Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][O:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]#[N:16])[CH:8]=[CH:9][CH:10]=1)=[O:4].[I-].[Li+]>CC(=O)C(C)(C)C.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][O:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]#[N:16])[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Agent: [I-]
Agent: [Li+]
Solvent: CC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(C(=O)O)c2)c1
Temperature: 25 °C

Procedure:
A solution of N-[2-[(3-(methoxycarbonyl)phenyl)methoxy]-1(S)-cyanoethyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (0.34 g, 0.58 mmol) in pinacolone (20 mL) is degassed with bubbling nitrogen for 10 minutes. Lithium iodide (0.78 g, 5.80 mmol) is then added, and the solution is refluxed in the dark for 24 hours, after which time it is cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 5% aq. sodium thiosulfate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organic layer is then dried over MgSO4, evaporated, and the residue is chromatographed (silica, 3% MeOH/CH2Cl2/0.05% acetic acid) to yield a clear glass, which is crystallized with an EtOAc/hexane (1:50) mixture to yield N-[2-[(3-carboxyphenyl)methoxy]-1(S)-cyanoethyl]-3-methyl-Nα-(diphenyacetyl)-L-phenylalaninamide as a white solid, m.p. 160-162° C.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>O>[Si:25]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ncc2c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Charge a 10 L reaction vessel with N,N-dimethylformamide (DMF, 2.50 L), 5-hydroxyindazole (150.20 g, 1.12 mol) and 1H-imidazole (114.35 g, 1.68 mol). Cool the mixture to 0° C. and add tert-butyldimethylchlorosilane (253.16 g, 1.68 mol) over 0.5 hours. Stir the mixture at 18° C. for 3 hours. Add water (2.5 L) to the reaction slowly with an ice bath at 5° C. to maintain an internal temperature at around 20° C. Transfer the mixture to a separating funnel and extract with EA (2×2.5 L). Combine the extracts and wash with water (3×2.5 L) and brine. Dry the organic solutions over anhydrous sodium sulfate, filter, and evaporate to a red oil. Pass the oil through a silica gel pad and elute with eluent (0% to 30% EA in hexane) to afford the title compound as an orange oil which crystallizes. Yield: 300 g (100%). MS (ES) m/z 249 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([CH:39]([OH:41])[CH3:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
A mixture of 62 mg (0.15 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 14) and 3.95 mg (0.105 mmol) sodium borohydride in 2 mL THF/0.2 mL MeOH was stirred at room temperature for 45 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, filtered and evaporated to dryness to yield 58 mg (93%) of the title compound as off-white solid. MS m/e: 595.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=[C:5]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[CH2:29]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1[C:5]1[N:4]=[C:3]([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=1)[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CN)n1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CNC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing (1S)—N-{[4-(aminomethyl)-2-(2,6-diethylphenyl)-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (9 mg, 0.021 mmol) in CHCl3 (2.0 mL) is added acetic anhydride (0.05 mL, 25.0 eq., 0.53 mmol) and allowed to stir at room temperature for 2 h. All solvent is then removed and excess acetic anhydride is removed azeotropically with toluene (3×2 mL). The sample is re-dissolved in CHCl3 and eluted through a plug of SiO2, washing with CHCl3. Concentration affords the title compound as a colorless gum. [mass expected (470.65); mass found (470.34)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (248 mg, 0.97 mmol) [prepared according to the procedure of Example 184], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (321 mg, 0.96 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (557 mg, 1.19 mmol) in chloroform (9.5 mL). DIEA (840 μL, 4.81 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (167 mg, 0.26 mmol, 67%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1>CSC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:3][CH2:2][CH2:1][N:4]=[C:5]=[O:6])=[CH:10][CH:9]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: C=CCN=C=O
Solvent: CSC
Product: O=C=NCCCSc1ccc(Cl)cc1

