Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)(=O)C>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:8](=[O:10])[CH3:9])=[CH:3][CH:4]=1
Reactant: Cc1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: CC(=O)Cl
Product: CC(=O)Cc1ccncc1
Temperature: 50 °C
Reaction time: 0.12 h

Procedure:
To 10 g of 4-methylpyridine and 32.75 g acetic anhydride, maintained at room temperature, was added 1 ml of acetyl chloride, dropwise over 5-10 min. The solution was then warmed to 50° C. for 6-16 hours. The black reaction mixture was then cooled to 0° C. and 100 mls of ethanol, was added dropwise. The reaction mixture was stirred for 1 hour after the addition, then refluxed for 4-12 hours. The alcohol was removed under reduced pressure and the residue taken up in 100-150 ml methylene chloride. The methylene chloride was washed 2 times with saturated 50 ml portions of sodium carbonate solution then dried over sodium sulfate and evaporated under reduced pressure. Toluene was added to the residue and the excess 4-methylpyridine removed by azeotropic distillation under reduced pressure. Yield: 4.3 gm of 4-pyridinyl-2-propanone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:42]([N:50]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[N:51]1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:53]5[CH:52]=[N:51][N:50]([CH2:42][CH2:43][C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)[CH:54]=5)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(CCc5ccccc5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Yield: 15.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 50) (150 mg, 0.215 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (76 mg, 0.258 mmol) using sodium carbonate (68 mg, 0.645 mmol) and Pd(PPh3)2Cl2 (8 mg, 0.0107 mmol) in toluene/ethanol/water (5/5/2 ml) to afford 25 mg (15.7% yield) of titled compound after purification by preparative TLC (Silicagel-1000 micron) using 1% methanol in DCM as eluent. MS: m/z=742.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:14][N+:15]([O-:17])=[O:16]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]=[CH:14][N+:15]([O-:17])=[O:16])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(C=O)cc2ccc(Br)cc21
Reactant: C[N+](=O)[O-]
Product: Cn1c(C=C[N+](=O)[O-])cc2ccc(Br)cc21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 6-bromo-1-methyl-1H-indole-2-carbaldehyde (422 mg, 1.77 mmol) and NH4OAc (137 mg, 1.77 mmol) in MeNO2 (10.0 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous phase was separated and extracted with EtOAc (3×). The organic extracts were dried over Na2SO4, filtered and concentrated to give title compound (490 mg, 99%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J=13.0 Hz, 1H), 7.67 (d, J=13.5 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 1.5 Hz, 1H), 7.05 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH2:9][CH2:8]2.Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)[CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)[CH3:34]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)c1ccc(CNC2CCc3cccc(OC)c3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CCCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2cccc(OC)c2C1

Procedure:
Under argon, 13.4 g (41.2 mmol) of the compound from Example 1A were dissolved in 160 ml of acetonitrile, 11.8 ml (15.5 g, 74.1 mmol) of ethyl 5-bromovalerate, 27 g (82.4 mmol) of cesium carbonate and 685 mg (4.1 mmol) of potassium iodide were added and the mixture was stirred under reflux overnight. After addition of a further 550 mg of potassium iodide, the mixture was once more stirred under reflux overnight. Another 2 g of potassium iodide were then added, and the mixture was again stirred under reflux overnight. After cooling, the precipitate was filtered off and the filtrate was concentrated. This residue was then purified chromatographically on 1.2 kg of silica gel using the mobile phase isohexane/ethyl acetate (gradient 10:1→5:1). This gave 10.95 g (59% of theory) of the title compound as a colorless solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([O:37]C)=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([OH:37])=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCCC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCCC5)cc4)cc3)o2)n1
Yield: 36.7 %

