Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:9][CH2:10][CH2:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)OCC[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.C(OCC)(=O)C>[CH2:1]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:9][CH2:10][CH2:11][C:12](=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NCCC1(c2ccccc2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)NCCC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 65C (3.86 g) in acetone (5 mL) and water (5 mL) was added pyridinium p-toluenesulfonate (120 mg). The mixture was stirred at 100° C. in a Biotage Initiator microwave reactor for 10 minutes. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product which was used without further purification in the next reaction.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]1[CH2:16][C:15]2[N:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH2:13]1>CCOC(C)=O>[N+:17]1([O-:6])[CH:18]=[CH:19][CH:20]=[C:14]2[CH2:13][CH2:12][CH2:16][C:15]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2c(c1)CCC2
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloroperoxybenzoic acid (11.6 g, 67.1 mmol) was dissolved in EtOAc (70 mL, 6 ml/g). The reaction mixture was stirred for 10 minutes at room temperature, and then cooled to 0° C. 2,3-cyclopentenopyridine was dissolved in EtoAc (25 ml, 5 mL/g) which was added dropwise to reaction mixture over 15 minutes keeping the temperature constant below 10° C. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with Sat. NaHCO3 (50 mL). The organic layer was dried over sodium sulfate and filtered. Acqu layer was extracted with DCM (40 mL) twice. The organic layer was dried over sodium sulfate and filtered. Combined organic layer was concentrated in vacuo and purification of the crude material via Isco (0-5% Methanol/DCM) gave rise to the desired 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (1.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[OH-]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(=O)O)cs2)CC1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
4-(4-Ethoxycarbonyl-thiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.0 g, 3 mmol) was dissolved in IMS (10 mL) and aqueous sodium ,hydroxide (1 M, 8 mmol) was added and the mixture stirred at 130° C. for 10 minutes. The solution was then cooled, filtered and acidified with 1 N hydrochloric acid to pH 4. The resulting precipitate was isolated by filtration and dried under vacuum to give the title compound as a white solid (0.47 g). LCMS m/z 308.48 [M−H]− RT=3.45 min (Analytical Method 4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16]>>[F:13][C:14]([F:18])([F:17])[CH2:15][NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(NCC(F)(F)F)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10 using 1H-indole-5-carboxylic acid and 2,2,2-trifluoroethanamine (0.93 g, 62%); MS: 243 (M+).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>>[N+:1]([C:19]1[CH:18]=[C:10]([CH:9]=[CH:8][C:7]=1[Cl:6])[C:11]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:12])([O-:4])=[O:2]
Reactant: O=C(c1ccc(Cl)cc1)c1nccs1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1nccs1
Reaction time: 1 h

Procedure:
Potassium nitrate (2.1 g., 0.02 mol) was added in one portion to a solution of 4.5 g. (0.02 mol) of 2-(4-chlorobenzoyl)thiazole in 25 ml. of concentrated sulfuric acid. After 1 hr. the mixture was cautiously poured into 250 ml. of ice water, the product collected, washed with water and dried to yield 2-(3-nitro-4-chlorobenzoyl)thiazole as pale-yellow prisms, mp. 118°-119° (acetone-water).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH2:5][CH2:4]1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([CH3:16])([CH3:17])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN1CCC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-ethyl-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (0.28 g) and Pd/C (0.060 g, 10% wt) in 10 ml of EtOAc was placed under H2 which was provided by a balloon and stirred at RT overnight. Then the mixture was filtered through Celite®, condensed, and the residue was purified by flash column chromatography (2% of EtOAc in CH2Cl2). The titled compound was obtained as a pink oil. MS(ES+) 204.8 (M+H)+. Calc'd for C11H16N—204.31.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1C(O)=O)([O-:5])=[O:4].[N+](C(O)C1C=CC=CC=1)([O-])=O.[Cl:26][C:27]([C:30]([OH:40])([N+]([O-])=O)C1C=CC=CC=1)([Cl:29])[Cl:28].CC(C)([O-])C.[K+].N>>[Cl:26][C:27]([CH:30]([OH:40])[C:13]1[CH:12]=[CH:11][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=1)([Cl:29])[Cl:28]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])C(O)(c1ccccc1)C(Cl)(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: N
Agent: O=[N+]([O-])C(O)c1ccccc1
Product: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Yield: 72 %