Procedure:
A solution of 41.5 grams (0.5 mole) of allyl isocyanate and 72.25 grams (0.5 mole) of p-chlorobenzenethiol in 50 ml dimethyl sulfide was irradiated with an ultraviolet lamp in the manner described in Example 1. Nmr indicated that in 48 hours 32% of the allylic double bonds reacted with the thiol to form the allylic monoadduct, i.e. 3-p-chlorophenylthiopropyl isocyanate. No other products could be observed.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([NH:6][C@H:7]([C:23](O)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)=[O:5].[C:31]([NH:35][OH:36])([CH3:34])([CH3:33])[CH3:32].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([N:35]([OH:36])[C:23](=[O:24])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:13][CH:14]=1)[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:30])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)NO
Reactant: COc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)N(O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine (0.098 g) and tert-butylhydroxylamine (0.047 g) in CH2Cl2 (5 mL) was added BOP reagent (0.17 g) followed by DIEA (0.1 mL) and the mixture was stirred overnight at room temperature. The mixture was evaporated and the residue was dissolved in EtOAc (30 mL). The EtOAc solution was successively washed with 1 N HCl, satd. NaHCO3, satd. LiCl, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (silica gel; eluent: hexane/EtOAc/CH2Cl2 6/1/1) and recrystallization from CH2Cl2/hexane to give 74 mg of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine N-(tert-butyl)-N-hydroxyamide. ESMS: m/z 515 (MH+).
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17]C(OCC)=O)[CH:10]=[CH:11][CH2:12]Cl)=O)C.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][NH:24]1.O>C1C=CC=CC=1>[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:10]=[CH:11][CH2:12][N:24]1[CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Oc1ccc(C=CCCl)cc1OC(=O)OCC
Solvent: O
Solvent: c1ccccc1
Product: Oc1ccc(C=CCN2Cc3ccccc3C2)cc1O
Reaction time: 2 h
Yield: 52 %

Procedure:
The process for preparing this compound and its physical properties will be given below. A solution of 2.6 grams of 3,4-diethoxycarbonyloxycinnamyl chloride in 10 milliliters of benzene is added dropwise with stirring to a solution of 3.8 grams of isoindoline in 20 milliliters of benzene while cooling the reaction system with ice. After completion of the dropping, the reaction is carried out for 2 hours at room temperature. On completion of the reaction, water and a large quantity of benzene are added followed by separating and collecting the benzene layer. After concentrating the benzene layer, it is left to stand under cooled conditions to precipitate crystals. When these crystals are recrystallized from a tetrahydrofuran-ether mixture, 1.1 grams (yield 52.1%) of N-(3,4-dihydroxycinnamyl)-isoindoline is obtained as crystals having a melting point of 60.5° C. (decomposition).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH2:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1.[CH:23](O)=[O:24]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH:22][CH:23]=[O:24])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=CO
Reactant: NCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Product: O=CNCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Yield: 33 %

Procedure:
A solution of C-[1-(3-thiazol-2-yl-phenyl)-1H-benzoimidazol-5-yl]-methylamine (1.4 g, 4.57 mmol) in formic acid (20 ml) was stirred at reflux for 3 hours. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and saturated, aqueous sodium carbonate. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (9:1 v/v) as the eluent to afford the desired product 0.5 g (33%). LC-ESI-HRMS of [M+H]+ shows 335.095 Da. Calc. 335.096657 Da. dev. −4.9 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]([OH:11])=[O:10])[O:3]1.[H][H]>O1CCCC1.[C].[Pd]>[CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]([OH:11])=[O:10])[O:3]1
Reactant: [H][H]
Reactant: CC1(C)CC(=O)C=C(C(=O)O)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)CC(C(=O)O)O1

