Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>CO.C(O)C.C1C=CC=CC=1>[CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[CH2:5][CH2:4]1
Reactant: C=CC(=O)OCC
Reactant: CN(C)C1CCc2[nH]c3ccccc3c2C1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCn1c2c(c3ccccc31)CC(N(C)C)CC2

Procedure:
Following a procedure similar to that described in Example 256 and using 20 g. of 3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole, 20 g. of ethyl acrylate, 1 ml. of 35% benzyltrimethylammonium hydroxide in methyl alcohol and 150 ml. of benzene and increasing the reflux time to three hours, there was obtained, on the evaporation of the reaction mixture to dryness, an oil, a solution of which in ethyl alcohol was treated with hydrogen chloride in ethyl alcohol. The resulting solids were filtered to give, after recrystallization from aqueous ethyl alcohol, 20.5 g. of ethyl 3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole-9-propionate hydrochloride, m.p. 259°-261° C.
Reaction SMILES: [ClH:1].Cl.[S:3]1[CH:7]=[C:6]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[N:5]=[CH:4]1.S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[ClH:1].[CH3:18][O:12][C:11](=[O:13])[C@H:9]([CH2:8][C:6]1[N:5]=[CH:4][S:3][CH:7]=1)[NH2:10]
Reactant: N[C@@H](Cc1cscn1)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1cscn1
Temperature: 0 °C
Yield: 99 %

Procedure:
A solution of 0.50 g (2.04 mmol) of dl-β-(4-Thiazolyl)alanine dihydrochloride (dl connotes a 50/50 mixture of dextrorotatory and levorotatory isomers) in 9 ml of methanol was cooled to 0° C. and treated with 0.21 ml (2.86 mmol) of thionyl chloride. The resulting solution was heated at 55° C. for 16 h. Removal of the solvent in vacuo gave 0.56 g (99%) of the desired compound as a white solid. Mass spectrum: (M+H)+ =187.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:33][C@@H:34]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:35][NH:36][C@H:37]([C:39]([NH:41][C@H:42]([C:46]([NH:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH3:38]>CN(C=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:33][C@@H:34]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:35][NH:36][C@H:37]([C:39]([NH:41][C@H:42]([C:46]([NH:48][CH2:49][CH:50]([CH3:51])[CH3:52])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH3:38])=[O:12])=[O:6])[CH2:17][CH3:18]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1ccccc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@H](CN[C@@H](C)C(=O)N[C@H](C(=O)NCC(C)C)C(C)C)Cc2ccccc2)c1
Reaction time: 1 h
Yield: 51.2 %

Procedure:
3-[(Dipropylamino)carbonyl]benzoic acid, (52 mg, 0.21 mmol) is combined with EDC(40 mg, 0.21 mmol) and HOBT (30 mg, 0.22 mmol) in 2.5 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of N-[(2S)-2-amino-3-phenylpropyl]-L-alanyl-N1-isobutyl-L-valinamide (0.17 mmol) in 1 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 5% methanol in dichloromethane, affords 53 mg (0.087 mmol, 51%) of the title compound. Addition of several drops of deuterated methanol to the compound in deuterated chloroform is necessary. NMR (CDCl3+MeOD) δ 7.79 (br d, 1H), 7.69 (s, 1H), 7.44 (m, 2H), 7.30 (m, 4H), 7.26 (m, obscured by CHCl3), 7.19 (m, 2H), 4.33 (m, 1H), 4.03 (d, J=8 Hz, 1H), 3.5-3.4 (m, 3H), 3.13-3.0 (m, 6H), 2.90 (m, 1H), 2.68 (dd, 1H), 2.0 (m, 1H), 1.8-1.7 (m, 3H), 1.5 (m, 2H), 1.31 (d, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 0.93-0.86 (overlapping d, 12H), 0.72 (t, J=7 Hz, 3H). MS (FAB) m/z 608 (MH+).
Reaction SMILES: [C:1]([CH2:9][S:10]([C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][NH:19][CH2:20]2)=[CH:15][CH:14]=1)(=O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1CCC2C(=CC(S(Cl)(=O)=O)=CC=2)C1)(=[O:25])[CH3:24].C1C2C(=CC=CC=2)CCN1.C(N1CCC2C(=CC(S)=CC=2)C1)(=O)C>C(O)(=O)C.Cl>[C:23]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10][CH2:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)[CH2:20]1)(=[O:25])[CH3:24]
Reactant: O=C(CS(=O)(=O)c1ccc2c(c1)CNCC2)c1ccccc1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Agent: CC(=O)N1CCc2ccc(S)cc2C1
Agent: Cl
Agent: c1ccc2c(c1)CCNC2
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(SCC(=O)c3ccccc3)cc2C1