Procedure:
Several articles have described the condensation of substituted benzaldehyde derivatives with chloroform in the presence of various bases to produce the corresponding α-(trichloromethyl)benzyl alcohols. In the case of nitrosubstituted benzaldehydes, only Cannizzaro reaction products are obtained when powdered potassium hydroxide is used as the base without solvent. Phase transfer conditions produce a mixture of nitrobenzoic acid, nitrobenzyl alcohol, and trichloromethylnitrobenzyl alcohol. Potassium t-butoxide in liquid ammonia at -75° C. has been reported to effect the desired condensation to form trichloromethyl-3-nitrobenzyl alcohol in 72% yield (Ya. G. Bal'on, V. E. Paranyuk, and M. D. Shul'man, Zh. Obsch. Khim., 44, 2633 (1974)). Under the same conditions potassium hydroxide or calcium oxide in dimethyl sulfoxide gives 5-10% lower yields. The generation of trichloromethide anion in solution from the decomposition of trichloroacetic acid in dimethyl sulfoxide has been used to prepare trichloromethyl-4-nitrobenzyl alcohol in 60% yield (P. J. Atkins et al., J. Chem. Soc., Chem. Comm., 1983, pp. 283-4).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[C:29](S(C)(=O)=O)[CH:28]=[CH:27][N:26]=3)[N:22]([C:35]3[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[N:21]=2)=[O:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[C:29]([O:1][CH2:2][CH3:3])[CH:28]=[CH:27][N:26]=3)[N:22]([C:35]3[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[N:21]=2)=[O:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC[O-]
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(S(C)(=O)=O)ccn2)cn1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccnc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)nn2-c2ccc(OC)nc2)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In an argon atmosphere, sodium ethoxide (28.4 mg) was added to a solution of 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylsulfonyl-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.189 g) obtained in Example 48 in tetrahydrofuran (3.8 mL) at room temperature. The resultant mixture was stirred for 1 hour, and then stirred for 90 minutes at 80° C. Subsequently, sodium ethoxide (85.2 mg) was added thereto. The mixture was stirred at 80° C. for 2 hours and 20 minutes, and then cooled in air. The resultant mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate-chloroform), to thereby give 4-[5-(4-ethoxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.139 g, 79%) as a solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][CH:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)OC1(C)C>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:35]3[CH:36]=[CH:37][C:38]([N:41]4[CH2:46][CH2:45][CH:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]4)=[CH:39][CH:40]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CCOC(=O)C1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2)CC1
Yield: 44.7 %

Procedure:
Compound 2b (350 mg, 0.760 mmol) was subjected to Suzuki coupling conditions with ethyl 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carboxylate (881 mg, 2.28 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 18d as a brown solid (200 mg, 42% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H36N6O3: 589.3 (M+H). Found 589.2.
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:14]
Reactant: CC1=NC(C)(C)SC1=NO
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1SC(C)(C)N=C1C
Reaction time: 16 h

