Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Br)[C:5]1=[O:11].[OH-].[Na+].[O:16]1CCOCC1>O>[Br:13][C:2]([Br:12])=[CH:3][C@H:4]1[C:7]([CH3:8])([CH3:9])[C@H:6]1[C:5]([OH:11])=[O:16]
Reactant: C1COCCO1
Reactant: CC1(C)C(Br)C(=O)C1CC(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
700 mg (1.56 mmols) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-bromocyclobutanone are stirred with a solution of 190 mg of NaOH in 5 ml of water, to which 0.5 ml of dioxane has been added, for 2 hours at room temperature. The mixture is then stirred for 1 hour at 80° C. The clear solution is worked up to the acid in the customary way. 410 mg (88% of theory) of cis-2-(2',2'-dibromovinyl)-3,3-dimethylcyclopropanecarboxylic acid are obtained.
Reaction SMILES: CC([O:5][C:6]([C@@H:8]1[CH2:24][S:23][S:22][CH2:21][C@H:20]([NH:25]C([C@@H]2[C@@H](C3C=CC(O)=CC=3)CCN2C(=O)C)=O)[C:19](=[O:43])[NH:18][CH2:17][CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10](=[O:44])[NH:9]1)=[O:7])(C)C.Cl>ClCCl.O1CCOCC1>[NH2:25][C@@H:20]1[C:19](=[O:43])[NH:18][CH2:17][CH2:16][C:11]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:44])[NH:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:24][S:23][S:22][CH2:21]1
Reactant: CC(=O)N1CC[C@H](c2ccc(O)cc2)[C@H]1C(=O)N[C@H]1CSSC[C@@H](C(=O)OC(C)(C)C)NC(=O)C2(CCCC2)CCNC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CSSC[C@@H](C(=O)O)NC(=O)C2(CCCC2)CCNC1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 56.3 %

Procedure:
To a solution of this ester (3.01 g) in 15 mL of dry dichloromethane was added 4N HCl in dioxane (50 mL) in one portion at room temperature. The resulting solution was stirred at room temperature for 4.5 hours to give a suspension. The suspension was diluted with 50 mL of mixed solvent (3:7 dichloromethane:ether) and was filtered. The light yellow filter-cake was washed with above mixed solvent (2×20 mL) followed by ether (2×20 mL). The cake was dried under vacuum to give a light yellow powder (2.51 g, HLPC purity: >85%). The final purification was effected with RP-HPLC to give (8R,13R)-13-amino-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid as a white solid (1.55 g, 2.61 mmol) in 52 % yield. HRMS (M+H) Obs. 593.209, Calcd. 593.2103.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][C@@H:32]([OH:34])[CH3:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 25 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and (2S)-1-amino-2-propanol (0.05 mL), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(2S)-2-hydroxypropyl]-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (16 mg, 25% yield) as a white solid after purification by reverse phase HPLC. Analytical data was identical to that described in example 578.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([C:15]1[N:22]2[C:18]([S:19][C:20]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:21]=32)=[N:17][CH:16]=1)=[O:14].[BH4-].[Na+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]([C:15]1[N:22]2[C:18]([S:19][C:20]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:21]=32)=[N:17][CH:16]=1)[OH:14]
Reactant: O=C(CCc1ccc2ccccc2c1)c1cnc2sc3c(n12)CCCCC3
Agent: [BH4-]
Agent: [Na+]
Product: OC(CCc1ccc2ccccc2c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone (Formula O-3), 0.10 g, was reduced with NaBH4 by non-critical variations of EXAMPLE 12 to yield pure α-[2-(2- Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol (Formula O-4, X=H), m.p. 124-127°.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:5])[CH3:4].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23](Cl)=[O:24])[S:22][C:15]=12>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([O:1]/[N:2]=[C:3](\[NH2:5])/[CH3:4])=[O:24])[S:22][C:15]=12
Reactant: CC(N)=NO
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C/C(N)=N/OC(=O)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
A 100 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 6 drops of DMF. Oxalyl chloride (0.248 ml, 2.85 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo to yield 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride as a brown solid. This material was suspended in chloroform (5 mL). N′-hydroxyacetamidine (0.186 g, 2.50 mmol), triethylamine (0.347 ml, 2.50 mmol), and chloroform (15 mL) were stirred together in a 50 mL flask to form a slurry, which was slowly added to the 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride suspension, then stirred for 1.5 hours at room temperature. The reaction mixture was diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was triturated with toluene, and the precipitate collected to obtain the title compound (0.282 g, 46% yield) as a tan solid.
Reaction SMILES: [CH:1](=[C:5]1/[C:6](=[O:11])[CH2:7][C:8](=[O:10])[NH:9]/1)\[CH:2]([CH3:4])[CH3:3].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:12]([O:11][C:6]1=[CH:7][C:8](=[O:10])[NH:9]/[C:5]/1=[CH:1]\[CH:2]([CH3:4])[CH3:3])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)/C=C1\NC(=O)CC1=O
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)OC1=CC(=O)N/C1=C\C(C)C
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
31.8 g of (Z)-5-isobutylidenepyrrolidine-2,4-dione was suspended in 318 ml of dichloromethane and cooled to -5° C. Then first 23.22 g of butyryl chloride was added and then 27.32 g of triethylamine was added. After the addition the mixture was stirred another 10 minutes at 0° C., then diluted with 100 ml of dichloromethane, and washed twice with 100 ml of 5 percent NaHCO3 solution each and twice with 100 ml of 0.4M hydrochloric acid each. The aqueous phases were extracted separately with dichloromethane and the combined organic phases were dried on magnesium sulfate. After the distilling off of the solvent, the crude product (46 g) was recrystallized from hexane. The yield of the title compound was 38.8 g (84 percent of theory). The title compound had a melting point of 111° to 112° C. Other data concerning the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([OH:24])=O)=[CH:14][C:12]=2[N:13]=1.[CH3:26][C:27]([CH3:32])([CH3:31])[CH:28]([NH2:30])[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([NH:30][CH:28]([C:27]([CH3:32])([CH3:31])[CH3:26])[CH3:29])=[O:24])=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Reactant: CC(N)C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(o1)c(C(=O)NC(C)C(C)(C)C)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 24.7 %