Procedure:
The starting appropriately substituted tetrahydroisoquinolines of the formula (A) are conveniently prepared by standard reactions well known in the chemical arts as shown below: ##STR3## 2-Acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline, which is prepared by acylating and then chlorosulfonating 1,2,3,4-tetrahydroisoquinoline, is reduced to 2-acetal-7-mercapto-1,2,3,4-tetrahydroisoquinoline employing stannous chloride in acetic acid-hydrochloric acid mixture. The 2-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline is then condensed with the appropriately substituted α-bromo acetophenone to afford 2-acetyl-7-benzoylmethylthio-1,2,3,4-tetrahydroisoquinoline (B) which is then oxidized with m-chloroperbenzoic acid and hydrolyzed to yield the desired 7-benzoylmethylsulfonyl-1,2,3,4-tetrahydroisoquinoline (A). Bis(chlorosulfonyl)imide is prepared from chlorosulfonic acid and chlorosulfonylisocyanate.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:7][CH:6]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[ClH:1].[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:7][CH:6]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: CC(=O)NCCc1ccc(C(=O)CCl)cc1
Solvent: CCO
Product: CC(=O)NCCc1ccc(-c2csc(N)n2)cc1
Product: Cl
Temperature: 25 °C
Yield: 90.4 %

Procedure:
N-{2-[4-(2-Chloroacetyl)phenyl]ethyl}acetamide (1.06 g) and thiourea (505 mg) were dissolved in ethanol (20 mL). The mixture was refluxed for 1 hour and allowed to cool to room temperature. The white solid was collected with filtration and washed with ethanol to give N-{2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}acetamide hydrochloride (1.19 g, 90.4%).
Reaction SMILES: [C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][C@@H:12]([CH2:21][OH:22])[CH2:11][N:10]4[CH3:23])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[OH-:29].[NH4+].[CH3:31]O>O>[C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:29][CH3:31])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:21][OH:22])[CH2:11][N:10]4[CH3:23])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C[C@H](CO)C=C2c3cccc4c3c(cn4C(C)(C)C)C[C@H]21
Reactant: [OH-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13

Procedure:
A solution of 6 g of 1-(t-butyl)-9,10-didehydro-6- methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 1, in 500 ml of methanol and 5 ml of sulphuric acid was irradiated at 20° C. in a Pyrex flask with a Hanau PL 321 lamp for about 6 hours, until the absorption at 315 nm completely disappeared. The solution was diluted with iced water, made basic with ammonium hydroxide, evaporated to 100 ml and extracted with ethyl acetate. After evaporation of the solvent the residue was chromatographed in silica gel and on elution with 97:3 dichloromethane:methanol, 5 g of the title compound was isolated, m.p. 172° to 174° C. from acetone.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24](O)=[O:25])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH:30][CH3:31].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:29][N:30]([CH3:31])[C:24]([C:22]1[N:23]=[C:17]2[CH:16]=[C:15]([NH:14][C:12]([C:11]3[N:10]([CH3:27])[N:9]=[CH:8][C:7]=3[C:5]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]2[N:21]=1)=[O:25]
Reactant: CNC
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
A mixture of ethyl 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (example 33, step d) (658 mg, 1.66 mmol) and lithium hydroxide hydrate (139 mg, 3.31 mmol) in methanol (20 ml) and water (5 ml) and tetrahydrofuran (10 ml) was stirred for 6 hours at 60° C. (soluble when heated). The mixture was neutralized using hydrochloric acid 2N (1.655 ml, 3.31 mmol) and the mixture was evaporated affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (776 mg, 77.4%) as a light brown solid which was used in the following reactions. A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (120 mg, 244 μmol), dimethylamine hydrochloride (99.4 mg, 1.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 359 μl, 609 μmol) and diisopropylethylamine (298 μl, 1.71 mmol) in tetrahydrofuran (7 ml) was stirred for 20 hours at 25° C. The solvent was evaporated, the residue was triturated with sodium bicarbonate solution, the precipitated solid was filtered off, washed with water and dried. The material was applied on silicagel and purified by flash chromatography over a 5 g silicagel column using dichloromethane/methanol 5% as eluent affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid dimethylamide (39 mg, 40.4%) as an off-white foam. MS: m/z=397.1 (M+H+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:8]([NH2:10])=S.[CH2:18](N)[CH2:19][NH2:20]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:8]1[NH:20][CH2:19][CH2:18][N:10]=1)([CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(N)=S)(c1ccccc1)c1ccccn1
Reactant: NCCN
Product: CC(C1=NCCN1)(c1ccccc1)c1ccccn1
Temperature: 140 °C