Procedure:
20.0 g (0.126 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are dissolved in 100 ml of chloroform. To the solution are added 15 ml (0.252 mol) of freshly distilled methyl isocyanate as well as 3 drops of triethylamine. The mixture, which warms slightly after a short time, is left to stand at room temperature for 16 hours. Subsequently, the slightly turbid solution is filtered, and the solvent and excess methyl isocyanate are distilled off in vacuo. The oily residue is purified chromatographically on 250 g of silica gel using ethyl acetate/n-hexane (1:1) for the elution. The solvent is removed by evaporation, and the resulting residue is recrystallized from methyl chloride/n-hexane/diethyl ether to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(methylcarbamoyl)oxime as white crystals, m.p. 90°-92° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:17][O:13][C:12](=[O:14])[CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[NH:3]1
Reactant: CI
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (Rowe F. M., et al., J. Chem. Soc., 1098, 1936) (20 g, 104.6 mmol) in 100 mL of DMF is added to a suspension of NaH (2.5 g, 104.6 mmol) in 200 mL of DMF at room temperature under argon. Some cooling is required during the addition to keep the mixture at room temperature. The mixture is stirred at room temperature for 30 minutes. Methyl iodide (14.8 g, 104.6 mmol) is added, and the mixture is stirred at room temperature overnight. The reaction is quenched by addition of 5 mL of acetic acid, and the DMF is evaporated. Residual DMF is removed by heating the wet solid in a steam bath under high vacuum. The dried solid is stirred into 300 mL of CH2Cl2 for 1 hour. The solid is removed by filtration, and the filtrate is evaporated to give 12 g (56% yield) of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid methyl ester.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:17])[CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:3]1.[ClH:18].O1CCOCC1>>[ClH:18].[NH2:9][CH2:8][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC[C@H](F)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
Compound 20a (98.1 mg) was dissolved in 4N HCl-1,4-dioxane solution, and the solution was stirred at room temperature for 4 hours, to thereby yield compound 20b (33.5 mg, yield: 46%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+].Cl[C:54]1[CH:63]=[CH:62][C:61]2[CH2:60][N:59]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:58][CH2:57][C:56]=2[N:55]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:10]2[C:54]1[CH:63]=[CH:62][C:61]2[CH2:60][N:59]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:58][CH2:57][C:56]=2[N:55]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)ccc2C1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc(C3C(=O)Nc4ccc(C#N)cc43)ccc2C1
Temperature: 100 °C
Yield: 59 %

Procedure:
The title compound was prepared as described for Example 1.2 using 2-oxoindoline-5-carbonitrile (59 mg, 0.373 mmol), X-PHOS (14.23 mg, 0.030 mmol), K2CO3 (103 mg, 0.746 mmol), tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (120 mg, 0.448 mmol), and Pd2(dba)3 (6.83 mg, 7.46 μmol). The mixture was heated in a microwave oven at 100° C. for 2 h min. The mixture was cooled to RT and the resulting precipitate was removed by filtration. The remaining residue was dissolved in a mixture of dichloromethane and 2-propanol and the solution was washed with water. The aqueous layer was re-extracted with dichloromethane/2-propanol (3/1, v/v). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness. Amount 86 mg. Yield 59%.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=1.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[O:21][CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=3)[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COC(=O)c1csc(CBr)c1
Reactant: COc1ccc(O)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(COc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1

Procedure:
210 mg (7 mmol) of sodium hydride (80% in oil) and 10 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 1.8 g (7 mmol) of 3-(1-adamantyl)-4-methoxyphenol in 20 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. A solution of 1.7 g (7.2 mmol) of methyl 2-bromomethyl-4-thiophenecarboxylate in 15 ml of DMF was then added and the mixture was stirred at room temperature for two hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid obtained was triturated from hexane, filtered off and dried. 2.6 g (90%) of the expected methyl ester, having a melting point of 97°-8° C., were recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[C:30]#[N:31])[C:20]=2[N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[C:30]3[NH:42][N:41]=[N:40][N:31]=3)[C:20]=2[N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnn2c(N3CCOCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc(-c3cnc4c(-c5nnn[nH]5)cnn4c3N3CCOCC3)cc2)cc1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
According to a modification of a literature procedure (Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379-3393) a solution of 35 mg (0.085 mmol) of 6-(4-benzyloxy-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 1.5 mL of toluene and 0.5 mL of dimethylformamide was added 71 mg (0.513 mmol) of triethylamine hydrochloride (Et3N—HCl), and 33 mg (0.513 mmol) of sodium azide and the resulting heterogeneous mixture was heated at reflux for 72 h, during which time 71 mg (0.513 mmol) of triethylamine hydrochloride (Et3N—HCl), and 33 mg (0.513 mmol) of sodium azide was added to the reaction mixture after every 24 h. The mixture was then cooled to rt, filtered and concentrated to a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 15 mg (38% yield) of 6-(4-benzyloxy-phenyl)-7-morpholin-4-yl-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidine (370) as a solid as indicated by 1H-NMR. (LC-MS calcd for C24H22N8O2 [M+H]+455.18; found 455.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1ccc(N)c(F)c1

