Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([O:21][Si](C)(C)C)[C:19]#N)=[CH:14][CH:13]=1.[OH2:28]>C(OCC)C>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:28])=[O:21])=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C[Si](C)(C)Oc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O
Solvent: CCOCC
Product: O=C(c1ccc(O)cc1)C(O)c1ccccc1

Procedure:
Following the method of Krepski et al., Tetrahedron Lett., 1983, 24, 4075-78, 185 mL of a 3.0 M phenylmagnesium bromide solution in diethyl ether (Aldrich) was added to a stirred solution of 143 g (0.49 mol) 4-trimethylsilyloxy-α-trimethylsilyloxyphenylacetonitrile from Example 54 in 1.0 L diethyl ether at 0° C. When addition was complete, the solution was allowed to stand at room temperature overnight before 50 mL water was added slowly.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH:23]O.[OH-].[Na+]>C1COCC1.O.CCOCC>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH2:3][OH:23])[N:5]=[CH:6]2
Reactant: C=CCn1ncc2cc(Br)ccc21
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCCCn1ncc2cc(Br)ccc21
Temperature: 0 °C

Procedure:
1-Allyl-5-bromo-1H-indazole (1s) (0.50 g, 2.1 mmol) was dissolved in 2 mL THF and cooled to 0° C. A solution of 9-BBN in THF (0.5 M solution, 8.9 mL, 4.4 mmol) was then added slowly via syringe under nitrogen and stirring. The reaction was warmed to room temperature over 6.5 hours. Then, a solution of aqueous H2O2 (30% wt. solution; 1.4 mL) in 1 N NaOH (14 mL, 14 mmol) was added slowly to the solution. The reaction was stirred at room temperature overnight, resulting in the formation of a white precipitate. The reaction was diluted with H2O and Et2O. The layers were separated and the organic phase was washed with brine. The aqueous phases were extracted once with Et2O. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude material (2s) was carried on to the next step without characterization.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH:15](=[O:18])[CH2:16][CH3:17].C(O)(=O)C>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([CH3:17])[CH:15]=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
108.5 g of p-tert.butyl-benzaldehyde are added under nitrogen gasification to a solution of 1.4 g of potassium hydroxide in 100 ml of methanol and 39.2 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. Subsequently, the mixture is further stirred at 40° C. for 1 hour, 1.5 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-2-methyl-acrolein of boiling point 165° C./11 Torr.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.Cl.[NH2:21][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23](=[O:24])[C:22]([NH:21][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:19])([CH2:29][CH3:30])[CH2:27][CH3:28]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: CCC(N)(CC)C(=O)OC
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=391.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:5]2[N:23]=[C:24]([CH3:31])[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[C:4]=2[C:3]=1[CH3:32].Cl.C(OCC)(=O)C.CCCCCC>CO.[OH-].[OH-].[Pd+2]>[CH2:29]([O:28][CH2:27][CH2:26][N:25]1[C:4]2[C:3]([CH3:32])=[CH:2][N:7]=[C:6]([NH2:8])[C:5]=2[N:23]=[C:24]1[CH3:31])[CH3:30]
Reactant: CCOCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCOCCn1c(C)nc2c(N)ncc(C)c21
Reaction time: 4 h
Yield: 49.2 %

Procedure:
6-Chloro-1-(2-ethoxyethyl)-2,7-dimethyl-N4,N4 -bis(phenylmethyl)-1H -imidazo[4,5-c]pyridin-4-amine (0.7 g, 1.56 mmole) was taken up in methanol saturated with anhydrous hydrochloric acid (100 mL), combined with palladium hydroxide on carbon and then hydrogenated on a Paar apparatus for four hours. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was partitioned between methylene chloride/water/sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide an off white solid. This material wasrecrystallized from ethyl acetate/hexane to provide 0.18 g of the desired product as a solid, m.p. 129°-130° C. Analysis: Calculated for: C12H18N4O+1/4H2O: % C, 60.35; % H, 7.81; % N,23.46; Found: % C, 60.64; % H, 7.50; % N, 23.39.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C(N)(CO)CO>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][O:1]2
Reactant: Oc1cccc2c1CCCO2
Reactant: COC(=O)CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1cccc2c1CCCO2
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A solution of chroman-5-ol (2.1 g, 14 mmol), methyl bromoacetate (1.6 mL, 16.8 mmol), and cesium carbonate (6.8 g, 21 mmol) in 50 mL acetonitrile was heated at 60° C. for 3 hours. PS-Trisamine scavenger resin was then added to the warmed solution followed by an additional 30 minutes heating. The reaction mixture was then cooled and filtered. The filtrate was collected, diluted with 100 mL ether, washed with brine (1×50 mL), dried (Na2SO4), and the solvent removed in vacuo to give 2.1 g (68%) of the title compound, pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 6.92 (t, 1H, J=8.3 Hz), 6.33 (d, 1H, J=8.3 Hz), 6.31 (d, 1H, J=8.3 Hz), 4.72 (s, 2H), 4.02 (t, 2H, J=5.1 Hz), 3.64 (s, 3H), 2.56 (t, 2H, J=6.6 Hz), 1.83 (m, 2H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:34]1([C:40]#[C:41][C:42]2[S:43][CH:44]=[C:45]([C:47](O)=[O:48])[N:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([NH:4][C:47]([C:45]2[N:46]=[C:42]([C:41]#[C:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:43][CH:44]=2)=[O:48])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(O)c1csc(C#Cc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1csc(C#Cc2ccccc2)n1
Reaction time: 16 h

