Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:40])([C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]([C:23]([S:26]([CH3:29])(=[O:28])=[O:27])([CH3:25])[CH3:24])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH:8]=1)C.CC(C[Al]CC(C)C)C.[BH4-].[Na+]>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[F:40][C:5]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]([C:23]([S:26]([CH3:29])(=[O:27])=[O:28])([CH3:24])[CH3:25])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH:8]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[Al]CC(C)C
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(c1cc(-c2cccc(CC(F)(CO)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 27 (1.15 g, 1.95 mmol) in CH2Cl2 (80 mL) at −78° C. was added dibal-H (0.82 mL, 4.6 mmol). The resulting reaction mixture was stirred 1 h at −78° C., then quenched with sodium potassium tartrate solution and stirred at 21° C. for 3 h. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. To the residue dissolved in THF/MeOH (2:1, 22 mL) at 21° C. was added NaBH4 (180 mg, 4.9 mmol). After 12 h, the reaction mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated to provided the title compound as a white solid.
Reaction SMILES: [I-].[Na+].C[O:4][CH:5]([CH2:19][CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:17][CH2:16][CH:15]2[CH:11]1[CH2:12][C:13](=[O:18])[CH2:14]2.C[Si](Cl)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[OH:4][CH:5]([CH2:19][CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:17][CH2:16][CH:15]2[CH:11]1[CH2:12][C:13](=[O:18])[CH2:14]2
Reactant: CCC(CCCCC1CCC2CC(=O)CC12)OC
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CCC(O)CCCCC1CCC2CC(=O)CC12
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
Sodium iodide (3 g) is added to a solution of 1 g of 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} in 20 ml of acetonitrile. The resultant red solution is stirred at room temperature and 2.5 ml of trimethylsilyl chloride is added. After 7.5 hours, water is added, followed by a saturated aqueous sodium thiosulfate solution. The solvent is removed under vacuum, leaving a light yellow oil. Chromatography on silica gel leaves pure 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone}.
Reaction SMILES: [CH2:1]([O:17][C:18](=[O:35])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[C:43](Cl)(=[O:47])[C:44]([CH3:46])=[CH2:45].[OH-].[K+]>O1CCCC1>[CH2:1]([O:17][C:18]([CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:43](=[O:47])[C:44]([CH3:46])=[CH2:45])=[CH:23][CH:22]=1)=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(OCCCCCCO)cc1
Reactant: C=C(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
To an ice-cooled solution of 3-[4-(6-hydroxy-hexyloxy)-phenyl]-acrylic acid hexadecyl ester (2.6 g, 5.3 mmol), triethylamine (0.99 ml, 7.4 mmol) and 4 crystals of BHT in tetrahydrofuran (30 ml) was added dropwise methacryloyl chloride (0.68 g, 6.9 mmol). The reaction mixture was allowed to react for 7.5 hours, warming to room temperature. Potassium hydroxide solution (5 wt %, 50 ml) was added and the solution extracted 3×100 ml ethyl acetate. The combined organic layers were washed with 100 ml portions of 1M HCl, water, brine and then dried with magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane, followed by recrystallization from hexane, to give 0.37 g white solid, 95% pure by HPLC. H1 NMR (CDCl3): 7.65 (d, 1H, J=16 Hz), 7.49 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=8.8 Hz), 6.33 (d, 1H, J=15.8 Hz), 6.12 (m, 1H), 5.57 (m, 1H), 4.19 (m, 4H), 4.00 (m, 2H), 1.96 (m, 3H), 1.8-1.4 (m, 8H), 1.28 (s, 32H), 0.90 (vt, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC(C)C

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (20.0 g), anhydrous potassium carbonate (26.2 g) and 2-bromopropane (18.3 mL) in dry dimethylformamide (300 mL) is stirred and heated at 55°-65° C. for 24 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo at 40° C., to give 4-methoxy-3-prop-2-yloxybenzaldehyde, in the form of an oil (24.2 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12]N1C(=O)CCC1=O>CC(O)=O>[Cl:12][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: Oc1ccnc2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=c1c(Cl)c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxyquinoline (5.33 g, 36.7 mmol) in AcOH (184 mL) was treated with N-chlorosuccinimide (6.37 g, 47.7 mmol) and the yellow homogeneous mixture was stirred and heated at 60° C. After 3 h, the mixture was cooled to room temperature and concentrated in vacuo. Saturated aqueous NaHCO3 solution (300 mL) was added until pH became ˜8.5. The resulting solid was collected by filtration, washed with water (300 mL), and dried under high vacuum to give 3-chloroquinolin-4(1H)-one (A275-1) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.28 (1H, br. s.), 8.40 (1H, d, J=6.5 Hz), 8.15 (1H, dd, J=8.2, 1.4 Hz), 7.65-7.73 (1H, m), 7.58-7.63 (1H, m), 7.39 (1H, ddd, J=8.1, 6.9, 1.2 Hz); LCMS (ESI) m/z 180.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:28][C:29]([CH3:31])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:29]([CH3:31])[CH3:28])[CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc2cc(OC3CCNCC3)ccc2n1-c1cncnc1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2n1-c1cncnc1

