Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:34]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:22]1[CH:23]=[C:24]([C:26]2[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=2)[NH:25][C:21]=1[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])=[CH:8][CH:9]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cnc(-c2cc(Cl)c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (300 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (82.3 mg) at 0° C., and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (210 mg). The mixture of the obtained positional isomers was dissolved in hexane-2-propanol (700:300, volume ratio, 18.8 mL), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRY LTD.). Using hexane-2-propanol (700:300, volume ratio) as a mobile phase, the solution was eluted at flow rate 60 mL/min and at 30° C., and the fraction was separated at retention time 22.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (85.9 mg, yield 27%) as a colorless amorphous solid. MS: 521 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[S:11][CH:12]([CH3:14])[CH3:13].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:16])=[N:6][C:5]=1[S:11][CH:12]([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(C)nc1SC(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C(=O)OC)c(SC(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
After 2-isopropylsulfanyl-6-methyl-nicotinic acid methyl ester (105 mg, 0.46 mmol) was dissolved in THF (3 mL), KHMDS (1 mL, 0.51 mmol) was added slowly thereto at −78° C., and the mixture was stirred for 30 minutes. MeI (72 mg, 0.51 mmol) was added slowly to the reactant at −78° C., and the mixture was stirred at room temperature for 1 hour. The reactant was cooled, diluted with water, and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent EtOAc/Hex=1/5) to obtain the title compound (60 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:13]2[CH:14]=[CH:15][C:10]([C:9](=[O:20])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:33][CH:34]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of the product of Example 10A (5.132 g, 14.45 mmol) in anhydrous N,N-dimethylformamide (50 mL) was treated with N-Boc-4-hydroxyaniline (3.024 g, 14.45 mmol) and potassium carbonate (3.994 g, 28.90 mmol) at room temperature, then heated at 80° under a nitrogen atmosphere for 4.5 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (4×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give the product as a dark yellow solid (7.38 g, 13.97 mmol, 97%).
Reaction SMILES: [OH:1][C:2]1[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:4][C:3]=1[CH:19]([CH3:21])[CH3:20].Cl[C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:16]([C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([CH:19]([CH3:21])[CH3:20])[C:2]=1[O:1][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1)[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:17])[CH3:18]
Reactant: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cc(C(C)C)c(Oc2nnnn2-c2ccccc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
11 g of Methyl 3-(4-hydroxy-3,5-diisopropylbenzoyl]propionate was dissolved in 200 ml of N,N-dimethylformamide, followed by the addition of 8.15 g of 5-chloro-1-phenyl-1H-tetrazol and 10.4 g of potassium carbonate. The obtained mixture was stirred for 1 hour under heating, cooled to room temperature by allowing to stand and poured onto ice-water. The resultant mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel chromatography (developer: 20% ethyl acetate/n-hexane) to give 14.1 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.S(=O)(=O)(O)[OH:9].[CH2:13]([OH:17])[CH2:14][CH2:15]C>>[C:13]([O:17][CH2:5][CH2:6][CH2:1][CH3:7])(=[O:9])[CH:14]=[CH2:15]
Reactant: O=S(=O)(O)O
Reactant: CCCCO
Reactant: Cc1ccccc1
Product: C=CC(=O)OCCCC
Temperature: 100 °C

Procedure:
A typical cleavage reaction was performed by dispersing 0.1602 g GCNF-PBA3 into 100 mL toluene followed by adding 100 mL n-butanol and 5 mL concentrated sulfuric acid and refluxing the mixture at 100° C. for 9 days. Solvent was removed by rotary evaporation under reduced pressure. The residual solid was dispersed into 100 mL CHCl3 and extracted with water three times to remove any sulfuric acid. The organic dispersion was filtered through a 0.2 μm Nylon membrane and washed with CHCl3. The filtrate was distilled under reduced pressure to remove the solvent and dried in vacuum overnight at 40° C. Molecular weight and polydispersity of the cleaved PBA were measured by GPC. (Mw=31,300, Mw/Mn=1.73)
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:15]=1[C:16]#[N:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH2:12][C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:6]2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:15]=1[C:16]#[N:17]
Reactant: [H][H]
Reactant: CCCC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Yield: 80.6 %

Procedure:
To a solution of (R)-2-((1-butyrylpiperidin-2-yl)methoxy)-6-nitrobenzonitrile (Example 16b, 1.5 g, 4.53 mmol) in ethanol (40 mL) was added 10% Pd/C (300 mg). The reaction mixture was charged with hydrogen balloon at room temperature overnight then then filtered through celite and concentrated under reduced pressure. The residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%) to give the desired product as an oil (1.1 g, 81%). H NMR (400 MHz, DMSO-d6) δ 0.86 (t, J=7.2 Hz, 3H), 1.46-1.65 (m, 7H), 1.77-1.85 (m, 1H), 2.24-2.30 (m, 1H), 2.38-2.42 (m, 1H), 2.56-2.63 (m, 0.5H), 3.1-3.16 (m, 0.5H), 3.71-3.74 (m, 0.3H), 3.92-3.98 (m, 1H), y 2H), 7.15-7.19 (m, 1H). MS 302 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(OCc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(COC(=O)c3ccccc3)sc2c1
Yield: 96.2 %