Procedure:
Cyclopropylamine (2.49 mg, 0.00436 mmol), 1-hydroxybenzotriazole (0.589 mg, 0.00436 mmol), triethylamine (1.82 μL, 0.0131 mmol), N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (2.09 mg, 0.0109 mmol) and CH2Cl2 (2 mL) were combined, and then 2-phenylethynyl-thiazole-4-carboxylic acid (10 mg, 0.004 mmol) was added. The reaction was left standing for about 16 hours and then purified by preparative HPLC. LC/MS (Method 5), RT=1.33 min. Calculated [M+H]+=269; Observed [M+H]+=269.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C(OCC)(=O)[CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].Cl>O.C(O)(C)(C)C>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=CCC(=O)O)c2ccc(C)cc2)cc1

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 29.7 grams (141 mmol) 4,4'-dimethylbenzophenone and 141 mL t-butanol forming a solution, followed by 17.4 grams (155 mmol) potassium t-butoxide and 29.5 grams (170 mmol) diethyl succinate. The reaction was refluxed for 18 hours, cooled, and acidified with 6N hydrochloric acid, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated, and the residue taken up in 200 mL glacial acetic acid. It was then treated with 70 mL 48% hydrobromic acid and refluxed for 36 hours. The reaction was cooled, partitioned between water and ethyl acetate, and the combined organic layers washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford the product as low melting solid, 25.0 grams (66%), Rf =0.25 in 5% methanol/methylene chloride on silica gel. This material was used directly in the next step.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(O)=O.[Na+].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1cnc2sccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(Cl)c1csc2ncccc12
Temperature: 100 °C

Procedure:
A solution of thieno[2,3-b]pyridine (0.70 g, 5.2 mmoles), prepared as described in Example 1 (A), in chlorosulfonic acid, (7 ml) was heated to 100° C. for 15 minutes, then cooled to ambient temperature and added to ice (100 ml). The pH of the aqueous phase as adjusted to 8 with sat. NaHCO3, then extracted with CHCl3 (2×125 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect 0.95 g (78%) of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:52]([OH:60])(=[S:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:59][C:52](=[O:60])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:9][C@H:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCCn1ccnc1
Reactant: OC(=S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCCn1ccnc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (12.5 g) in tetrahydrofuran (125 ml) were added successively triphenylphosphine (17.6 g) and diethyl azodicarboxylate (10.6 ml) at -10° C. and the solution was stirred at the same temperature for 30 minutes. Then thiobenzoic acid (9.5 ml) was added at the same temperature and the solution was stirred for 3 hours. To the solution was added ethyl acetate (125 ml) and washed with saturated aqueous sodium hydrogen carbonate (125 ml×2) and brine (250 ml). The solution was dried over magnesium sulfate and the solvent was evaporated to give a yellow oil. The oil was chromatographed on a 500 g of silica gel to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[3-(imidazol-1-yl)propyl]pyrrolidine (15.3 g) as a yellow paste.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](Cl)[N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Solvent: CCO
Product: COc1cccc2c(Nc3ccccc3C)nc(Nc3ccccc3C)nc12