Procedure:
In analogy to the procedure described for the synthesis of example 43, step 7, the title compound was synthesized from 5-(piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indole-2-carboxylic acid ethyl ester (example 44, step 2) and acetone. The title compound was obtained in 46% yield as light brown foam. MS (m/e): 409.4 (MH+, 100%).
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:7][S:8][C@H:3]12.C[Si](NC(=O)N[Si](C)(C)C)(C)C.Cl.[CH2:49]([O:52][N:53]=[C:54]([C:58]1[N:62]=[C:61]([NH2:63])[S:60][N:59]=1)[C:55](Cl)=[O:56])[CH:50]=[CH2:51].C(Cl)(Cl)Cl>C(Cl)Cl.O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O>[CH2:49]([O:52][N:53]=[C:54]([C:58]1[N:62]=[C:61]([NH2:63])[S:60][N:59]=1)[C:55]([NH:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:7][S:8][C@H:3]12)=[O:56])[CH:50]=[CH2:51]
Reactant: C=CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3ccccn3)CS[C@H]12
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3ccccn3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7-amino-3-[(Z)-2-(2-pyridyl)vinylthio]-3-cephem-4-carboxylate (600 ml) and bis(trimethylsilyl)urea (981 mg) in methylene chloride (6 ml) was stirred at 30°~35° C. for 30 minutes to give a clear solution. To the clear solution was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride monohydrochloride (syn isomer) (480 mg) at 20° C. and the mixture was stirred for 30 minutes at -10°~-15° C. The mixture was poured into a mixture of chloroform and water. The organic layer was separated and concentrated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran, ethyl acetate and dilute aqueous solution of sodium bicarbonate. The organic layer was separated, washed with dilute aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo, and the residue was triturated with diisopropyl ether to give benzhydryl 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[(Z)-2-(2-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (848 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17][CH3:18])[CH:14]=[CH:13][N:12]=3)=[N:9][N:8]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:6][CH:7]=1.FC1C=C2C(B3OC(C)(C)C(C)(C)[O:49]3)=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C2=NC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17]([CH3:18])=[O:49])[CH:14]=[CH:13][N:12]=3)=[N:9][N:8]([C:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)OC1(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) mixture of 5-fluoro-3-(4-(methylthio)pyrimidin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine, 135a, (0.70 g, 1.38 mmol) in dichloromethane (10.4 mL) was added mCPBA (0.43 g, 1.93 mmol). After 30 minutes, the mixture was diluted with dichloromethane and washed with 2N NaOH and brine. The organic phase was brine dried over Na2SO4, filtered and stripped down twice with CH3CN to afford 660 mg of desired product that was used without further purification: LCMS Gradient 60-98%, 0.1% formic acid, 7 min, C4/ACN, Retention Time=2.68 minutes (M+H) 520.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of p-toluenesulfonyl chloride (3.17 g, 19.3 mmol) in 20 mL of pyridine was added 2-(2-(2-methoxyethoxy)ethoxy)ethanol (4 g, 21 mmol), stirred at 0° C. for 12 h and at RT for 2 h. To this suspension, water and hexanes and ethyl acetate were added and separated. The organic layer was neutralized with dilute HCl and separated again; organic fractions were pooled, dried (MgSO4 and NaHCO3), filtered, and concentrated under reduced pressure to give 4.87 g, 15.3 mmol (79%) of 2-(2-(2-methoxyethoxy)ethoxy)-ethyl 4-methylbenzene sulfonate as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]CC(OCC)=O)=[CH:20][CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)COc1ccc(-c2cc3ccccc3c(N3CCN(C)CC3)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
1-(1-Methylpiperazin-4-yl)-3-[4-(ethoxycarbonylmethoxy)phenyl]isoquinoline (320 mg) was dissolved in tetrahydrofuran (5 ml), to which was added lithium aluminium hydride (16 mg) under ice-cooling, followed by stirring for 5 min. To the resulting reaction mixture were then added water (16 ml), 5N sodium hydroxide (16 ml) and water (48 ml) in this order. After diluting with ethyl acetate, it was filtered through Celite and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), which was converted into a hydrochloride in a conventional manner, and then recrystallized from in ethanol, to give the hydrochlroide of the title compound as yellow crystals (105 mg, yield; 50%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>C1COCC1>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
Diketene (1.68 mL, 21.9 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(4-aminobutyl)-4,4-diphenylpiperidine (4.50 g, 14.6 mmol, 1.00 equiv) in anhydrous THF (40 mL) under argon, and stirring was continued at room temperature for 1.5 hours. The mixture was concentrated and the residual oil washed with hexane (3×50 mL) to give 5.17 g (90%) of light yellow oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]2[NH:7][CH:8]=[CH:9][C:10](=O)[C:11]=2[N:12]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>>[Cl:16][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[N:12][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc2c(=O)cc[nH]c2s1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2c(Cl)ccnc2s1
Yield: 89 %