Procedure:
The title compound was prepared following the procedure described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.050 g, 0.132 mmol), propyl phosphonic anhydride (0.084 g, 0.265 mmol), TEA (0.027 g, 0.265 mmol), DMF (3.0 mL) and 3,3-dimethyl-2-butyl amine (0.027 g, 0.318 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 0.96 (s, 6H), 1.11 (d, J=6.9 Hz, 3H), 2.50 (m, 3H), 3.95-3.97 (m, 1H), 6.65 (s, 1H), 7.35 (s, 1H), 7.63 (d, J=9.0 Hz, 1H), 8.45 (s, 2H), 11.20 (s, 1H), 11.80 (s, 1H); MS [M+H]+: 460.34.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[C:21]([CH:23]5[CH2:25][CH2:24]5)[N:20]([CH3:26])[C:19]=4[CH:27]=3)[C:11](=[O:28])[CH:10]=2)[S:5][CH:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]5[S:5][CH:6]=[C:2]([CH:29]6[CH2:31][CH2:30]6)[N:3]=5)=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:25][CH2:24]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
Reactant: OB(O)C1CC1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C5CC5)cs4)cc3=O)cc21
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 4-((4-bromo-1,3-thiazol-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (50 mg), cyclopropylboronic acid (10.3 mg), tetrakis(triphenylphosphine)palladium (6.3 mg), potassium carbonate (60.4 mg), DME (1 ml) and water (0.3 ml) was heated at 150° C. for 15 min under microwave irradiation. Additional cyclopropylboronic acid (14.1 mg) was added to the mixture, and the mixture was heated 150° C. for further 15 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (14.1 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1.O1CCCC1.[OH-].[Li+]>CO>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:33][CH:34]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
Isomer 1 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate (0.300 g, 0.597 mmol) was dissolved in methanol (8.0 mL) and tetrahydrofuran (4.2 mL) and treated with 2N aqueous lithium hydroxide (4.2 mL, 8.4 mmol). The mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was concentrated and the residual solid was dissolved in water and acidified to pH=4 with 1.0M aqueous hydrochloric acid. A brown precipitate formed. The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoic acid, Isomer 1 (0.220 g, 78%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.6 Hz, 2H), 7.35 (d, J=6.8 Hz, 2H), 7.27 (d, J=7.2 Hz, 2H), 7.03-6.88 (m, 1H), 6.60-6.42 (m, 2H), 4.33 (t, J=6.3 Hz, 1H), 3.64 (s, 2H), 2.72-2.54 (m, 2H), 1.87-1.65 (m, 2H), 1.51-1.22 (m, 2H), 0.90 (t, J=7.0 Hz, 3H). MS (M+1): 475.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[F:25])(O)O>>[F:25][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:16]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(F)c1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and 4-borono-3-fluorobenzoic acid. 1H NMR (CD3OD, 400 MHz): δ 8.31 (d, J=8.4 Hz, 1H), 7.94-7.86 (m, 3H), 7.81-7.74 (m, 2H), 7.35 (dd, J=9.2, 2.8 Hz, 1H), 7.15 (d, J=2.8 Hz, 1H). MS (ESI): m/z 283.6 [M+H]+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[C:10]([C@@H:15]([C@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[OH:18])O)([O:12][CH2:13][CH3:14])=[O:11]>>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]2[O:18][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C@H:15]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:8]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Product: CCOC(=O)[C@@H]1OC(c2ccc(C)cc2)O[C@H]1C(=O)OCC

