:29]
Reactant: COC(=O)C1=C(N)C(CCCCC(=O)N2CCCCC2)SC1
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C1=C(NC(C)=O)C(CCCCC(=O)N2CCCCC2)SC1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 7.4 g (.0226 mole) of 3-amino-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid piperidide in 50 ml of acetic anhydride was added dropwise 1 ml of perchloric acid. The reaction was stirred for 1.5 hrs. and then was worked up. Acetic anhydride was removed under vacuum. The residue was partitioned between 50 ml of 10% by weight aqueous sodium bicarbonate solution and 150 ml of methylene chloride. The basic, aqueous phase was extracted three times with 30 ml portions of methylene chloride. The methylene chloride phase was dried over sodium sulfate, filtered, and evaporated to yield 8.2 g (0.022 mole, 100%) of 3-acetamido-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid piperidide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(F)cc2)N1

Procedure:
The same method as employed in the preparation of intermediate 1 and 2 but starting from racemic tryptophan methyl ester and 4-fluorobenzaldehyde gave the cis isomer as white crystals m.p.:92° C. and the trans isomer as pale yellow crystals m.p.:183° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH2:21][CH2:22][OH:23])[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]([CH2:21][CH2:22][O:23][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzaldehyde (1.5 g) and 2-[N-methyl-N-(2-benzothiazolyl)amino]ethanol (2.4 g) in dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (2 g) was stirred at 100° C. for 24 hours. The mixture was cooled to room temperature and added to water (300 ml). The aqueous solution was extracted with diethyl ether (2×300 ml). The organic extracts were washed with brine (1×300 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as a waxy solid following chromatography on silica-gel in 1% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C@@H:13]3[C@@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46](O)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:46]([O:19][C@H:18]1[C@@H:13]2[N:14]([N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:12]2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:16][CH2:17]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2=NN3CC[C@@H](OC(=O)c4ccccc4)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (80 mg, 0.235 mmol) in THF (3 mL) were added PPh3 (123 mg, 0.470 mmol), benzoic acid (58 mg, 0.470 mmol) and DIAD (0.09 mL, 0.470 mmol) and the reaction mixture was stirred at room temperature for 3 h. Then it was diluted with ethyl acetate and washed with saturated NaHCO3 solution, water, and brine, then dried over Na2SO4 and concentrated to get the crude product which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:14][OH:15])=[C:12]=[CH2:13])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:14][O:15][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]=[CH2:13])=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C=C(CO)CCOCc1ccc(OC)cc1
Solvent: c1ccncc1
Product: C=C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1

Procedure:
Combine 5-(p-methoxybenzyloxy)-3-hydroxymethylpent-1,2-diene (25.0 mmol) and benzoyl chloride (25.0 mmol) in pyridine (25 mL) and stir for 16 hours. Partition the reaction mixture between diethyl ether and water, wash the organic layer 3X with saturated sodium bicarbonate and 1X with water, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel to give the title compound.