Procedure:
The product of Example 5F (123 mg, 0.6332 mmol) and phosphorous oxychloride (2 mL) were refluxed for 1 hour under a nitrogen atmosphere. The solution was cooled in an ice bath, treated with ice, and the pH adjusted to 7 with 6N aqueous sodium hydroxide. Extracted with methylene chloride (3×50 mL) and dried the combined organic extracts over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound as a brown oil (120 mg, 0.564 mmol, 89%).
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]=2[CH:31]=1.[I-].[K+]>O1CCCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][NH:8][CH2:7][CH:4]4[CH2:6][CH2:5]4)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]=2[CH:31]=1
Reactant: NCC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and potassium iodide in tetrahydrofuran to give 8-bromo-1-[[(cyclopropylmethyl)amino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH:9]2[CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[CH:8]2[CH2:7][CH:6]([C:20]([OH:22])=[O:21])[CH2:5]1)[NH:13][CH:12]=3.[C:23]1(C)[CH:28]=[CH:27]C(S(OC(CC)CC)(=O)=O)=[CH:25][CH:24]=1>CS(C)=O>[CH2:24]([CH:23]([N:13]1[C:14]2[C:19]3[C:11]([CH2:10][C@@H:9]4[C@@H:8]([C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]([C:20]([OH:22])=[O:21])[CH2:5][N:4]4[CH3:3])=[CH:12]1)[CH2:28][CH3:27])[CH3:25]
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Reactant: CCC(CC)OS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC(CC)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
A 500 ml, three-neck round bottom flask was charged with 11.72 g (180.0 mmol) of 86% pure powdered potassium hydroxide, 10.0 g (33.9 mmol) of 92% pure 9,10-dihydrolysergic acid and 150 ml of DMSO. The mixture was stirred at room temperature for 15 minutes, and 10.3 g (42.6 mmol) of p-toluenesulfonic acid, 1-ethylpropyl ester was added. The mixture was stirred at room temperature for 19 hours, and 1000 ml of ice water was added. The mixture was washed twice with 250 ml aliquots of ethyl acetate, and the pH of the aqueous layer was adjusted to 5 with glacial acetic acid. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The solid was dried under vacuum to provide 7.94 g of 1-(1-ethylpropyl)-6-methylergoline-8carboxylic acid. A second crop of material was obtained to provide 0.9 g of product. The purity of the first crop was 96.7%, and the purity of the second crop was 96%. Total yield 72.1%. The identity of the product was determined by thin layer chromatography as compared to an authentic reference standard.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-3-nitro-6-methylpyridine (8.5 g, 55 mmol) in conc. H2SO4 (100 mL) at 0° C. was added HNO3 (2.74 mL, d=1.49, 58.3 mmol) dropwise over 10 min. The mixture was warmed to r.t. for 30 min then heated to 50° C. for 90 min. The reaction mixture was cooled and poured into 200 g of ice. The resulting percipitate was filtered and air dried to give 2-amino-3,5-dinitro-6-methylpyridine as a yellow solid.
Reaction SMILES: N1C=C[CH:4]=[CH:3][C:2]=1[C:7]([C:9]1C=CC=CN=1)=O.CO.[CH3:17][C:18]([OH:20])=[O:19].C(Cl)Cl>>[C:18]([OH:20])(=[O:19])/[CH:17]=[CH:4]/[CH2:3][CH2:2][CH2:7][CH3:9]
Reactant: CC(=O)O
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: CCCC/C=C/C(=O)O
Yield: 58 %

Procedure:
Prepared as above from 375.3 mg (0.88 mmol) of the pyridyl ketone and 796.8 mg (1.76 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) yielded 266.2 mg (58%) of the pure (E)-heptenoic acid as a white fluffy sold: mp 48-55° C.; 1H NMR (CDCl3) δ8.60 (br s, 1H), 8.48 (br s, 1H), 8.26 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.48 (br s, 1H), 7.46 (br s, 1H), 7.38-7.25 (m, 6H), 7.27 (d, J=8.2 Hz, 2H), 6.20 (t, J=7.4 Hz, 1H), 4.57 (s, 2H), 3.67 (s, 4H), 2.32 (dd, J=7.1, 6.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 6.8 Hz, 2H), 1.68-1.52 (m, 4H); FDMS 526 (M+1). Anal. (C31H31N3O5) C, H, N.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(C)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (471 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 μL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (407 mg, 92%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:65])[N:50]([C@@H:52]2[C@@H:56]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:55][NH:54][CH2:53]2)[CH3:51])=[CH:44][CH:43]=1>CN(C=O)C.C(OCC)(=O)C>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:65])[N:50]([C@@H:52]2[C@@H:56]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:55][N:54]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:53]2)[CH3:51])=[CH:44][CH:43]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCOCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.6 %

Procedure:
To a solution of tetrahydropyran-4-yl-carboxylic acid (51 mg, 0.39 mmol) in DMF (1 mL) was added ambient temperature 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.36 mmol) and N,N-diisopropyl ethyl amine (125 mg, 0.97 mmol). After stirring for 15 min at this temperature a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (124 mg, 0.32 mol) in DMF (1 mL) was added and stirred for 20 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with aqueous sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=98:2 to 85:15) afforded the title compound (92 mg, 57%) as a white oil. MS m/e: 495.3 [M]+.