Procedure:
In a fashion similar to that described in Example 3, p-tolualdehyde was condensed with diethyl L-tartrate to provide (4R,5R)-2-(4-methylphenyl)-4,5-dicarboethoxy-1,3-dioxolane, an oil, GLC analysis: 93%, [α]D25 -9.6° (c,0.1,methanol), 1H-NMR (CDCl3)δ7.47 (2H,d,J=8.0 Hz), 7.18 (2H,d,J=8.0 Hz) 6.12 (1H,s), 4.93 (1H,d,J=4.0 Hz), 4.81 (1H,d,J=7.2 Hz), 4.34-4.22 (4H,2 q, overlapping, J=7.2 Hz), 2.34 (3H, s), 1.35-1.26 (6H 2 t, overlapping, J=7.2 Hz). IR (film) 2980, 1740, 1615 cm-1. MS m/e (% abundance) 308(2), 293(1), 279(1), 235(12), 136(68), 119(100), 105(50), 91(20), 77(8), 43(6).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (500 mg, 1.7 mmol) was dissolved in DCM (10 ml), and TEA (343 mg, 3.4 mmol) and methanesulfonyl chloride (290 mg, 2.6 mmol) were added. The mixture was stirred at RT for 2 hours, then was washed with HCl 1N (2×). The organic layer was dried over Na2SO4 and evaporated under vacuum to give 570 mg (90%) of the title compound which was employed in the next step without any further purification. MS/ESI+ 374.12 [MH]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>C(OCC)C>[ClH:22].[C:16]1([C:10]2([CH2:13][CH2:14][OH:15])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(c2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: OCCC1(c2ccccc2)CCNC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (13.0 g, 44.6 mmol) and a solution of hydrochloric acid in dioxane (22.3 mL, 4M, 89.2 mmol). Heat to 50° C. After 1 hour, cool and add diethyl ether to give a solid. Collect the solid by filtration to give, after drying, the title compound: mp; 161°-163° C. [α]2D0 =+11.8 (c=0.563, methanol). Elemental Analysis calculated for C12H17NO·HCl: C 63.29; H 7.97; N 6.15; Found: C 63.21; H 7.86; N 6.05.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[C:1]1([C:7]2[N:11]=[C:10]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)n[nH]2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccccc3)n[nH]2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 24 %

Procedure:
This compound was synthesized from (4-(3-phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 24%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.02 (dd, J=7.3 Hz, 1.8 Hz, 2H), 7.89 (br s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.46 (m, 3H), 3.97-3.92 (dt, J=11.9 Hz, 4.5 Hz, 2H), 3.83 (d, J=5.8 Hz, 2H), 3.71-3.66 (m, 2H), 2.44-2.42 (d, J=13.6 Hz, 2H), 1.96-1.89 (ddd, J=13.4 Hz, 9.2 Hz, 3.5 Hz, 2H). MS (ESI) m/z: Calculated for C24H21F3N6O3: 498.16. found: 499.2 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:22])=[C:11]([C:16]([CH3:21])=[CH:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24](=[CH:26][CH2:27][CH2:28][CH:29]([CH2:31][CH2:32]O)[CH3:30])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:30][CH:29]([CH2:28][CH2:27][CH2:26][C:24]([CH3:25])=[CH2:23])[CH2:31][CH2:32][O:19][C:18](=[O:20])/[CH:17]=[C:16](/[C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[OH:22])\[CH3:21]
Reactant: CC(C)=CCCC(C)CCO
Reactant: CC(=CC(=O)O)c1ccc(O)c(C(=O)c2ccccc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: C=C(C)CCCC(C)CCOC(=O)/C=C(\C)c1ccc(O)c(C(=O)c2ccccc2)c1O