Procedure:
Methyl 6-(2-(3-(4′-(piperidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (11 mg, 0.022 mmol) was dissolved in THF/H2O (3:2, 2 mL) and LiOH (1.5 mg, 0.065 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 20 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-(piperidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a white solid (4 mg, 38%): 1H NMR (CDCl3, 600 MHz) δ 8.22 (d, 1H, J=5.7 Hz), 8.05-8.01 (m, 3H), 7.63 (d, 2H, J=8.0 Hz), 7.58 (d, 2H, J=8.0 Hz), 7.47 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 4.20 (s, 2H), 3.50 (t, 21-1, J=7.5 Hz), 3.15 (t, 2H, J=7.4 Hz), 2.15-1.95 (m, 10H); 13C NMR (CDCl3, 150 MHz) δ 187.2, 165.8, 157.4, 152.1, 145.4, 142.4, 140.1, 138.9, 138.0, 131.9, 129.0, 128.0, 127.6, 127.3, 127.2, 124.4, 123.2, 60.5, 52.6, 40.5, 29.4, 22.6, 22.2; HR ESI-TOF m/z 496.2227 (M+H+, C30H29N3O4, requires 496.2231).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=O)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=O)[CH3:8].Cl.O=P(Cl)(Cl)[Cl:34]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:34][C:17]1[C:18]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[C:7]([CH3:8])[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:16]=1
Reactant: CC(=O)c1ccccc1NC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(N2C(=O)c3ccccc3C2=O)c(Cl)nc2ccccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
1.4 g (10.4 mmol) of K2CO3 were added to a solution of 2.7 g (6.9 mmol) of N-(2-acetylphenyl)-2-(1,3-dioxoisoindolin-2-yl)-acetamide in DMF (27 ml), and the mixture was heated for 16 h at 60° C. After cooling to RT, the pH was adjusted to 2-3 with 2N hydrochloric acid. The resulting precipitate was filtered off with suction and dried in vacuo at 70° C. 9 ml (97 mmol) of POCl3 were added to the residue. This solution was heated for 2 h at 100° C. and then stirred for 16 h at RT. Toluene was then added and concentration was carried out in vacuo. This procedure was repeated, there being obtained as residue 2.13 g (5.5 mmol, 79%) of 2-(2-chloro-4-methylquinolin-3-yl)isoindoline-1,3-dione, which was reacted further without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:21])(=[O:30])=[O:29])[CH:7]=[CH:6]2
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2C)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
To a solution of 1-(5-methoxy-11H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-methylbenzene-1-sulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (7 mg, 28%) as a white solid. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)=[CH:4][N:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25].CO.C(Cl)(Cl)Cl>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1COCC1.C1(C)C=CC=CC=1>[CH3:7][N:6]1[C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:27]([NH:26][CH2:24][CH3:25])=[O:28])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)=[CH:4][N:3]=[C:2]1[CH3:1]
Reactant: Cc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)n1C
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(C)n3C)n2n1
Temperature: 0 °C

Procedure:
A mixture of the product of Step 1 (0.37 g, 1.21 mmol), ethylisocyanate (0.43 g, 6.05 mmol) and a catalytic quantity of dibutyltin diacetate (5 drops) in THF/toluene (1:1, 10 mL) was heated in a sealed tube at 100° C. for 15 h. This mixture was cooled to 0° C., the solid obtained was filtered and washed with 10% CHCl3/hexanes to isolate crude product. The solid was taken up into MeOH/CHCl3, and dried onto silica gel. This material was then purified by column chromatography on silica gel (1-8% MeOH/CHCl3 as eluant) followed by trituration with chloroform (10 mL) and hexanes (500 mL) to isolate the title compound as a solid. LCMS (APCI+) 377.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][CH3:27])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C(N)=NC=2C=1)C1C=CC=CC=1>>[CH2:26]([C:20]1[N:21]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:27]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Yield: 35.8 %

Procedure:
The general method described in Part J of Example 1 was followed using 7-benzyloxy-2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (3.43 g, 9.54 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The crude product was recrystallized from acetonitrile, isolated by filtration, and dried for two days in an oven at 60° C. to provide 0.92 g of 2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol as an off-white solid, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:31]([CH3:33])[CH3:30])[CH2:14][CH2:13]1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2cc[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (195 mg, 0.47 mmol) and acetone (2.0 mL, 27 mmol) afforded, after purification (SiO2: 0 to 2.5% isopropylamine in 1:1 hexane:EtOAc), 120 mg (60%) of the title compound.
Reaction SMILES: O=C1NC2C3C1(O)C[C@@H]1C(C=3C=CC=2)=C[C@@H](C(=O)O)CN1C.[CH2:23]([N:25]([CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])[C:26]([C@@H:28]1[CH:43]=[C:42]2[C@@H:32]([CH2:33][C:34]3([OH:46])[C:44]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]2=4)[NH:36][C:35]3=[O:45])[N:30]([CH3:31])[CH2:29]1)=[O:27])[CH3:24].[OH-].[K+].Cl>O1CCCC1.O>[CH2:23]([N:25]([CH2:47][CH2:48][C:49]([OH:51])=[O:50])[C:26]([C@@H:28]1[CH:43]=[C:42]2[C@@H:32]([CH2:33][C:34]3([OH:46])[C:44]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]2=4)[NH:36][C:35]3=[O:45])[N:30]([CH3:31])[CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3C(O)(C[C@H]2N(C)C1)C(=O)N4
Agent: CN1C[C@H](C(=O)O)C=C2c3cccc4c3C(O)(C[C@H]21)C(=O)N4
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCC(=O)O)C(=O)[C@@H]1C=C2c3cccc4c3C(O)(C[C@H]2N(C)C1)C(=O)N4
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-oxo-3-hydroxy lysergic acid Nethyl N-(2-carbethoxy)ethyl amide 7 (63.6 mg, 0.15 mmol) in 5 ml of tetrahydrofuran (THF) and 5 ml of water was added solid potassium hydroxide (12.5 mg, 0.22 mmol). The reaction was stirred at room temperature for 3 hours (h) until the reaction was complete by TLC analysis. The reaction solution was neutralised to pH 7 using 1N HCl and concentrated to dryness under reduced pressure. The residue was dissolved in a 10% methanol in chloroform mixture and the inorganic salts were removed by filtration. Evaporation of the solvents yielded 2-oxo-3-hydroxy lysergic acid N-ethyl N-(2-carboxy)ethyl amide (Hapten A) (45 mg, 76%) as an amorphous brown solid (Rf 0.52 on silica using 20% methanol in chloroform as eluent). υmax/cm−1 3297, 2963, 1723, 1557, 1099, 1026, 802 (FT-IR)
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:36][CH3:37].[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[CH3:37][O:36][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:2]=1[NH:1][C:38](=[O:40])[CH3:39])[C:6]([N:8]([CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:23][CH2:24]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)c(OC)c2)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)c(OC)c2)c1
Yield: 77.8 %