Procedure:
A solution of α-bromoisovaleric acid (8.17 mmole) in methanol is titrated to the phenophthalein end point using sodium methoxide. The solvent is removed by rotoevaporation and then there is added potassium carbonate (1.69 g), 2-fluoro-4-methylaniline (16.38 mmole) and 3 ml HMPT. The reaction is heated at 60° for about 5 hours and then worked up with 5% sodium hydroxide/ether and washed with water (3×). The basic layer is acidified and extracted with ether, washed with water and brine, dried over sodium sulfate and rotoevaporated to yield α-(2-fluoro-4-methylphenylamino)isovaleric acid. (2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.)
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])C.[OH-].[K+]>C(O)C.O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)Cc1sccc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1sccc1Nc1c(Cl)cccc1Cl

Procedure:
330 mg (1 mmole) of 3-(2,6-dichloroanilino)-2-thiophenacetic acid ethyl ester are boiled with 1 g of potassium hydroxide in 5 ml of ethanol for one hour. The mixture is then diluted with 20 ml of water and extracted with 20 ml of methylene chloride. The aqueous solution is acidified, and the precipitate which has formed is filtered off and washed with 3 ml of diisopropyl ether. 3-(2,6-Dichloroanilino)-2-thiophenacetic acid (m. 164° to 168°) is obtained.
Reaction SMILES: C[N:2]([CH2:4][CH:5]1[CH2:12][N:11]2[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]1=[O:13])[CH3:3].[CH3:14][C:15]1[CH:21]=[CH:20]C(N)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:21]=[CH:20][C:3]([NH:2][CH2:4][CH:5]2[CH2:12][N:11]3[C:7](=[CH:8][CH:9]=[CH:10]3)[C:6]2=[O:13])=[CH:17][CH:16]=1
Reactant: CN(C)CC1Cn2cccc2C1=O
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NCC2Cn3cccc3C2=O)cc1
Reaction time: 12 h
Yield: 83 %

Procedure:
A solution of 17.5 g, compound (2) and 10 g 4-methylaniline was allowed to stand at room temperature for 12 hours. 22 g yellow solid was obtained after filtering. Recrystallized from ethanol, 19 g (5) was obtained as a white crystal, mp 112°-114° C., yield 83%.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[F:10][C:11]1[CH:12]=[C:13]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:1]1([CH2:6][C:7]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:40])=[C:11]([F:10])[CH:12]=3)[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)c(F)c2)CN1
Reactant: O=C(O)Cn1ccnn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)c(F)c2)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)-4-(3,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 226, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(3,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.56 (d, 2H), 7.42-7.31 (m, 2H), 7.24-7.06 (m, 3H), 7.04-6.91 (m, 4H), 5.44 (q, 2H), 4.55-4.49 (m, 1H), 3.88-3.78 (m, 1H), 3.42-3.33 (m, 2H), 2.80-2.68 (m, 3H), 2.02-1.94 (m, 2H). MS (EI) for C28H24F3N5O3. found 536.2 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2].CN([CH:16]=[O:17])C>C1COCC1>[C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9]([CH:16]=[O:17])[C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1ncc(Cl)cc1F
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(Cl)c(C=O)c1F
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 2-acetylamino-5-chloro-3-fluoropyridine (50 mg, 0.27 mmol) and DMF (123 μL, 1.6 mmol) were dissolved in THF (0.5 mL) at room temperature. The solution was cooled to −20° C., a 24 wt % lithium hexamethyldisilazide THF solution (492 μL, 0.61 mmol) was added dropwise, and the mixture was stirred for 3 hours at that temperature. The reaction mixture was subjected to HPLC analysis under the same conditions as Example 8, and the purity and conversion rate were calculated from the area ratio of the title compound and the starting compound (2-acetylamino-5-chloro-3-fluoropyridine). The formula used was: Conversion rate (%)=100−(area ratio of starting compound).