Procedure:
A solution of 3-(3-benzoyl-2,4-dihydroxyphenyl)-but-2-enoic acid (5.97 g, 20.0 mmol), citronellol (3.13 g, 20.0 mmol) and p-toluenesulfonic acid (1 g) in cyclohexane (150 mL) is refluxed for 6 h under vacuum using a Dean Stark separator. The reaction mixture is partitioned between methylene chloride (150 mL) and water (150 mL); the organic layer is removed and washed with methylene chloride (100 mL). The combined organic layers are washed sequentially with saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to give (E)-3-(3-benzoyl-2,4-dihydroxyphenyl)-but-2-enoic acid 3,7-dimethyl-oct-7-enyl ester as an oil which can be purified by flash chromatography.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27]C[CH2:25][C:24](=O)[CH2:23]2)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:23][CH2:24][CH2:25][C:1]([O:4][CH3:5])([O:6][CH3:7])[CH2:27]2)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(OC)OC
Reactant: O=C1CCCC(c2cccc(OCc3ccccc3)c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC1(OC)CCCC(c2cccc(OCc3ccccc3)c2)C1
Reaction time: 0.08 h

Procedure:
Trimethyl orthoformate (2 ml) was added to montmorillonite clay (1.3 g) and the mixture was shaken for 5 minutes and then filtered. The solid so obtained was added to a solution of 3-(3-benzyloxyphenyl)cyclohexanone (0.28 g) in carbon tetrachloride (4 ml) and the resultant mixture was stirred at ambient temperature for 20 hours. The mixture was basified by the addition of sodium bicarbonate (0.05 g) and filtered. The filtrate was evaporated to give 3-(3-benzyloxyphenyl)-1,1-dimethoxycyclohexane as an oil (0.326 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([NH:19][CH3:20])=[O:18])[C:6]=2[CH:21]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:22]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)=[C:7]([C:17]([NH:19][CH3:20])=[O:18])[C:6]=2[CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(Cl)cc3)S(C)(=O)=O)c(Br)cc12

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (0.55 g, 1.25 mmol), 1-chloro-4-(chloromethyl)benzene (0.24 g, 1.5 mmol), K2CO3 (0.35 g, 2.5 mmol) and KI (0.25 g, 0.15 mmol) in DMF (10 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated in vacuo and the resulting residue was washed by H2O and filtered to provide the white solid 5-bromo-6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.81˜7.84 (m, 2H), 7.15˜7.25 (m, 7H), 5.79 (br s, 1H), 5.15 (d, J=7.4 Hz, 1H), 4.55 (d, J=7.4 Hz, 1H), 3.10 (s, 3H), 2.96 (d, J=4.8 Hz, 3H). MS (M+H)+: 565/567.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.CN(C)C=O>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:24]=[CH:8]/[CH:7]=[CH:6]/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To an ice-cooled solution of triethyl 4-phosphonocrotonate (24.0 g, 95.9 mmol) in tetrahydrofuran (100 mL) was added by small portions sodium hydride (60% in oil, 3.84 g, 96.0 mmol), and the mixture was stirred under nitrogen atmosphere for 30 min. A solution of 3-methoxybenzaldehyde (12.3 g, 90.0 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 2 hr. N,N-Dimethylformamide (50 mL) was added and the mixture was further stirred for 18 hr. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate/hexane) to give the title compound (7.70 g, yield 37%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:9]1=[O:22])(C)(C)C.[ClH:24]>CCOC(C)=O>[ClH:24].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C:9]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cccc(C#N)c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reaction time: 4 h

Procedure:
To a solution of [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (9.1 g, 29 mmol) in 150 mL of EtOAc at 0° C. is bubbled HCl gas for 10 minutes. After this time, the solution is stirred for 4 hours. The solution is then concentrated to give the title compound (7.3 g, 29 mmol) as a white solid.