Procedure:
Using 4-amino-3-methoxy-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (253.0 mg, 0.50 mmol) and acetic anhydride (0.095 ml, 1.00 mmol), the procedure of inventive Example 94 was repeated to obtain 213.0 mg (77.9%) of the title compound in a yellow amorphous form.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: N#CCc1cccc(N)c1
Temperature: 22 °C
Reaction time: 48 h

Procedure:
To a solution of 3-nitro-phenyl-acetonitrile (3.20 g, 19.7 mmol) in MeOH (50 mL) was added Pd/C (10% wt, ˜50% H2O, 0.32 g) and the mixture was placed under H2 (80 psi) and stirred for 2 days at 22° C. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to give crude product as a yellow oil. The residue was purified by silica gel chromatography (ISCO, elution with 0-10% ethyl acetate in hexanes) to give xix-l-1 (1.15 g, 44%): MS m/z=133 (M−H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:28]=2[O:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:33]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:29]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1OCCO2
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=495.3.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CO[C@@H](C)C(=O)O
Agent: Cl
Product: CO[C@@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10.2 mg, 35%), MS (ISP) m/z=418.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and (S)-2-methoxypropanoic acid
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17][C:18]#[N:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C=O)C>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:16][CH2:17][C:18]3[NH:28][N:27]=[N:26][N:19]=3)[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1ccc(-c2csc(N(CCC#N)Cc3cccs3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2csc(N(CCc3nnn[nH]3)Cc3cccs3)n2)cc1

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-[2-(1H-tetrazol-5-yl)-ethyl]-thiophen-2-ylmethyl-amine was prepared following general procedure H using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionitrile (278 mg, 0.756 mmol), sodium azide (657 mg, 99%, 10 mmol), ammonium chloride (535 mg, 10 mmol) and DMF (3 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:1, with 0.5% v/v acetic acid) gave the product compound (110 g, 0.268 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:54]=[C:55]([O:59][CH3:60])[C:56]=1[O:57][CH3:58])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([C:37]3[N:41]([CH2:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=4)[C:40]4[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=4[N:38]=3)=[O:36])[CH2:31][CH2:30]2)([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH3:60][O:59][C:55]1[CH:54]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:56]=1[O:57][CH3:58])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH:32]([C:35]([C:37]3[N:41]([CH2:42][C:43]4[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=4)[C:40]4[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=4[N:38]=3)=[O:36])[CH2:33][CH2:34]2)([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-(4-(t-butyldimethylsilyloxy)-phenyl)-pyrrolidine (6 mmol) and THF (20 mL). Cool using an ice bath. Add dropwise, a 1 M THF solution of tetrabutylammonium fluoride (7 mL). After 30 minutes, concentrate in vacuo to obtain a residue. Combine dichloromethane (50 mL) and the residue. Extract with water (3×15 mL), dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph on silica gel to obtain the title compound.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO>[F:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Fc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: CO
Product: O=c1[nH]nc(CCc2cccc(F)c2)cc1O
Yield: 63 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-fluorophenyl)ethynyl]pyridazine (Intermediate 10) except that the reaction was carried out in methanol. The resulting crude product was recrystallised from a mixture of ethanol and heptane to afford 6-[2-(3-fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one as cream crystals (yield=63%).