Procedure:
Under a nitrogen atmosphere, heat (bath at 140° C) under reflux conditions 2 g. of α-(2-pyridyl)-α-phenylthiopropionamide and 20 ml. of ethylene diamine. Evaporate off the excess diamine, dissolve the residue in benzene, filter, wash, dry and evaporate the benzene solution. Crystallize the residual pale green oil from isopropyl ether to yield 2-[α-(2-pyridyl)α-methylbenzyl]-imidazoline, m.p. 102-103° C. The maleate salt, crystallized from acetonitrile, melts at 156.5°-158° C.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>C(O)C.[Pd]>[C:13]1([C:4]2[N:1]=[C:36]([CH2:32][NH:1][C@H:4]3[C:13]4[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:10]=[CH:11][CH:12]=4)[CH2:7][CH2:6][CH2:5]3)[O:35][C:34]=2[C:33]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetra-hydronaphthalene (0.95 mg) and 10% Pd/C (0.2 g) in a mixture of ethanol (20 ml) and THF (20 ml) was stirred under H2 for 2 hours. The catalyst was filtered off and filtrate was evaporated. The residue was dissolved in DMF (10 ml) and then K2CO3 (600 mg) and (4,5-diphenyloxazol-2-yl)methyl bromide (700 mg) were added thereto. After being stirred for 2 hours at room temperature, the mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-(4,5-diphenyloxazol-2-yl)methylamino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g). MS (m/z): 636 (M+ +1) IR (Neat): 3400 cm-1NMR (CDCl3, δ): 1.09 (9H, s), 1.6-2.2 (4H, m), 2.6-3.2 (2H, m), 3.91 (1H, m), 4.06 (2H, s), 6.30 (1H, d, J=8 Hz), 6.72 (1H, t, J=8 Hz), 6.93 (1H, d, J=8 Hz), 7.2-7.8 (10H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+].CCOCC>C1COCC1>[NH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(C2(c3ccccc3)CCN(CCC#N)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(c3ccccc3)CCN(CCCN)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a stirred solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]propionitrile (1.41 g, 4.40 mmol, 1.0 equiv) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0M, 11.0 mL, 2.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 15 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6N aqueous NaOH and extracted with CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (10 mL) and treated with HCl in ether (1.0M, 9.0 mL, 2.0 equiv). The solvents were removed, ether (30 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×10 mL). Water (20 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1N NaOH, and the aqueous phase was extracted with CH2Cl2 (3×40 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 610 mg (43%) of white solid, which was characterized spectroscopically.
Reaction SMILES: C([O:4][C:5]1[CH2:8][C:7](=[O:9])[CH:6]=1)(=O)C.C(O)C.[CH:13]1([CH:19]([NH2:26])[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([CH:19]([NH3+:26])[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH:9][C:7]1[CH2:8][C:5](=[O:4])[CH:6]=1
Reactant: NC(C1CCCCC1)C1CCCCC1
Reactant: CC(=O)OC1=CC(=O)C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C=C(O)C1
Product: [NH3+]C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
3.24 g of 3-acetoxy-2-cyclobuten-1-one (triketene, 97.5 percent; 25.0 mmol) was dissolved in 1.9 g of ethanol (41.3 mmol) and 40 g of ethyl acetate. 9.83 g of dicyclohexylmethylamine (98.9 percent; 50.0 mmol), dissolved in 10 g of ethyl acetate, was instilled in this solution at 20° C. in 15 minutes and stirred for 1 hour at room temperature. After another hour of stirring at 5° C., the suspension was filtered and dried under vacuum. 3.21 g of the title product with a content of 94.5 percent (according to HPLC), corresponding to a yield of 43.5 percent, relative to the 3-acetoxy-2-cyclobuten-1-one, was obtained. Data for the title compound was:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[ClH:23]>O1CCOCC1>[ClH:8].[ClH:23].[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ncc(OC[C@H]2CCCN2)cc1Br