Procedure:
In 8 ml of tetrahydrofuran was dissolved 0.5 g of 3,4-dihydro-2,2-dimethyl-4-oxo-2H-pyran-6-carboxylic acid, followed by adding thereto 50 mg of 10% palladium-carbon, and the reaction was carried out with stirring in a hydrogen stream at room temperature for 3 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:19]\[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1cccc(/C=C\C(=O)O)c1OCc1ccccc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-methylbenzaldehyde (20 g, 88.39 mmol, 1.00 equiv), propanedioic acid (27.6 g, 265.23 mmol, 3.00 equiv), piperidine (1.5 g, 17.62 mmol, 0.20 equiv) and pyridine (200 mL). The resulting solution was heated to reflux for 2 h in an oil bath. The reaction was then quenched by the addition of 1.5 L of water/ice. The pH value of the solution was adjusted to 2-3 with hydrogen chloride. The solids were collected by filtration. The filter cake was washed with 2×500 mL of water and 2×500 mL of hexane. This resulted in 21 g (89%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid as a white solid. MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: O.[C:2](=[O:5])([O-:4])[O-].[K+].[K+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([N:25]4C(=O)[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]4=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:12][CH:11]=1)#[N:9].Cl>C(O)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([NH:25][C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:2]([OH:4])=[O:5])=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:45])[F:44])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:14][CH:15]=1)#[N:9]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)c3ccccc3C(=O)O)nn2C1c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 87.4 %

Procedure:
Water (1 ml) and potassium carbonate (23.1 mg, 167 μmol, 2 eq.) were added to a solution of ethyl 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)-phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (50.0 mg, 83.5 μmol; Example 1) in ethanol (6.25 ml). In a closed, pressure-proof glass tube, the reaction mixture was heated at 50° C. 1 N hydrochloric acid (670 μl, 670 μmol, 8 eq.) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 10 μm, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→100:0). This gave the product as a solid (45 mg, 87% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1.CC(C)(O)[C:16]#[N:17].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]1[C:16]#[N:17]
Reactant: CC(C)(O)C#N
Reactant: O=C1CCC=C1CCCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCCO
Yield: 72.5 %

Procedure:
A mixture of 2-(6-hydroxyhexyl)-2-cyclopenten-1-one (10.5 g., 0.058 mole), acetone cyanohydrin (5.6 g., 0.065 mole), 6% aqueous sodium carbonate (5.2 ml.) and methanol (35 ml.) was stirred and heated under reflux for 4 hours. Methanol was removed in vacuo, water (70 ml.) was added and the mixture was extracted with diethyl ether and dried over magnesium sulphate. The solvent was removed by evaporation and the residue was distilled under reduced pressure to give 2-(6-hydroxyhexyl)-3-oxocyclopentanecarbonitrile (8.8 g., 73%), b.p. 135°-178°C./0.15 mm.Hg, nD25 1.4812.
Reaction SMILES: C(=O)([O-])O.[K+].[I:6][C:7]1[CH:8]=[C:9]([C:14](=[NH:16])[NH2:15])[CH:10]=[CH:11][C:12]=1[CH3:13].Cl[CH2:18][C:19](=O)[CH3:20]>O1CCCC1.O>[I:6][C:7]1[CH:8]=[C:9]([C:14]2[NH:15][C:19]([CH3:20])=[CH:18][N:16]=2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CC(=O)CCl
Reactant: Cc1ccc(C(=N)N)cc1I
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(C)c(I)c2)[nH]1
Yield: 80.8 %

Procedure:
Potassium hydrogen carbonate (0.204 g, 2.0 mmol) was added to a solution of 3-iodo-4-methylbenzenecarboximidamide (preparation 59a, 0.53 g, 0.54 mmol) in tetrahydrofuran (5 mL) and water (1 mL) and the mixture was heated to reflux. Then 1-chloropropan-2-one (0.16 mL, 2.1 mmol) in tetrahydrofuran (2.50 mL) was added dropwise over 20 min and the mixture was refluxed overnight. The mixture was evaporated and the residue purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.13 g, 22%) as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1([CH3:30])[CH:15]([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:29])[CH:12]=2)[O:7]1>O.C(O)C>[N:1]([CH2:17][CH2:16][CH:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:29])[CH:12]=2)[O:7][C:6]1([CH3:5])[CH3:30])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3cc(F)ccc3OC2(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2ccc(F)cc2CC1CCN=[N+]=[N-]