Procedure:
8-methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (1.00 g, 0.0033 mol) was dissolved in ethanol (15 ml) with o-toluidine (1.06 g, 0.0099 mol) and heated in a sealed vessel at 150° for 5 hours. After cooling and removal of excess solvent in vacuo the solid was chromatographed (silica gel, chloroform). 8-Methoxy-2,4-bis(2-methylphenylamino)quinazoline was isolated as crystals (0.93 g, from ethanol/water, m.p. 185°-187°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH:23](O)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>ClCCl.O>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(=O)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
1-Acetyl-4-piperidinone (77 g) was dissolved in dichloromethane (300 ml), and trimethylsilyltrifluoromethanesulfonate (200 ml) and benzhydrol (92 g) were added thereto with stirring under ice-cooling. The mixture was allowed to stand at room temperature overnight, and then water (500 ml) and sodium acetate (50 g) were added thereto and the reaction mixture was vigorously stirred. The dichloromethane layer was preparatively separated, washed with an aqueous sodium bicarbonate solution, dried, and then the solvent was evaporated under reduced pressure. The residue was treated with ethyl ether to obtain 1-acetyl-3-benzhydryl-4-piperidinone as colorless crystals (132.6 g, 86%).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.[N:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]([O:20]C)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][NH:2][C:18]([C:9]1[N:8]=[CH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)=[O:20]
Reactant: CN
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a stirred solution of MeNH2.HCl (173 mg, 5.12 mmol) in toluene (5 mL) at 0° C., was added AlMe3 (2 M solution in Hexanes, 1.28 mL, 2.56 mmol). After 30 minutes the solution was canulated into a stirred solution dimethyl pyridine-2,5-dicarboxylate (500 mg, 2.56 mmol) in DCM (5 mL) at 0° C. before stirring over night at room temperature. An aliquot was taken and analysed by NMR, indicating that there was a 0.8:1 ratio of product to starting material. MeNH2.HCl (173 mg, 5.124 mmol) and AlMe3 (2M solution in Hexanes, 1.28 mL, 2.56 mmol) were added and the reaction stirred for 12 hours. The reaction was quenched by addition of H2O (2 mL) and extracted with EtOAc (2×10 mL). The organics were combined, dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (520 mg, quant. yield) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.O[CH2:18][NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22]>O>[F:22][C:21]([F:24])([F:23])[C:20]([NH:19][CH2:18][C:8]1[C:7]([Cl:11])=[C:3]([C:2]([Cl:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])=[O:25]
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(Cl)ccc(CNC(=O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step i): A mixture of 2,6-dichlorobenzoic acid (4 g; 20.94 mmol), conc. H2SO4 (50 mL) and N-(hydroxymethyl)trifluoroacetamide (2.996 g; 20.94 mmol) was stirred at rt overnight. The mixture was diluted with 500 mL crushed ice and 200 mL H2O, the precipitate was filtered and dried to give crude 3-(trifluoromethylcarbonylamino-methyl)-2,6-dichloro-benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:31])=[C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:9]([CH:16]([CH3:18])[CH3:17])=[N:10]2.[OH-].[Li+]>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([CH:16]([CH3:17])[CH3:18])[C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)=[C:7]2[CH3:31]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
A solution of [8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yl]acetic acid methyl ester (0.04 g) in tetrahydrofuran (3.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.3 mL), and the resulting mixture was stirred at room temperature for six hours. The mixture was concentrated under reduced pressure and the pH adjusted to 4 by the addition of 0.1M aqueous hydrochloric acid (3.0 mL). The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (5:95 to 98:2 by volume) to afford title compound as white solid (0.024 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](Cl)[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]1=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([SH:58])([CH3:57])([CH3:56])[CH3:55].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([S:58][C:54]([CH3:57])([CH3:56])[CH3:55])[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]1=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)Sc1cc(=O)n(Cc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 54 %

Procedure:
A mixture of 3-benzyl-6-chloro-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), tert-butylmercaptan (0.1 ml) and potassium carbonate (0.14 g) in acetonitrile (10 ml) was heated under reflux for 8 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow amorphous powders (0.2 g, 54%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]=[N+:14]=[N-:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]#[C:17][CH2:18][CH3:19]>C(O)C.CCCCCC.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:18]([CH3:19])=[C:17]([CH3:16])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCN(Cc2ccccc2)C1
Reactant: C#CCC
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1nnn(C2CCN(Cc3ccccc3)C2)c1C

Procedure:
To a solution of N-benzyl-3-azidopyrrolidine (2.02 g, 0.01 mole) in 30 ml of 98% ethanol was added 15 ml of butyne and heated in a sealed steel reaction vessel at 105°-110° C. for 24 hr. Removal of the solvent under reduced pressure afforded 2.55 g of the crude which contained 50% starting material. Chromatography over silica gel using hexane/ethyl acetate (1:1) as solvent yielded 0.88 g of the desired product. 1H NMR (CDCl3) δ: 7.36-7.2 (m, 5H), 4.95-4.8 (m, 1H), 3.7 (S, 2H), 3.2-3.1 (m, 1H), 2.93-2.76 (m, 3H), 2.48-2.3 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15]N(C)C>O.CN(C)C=O>[CH3:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC#N)c2c1C
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of potassium cyanide (0.74 g) in 20 mL water was added a solution of (5-methoxy-4-methyl-1H-indol-3-ylmethyl)dimethylamine (0.5 g) in 20 mL of N,N-dimethylformamide. The solution was heated to reflux for 40 min, cooled to rt, and 40 mL of ice water was added. The aqueous layer was extracted with three portions of toluene, and the combined toluene layers were washed with water and brine. The solvent was removed in vacuo and the product purified by column chromatography dichloromethane) as the mobile phase to yield (5-methoxy-4-methyl-1H-indol-3-yl)-acetonitrile (0.40 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=O)[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=N1.N1CCCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[N:25]1([C:19]([C:18]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:14][C:13]=3[CH:15]=[CH:16][CH:17]=2)=[O:21])[CH2:26][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carboxylic acid (40.0 mg, 0.136 mmol), 1-hydroxybenzotriazole (18.4 mg, 0.136 mmol) and pyrrolidine (0.017 ml, 0.204 mmol) in DMF (1 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52.2 mg, 0.272 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (42.0 mg, 89.2%) as an oil.