Procedure:
5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (150 mg) was stirred with HCl in dioxane (3 mL) at room temperature for 16 hours. The precipitate formed was triturated with ether, and the solid was dried under high vacuum to afford the title compound (99.2 mg). mp 230° C. MS (CDI/NH3) m/z 291/293 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 1.89-2.02 (m, 1h), 2.05-2.21 (m, 2H), 2.21-2.35 (m, 1H), 3.42 (t, J=7.2 Hz, 2H), 4/12 (m, 1H)), 4.25 (dd, J=7.8, 10.5 Hz, 1H), 4.47 (dd, J=3.2, 10.5 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H). Anal. Calcd for C10H12N2OBrCl·2 HCl: C, 36.61; H, 3.99; N, 8.54. Found: C, 36.69; H, 3.91; N, 8.41. [α]25D =-14.80° (c 0.25, MeOH).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]#[N:12])[CH2:2][CH3:3].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:22]Br>ClCCl.[Cl-].[Na+].O>[Br:22][C:8]1[CH:7]=[CH:6][C:5]([NH:10][C:11]#[N:12])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1
Reactant: BrBr
Reactant: CCCc1ccccc1NC#N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCc1cc(Br)ccc1NC#N
Reaction time: 2.5 h
Yield: 24.4 %

Procedure:
(2-propylphenyl)cyanamide (0.550 g, 3.43 mmol), sodium acetate (0.278 g, 3.4 mmol), and catalytic acetic acid were combined in dichloromethane (25 mL). Bromine (0.17 mL, 3.43 mmol) was added dropwise and allowed to stir 2.5 hours. The mixture was then poured into brine and extracted with diethylether. The solvent was dried over magnesium sulfate and evaporated in vacuo. The solid was triturated with 9/1 Hexane/acetone, filtered, and dried to give 4-bromo2-propylphenylcyanamide (0.200 g, 24%) an off white solid. HRMS: calcd for C10H11BrN2+H+, 239.01783; found (ESI-FTMS, [M+H]+), 239.01782.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][C:3]=1[O:16][CH3:17].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH:24]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[O:23][CH:24]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2cccs2)n1
Reactant: COc1cc(CCCn2ccnc2)ccc1O
Product: COc1cc(CCCn2ccnc2)ccc1OCc1coc(-c2cccs2)n1
Yield: 80 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(2-thienyl)oxazole to obtain 4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-(2-thienyl)oxazole. The yield was 80%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 94-95° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[O:30])[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[N:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]4)[CH:20]=[CH:19][N:18]=2)=[O:30])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccnc(C(=O)NCc4ccncc4)c3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCc1ccncc1)c1cc(-c2ccc3[nH]c(C(=O)O)cc3c2)ccn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 5-{2-[(Pyridin-4-ylmethyl)-carbamoyl]-pyridin-4-yl}-1H-indole-2-carboxylic acid ethyl ester (160 mg, 0.4 mmol) in ethanol (4 ml) is added aqueous sodium hydroxide (2N) and the mixture is stirred at 70° C. for 2 hours. The reaction is cooled, diluted with water (30 ml), acidified with aqueous HCl (3N) to pH 4-5, extracted with dichloromethane (50 ml). The combined organic layer is dried (sodium sulfate), filtered and evaporated in vacuo to give the title compound, 95 mg, 64%, LC/MS ESI m/z (M+H)+=273.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]Cl.[C:11](#[N:13])C>[C-]#N.C([N+](CC)(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][C:11]#[N:13])[CH:9]=1
Reactant: CC#N
Reactant: ClCc1cc(Br)ccc1Cl
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: N#CCc1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=3)[CH2:36][NH2:37])=[N:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[N:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=3)[CH2:36][NH:37][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[N:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[CH:24]=2)=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(CN)c2)n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
4-Trifluoromethylbenzoylchloride (0.054 g, 0.26 mmol) was added to a solution of 3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine (0.10 g, 0.26 mmol) (prepared as described in Example 17) and triethylamine (0.08 g, 0.79 mmol) in dry DCM (2.0 ml) at 0° C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 6 h. The organic layer was washed with water (2.0 mL) and dried over Na2SO4. The filtrate was evaporated to dryness to give an oil which was purified by flash chromatography, over silica gel, using dichloromethane/MeOH (98:0.2) as eluent, to afford N-{3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzyl}-4-trifluoromethyl-benzamide (0.110 g, 0.20 mmol, 76%).