Procedure:
A solution of 1.62 g (24.9 mmol) of sodium azide in 10 ml of water is added to a solution of 6.3 g (16.6 mmol) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in 100 ml of ethanol. The mixture is boiled under reflux for 18 hours. After cooling, the ethanol is evaporated off in vacuo and water is added to the residue. The aqueous mixture is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 4.13 g (100% of the theoretical yield) of 3-(2-azidoethyl)-2,2-dimethyl-6-fluoro-chroman in the form of a light-yellow oil.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18]1([C:21]2[NH:25][N:24]=[C:23]([NH2:26])[CH:22]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([NH:26][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[C:9]([S:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)(=[O:7])=[O:8])[CH:10]=3)[NH:24][N:25]=2)[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: Nc1cc(C2CC2)[nH]n1
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(pyrrolidin-1-ylsulfonyl)benzoic acid and 5-cyclopropyl-1H-pyrazole-3-amine as the starting materials.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:37]1([CH2:43][CH2:44][S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[OH:51][C:50]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:14][CH:15]=2)[O:21][C:47](=[O:48])[C:46]=1[S:45][CH2:44][CH2:43][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccc4ccccc4c3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(2-naphthalenylmethoxy)acetophenone (1.39 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 152-154° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 5.38 (s, 2 H), 6.68 (s, 1 H), 7.21 (m, 7 H), 7.54 (m, 2 H), 7.60 (d, 1 H), 7.96 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.O>[CH2:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]=[CH:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A solution of 6-bromoindole (5.0 g, 26 mmol) in dry DMF (45 mL) was cooled in an ice bath. Sodium hydride (2.2 g of 60% dispersion in oil, 55 mmol) was added. After stirring for 30 minutes under nitrogen at room temperature, the reaction mixture was cooled in an ice bath, and benzyl bromide (6.1 mL, 51 mmol) was added. After stirring for one hour at room temperature, the reaction mixture was poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was then washed with water and brine, then dried over anhydrous magnesium sulfate and evaporated to dryness. Purification of the residue by flash chromatography using hexane as an eluant and drying for 30 minutes at 60° C. yielded 1-benzyl-6-bromo-1H-indole (5.83 g, 80%) as a waxy solid, mp: 85-88° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ 7.7 (d, 1H, J=0.61 Hz), 7.50-7.55 (m, 2H), 7.30 (t, 2H, J=7.3 Hz), 7.2-7.25 (m, 1H), 7.2 (d, 2H, J=8.4 Hz), 7.15 (dd, 1H, J=8.4 Hz and 1.7 Hz), 6.5 (dd, 1H, J=3.1 Hz and 0.77 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH:7]([CH2:12][C:13]#[CH:14])[C:8]([O:10][CH3:11])=[CH2:9].C(N(CC)CC)C>C(Cl)Cl>[S:1]([O:6][CH:7]([CH2:12][C:13]#[CH:14])[C:8]([O:10][CH3:11])=[CH2:9])([CH3:4])(=[O:3])=[O:2]
Reactant: C#CCC(O)C(=C)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(OS(C)(=O)=O)C(=C)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Mesyl chloride (1.73 ml) was added dropwise to a solution of 3-hydroxy-2-methoxy-1-hexen-5-yne (2 g) and triethylamine (3.32 ml) in methylene chloride (20 ml) under ice-cooling over a period of 10 minutes. After being stirred for 48 hours at room temperature the mixture was washed successively with water, aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and evaporated in vacuo to give 3-mesyloxy-2-methoxy-1-hexen-5-yne (3.45 g).