Procedure:
10 g of the 6-nitro-2-benzoyloxymethylbenzothiazole obtained in the Preparation Example 3 was dissolved in a solution comprising a mixture of ethyl acetate and ethanol (1:1) and hydrogenated in the presence of 1 g of a palladium/carbon catalyst for 10 h. After the completion of the reaction, the catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure to give 8.7 g of the titled compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([NH:8][C:15]([C:13]1[N:14]=[C:10]([Br:9])[S:11][CH:12]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: NCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzyl amine was loaded to 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin (PAL) via reductive amination to give PAL-benzyl amine resin. See, Ding, S.; Grey, N. S. Wu, X.; Ding, Q.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 1594-1596. A reaction flask containing PAL-benzyl amine resin (200 mg, 0.2 mmol), 2-bromothiazole-4-carboxylic acid (83 mg, 0.4 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) (153 mg, 0.6 mmol) and diisopropylethylamine (0.17 mL, 1 mmol) in DMF (3 mL) was shaken for 24 hr at room temperature. The resin was washed with methanol, dichloromethane and dried in vacuo to give PAL resin-N-benzyl-2-bromothiazole-4-carboxamide, which was then added to a flame-dried reaction vial, followed by 4-aminopyrimidine (95 mg, 1 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and NaOtBu (192 mg, 2 mmol). The vial was sure safe capped and degassed, then charged with argon and anhydrous dioxane (1.5 mL). The reaction was shaken for 24 hours at 90° C. The resin was washed with sodium diethyldithiocarbamate solution (0.05 M in DMF), methanol and dichloromethane and dried in vacuo. The resin was subsequently cleaved with cleavage cocktail TFA:CH2Cl2:H2O (45:55:5) (2 mL) for 2 hr. The resin was filtered, the filtrate was collected and evaporated in vacuo to give the crude which was then purified by HPLC to give the title compound (30 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[O:52][CH2:53]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:53][O:52][C:51]2[CH:56]=[CH:57][CH:58]=[CH:59][C:50]=2[F:49])=[CH:18][CH:17]=1
Reactant: OCCOc1ccccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCOc4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Yield: 47.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene/triethylamine=10/1 (5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (76 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(2-fluorophenoxy)-1-ethanol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (38 mg, yield 44%).
Reaction SMILES: N1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17][CH3:18])=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])CCC1.F[C:26](F)(F)[C:27](O)=O.C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.BrCCCCBr.[NH:55]1[CH2:61]C[CH2:59][CH2:58][CH2:57][CH2:56]1>>[CH2:21]([O:20][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([O:17][CH3:18])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:61][N:55]2[CH2:27][CH2:26][CH2:59][CH2:58][CH2:57][CH2:56]2)=[C:13]([NH2:19])[N:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C(F)(F)F
Reactant: C1CCCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: BrCCCCBr
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,4-dibromobutane and hexahydro-1H-azepine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:21]1([C:20]2[CH:28]=[C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:6]3[N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[C:3]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[C:2]3[N:1]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nn3c(-c4ccccc4)cc(-c4ccccc4)nc3c2-c2ccncc2)cc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4yl)pyrazole (153 mg), dibenzoylmethane (162 mg) and conc. hydrochloric acid (0.1 ml) in ethanol (5 ml) was refluxed for 4 hours. The reaction mixture was cooled and poured into ice-water. The mixture was neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 5,7-diphenyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (250 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CO[Na].[H][H]>CO>[C:6]([O:8][CH3:9])(=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1.[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: [H][H]
Agent: CO[Na]
Solvent: CO
Product: COC(=O)c1ccccc1
Product: OCc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a 100 ml stainless steel autoclave, 6.0 mg (0.01 mmol) of complex 1 and 430 mg (2 mmol) of methyl p-bromobenzoate were added, and the autoclave was purged with nitrogen. Then, 0.5 ml (0.5 mmol) of 1 N MeONa and 1.5 ml of methanol were added thereto. Subsequently, hydrogen was introduced to a pressure of 5.0 MPa, followed by stirring at 80° C. for 16 hours. After cooling to room temperature, the reaction product was analyzed by GC. Merely dibromination of 31% of the substrate occurred which resulted in conversion to methyl benzoate (debrominated product), and p-bromobenzyl alcohol was not detected.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][C:37]([CH3:39])=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: CC(C)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@H]1F
Product: CC(C)N1C[C@@H](F)[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-4-fluoro-1-(1-methylethyl)pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 317) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.28–7.34 (m, 3H), 7.37–7.44 (m, 4H), 7.48 (dd, 1H, J=8.8, 2.4 Hz), 7.54–7.62 (m, 3H), 7.78 (d, 1H, J=8.8 Hz), 9.89 (s, 1H). MS: m/z 428.9 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.[NH2:15][NH2:16]>CCO>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:15][N:16]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CN(C)c1ccc(C(=O)CC#N)cc1
Solvent: CCO
Product: CN(C)c1ccc(-c2cc(N)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
3-(4-Dimethylamino-phenyl)-3-oxo-propionitrile (3.262 gms.) is then suspended in 100 mL of anhydrous EtOH. This suspension is treated with 1.09 mL of anhydrous hydrazine, and subsequently is heated to refluxing temperature for 2 h. The reaction mixture is cooled to room temperature and stored in a −20° C. freezer overnight to yield a white crystalline precipitate. This precipitate is filtered and the filtrate is concentrated in vacuo. The residue from the evaporation is triturated with ethyl acetate to give additional precipitate. The combined precipitates are again triturated with ethyl acetate for 45 min. due to the presence of starting material in the initial precipitate. The solid material is collected by filtration providing the 5-(4-dimethylamino-phenyl)-2H-pyrazol-3-ylamine in the amount of 0.86 gms. (37% yield).
Reaction SMILES: [Li]CCCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CS(C)=O.Cl[CH:19]([B:21]([OH:23])[OH:22])[CH3:20].OC(C(O)(C)C)(C)C.Cl.[C@@:33]12([OH:44])[CH2:41][CH:37]([C:38]1([CH3:40])[CH3:39])[CH2:36][CH2:35][C:34]2([OH:43])[CH3:42]>C1COCC1>[CH2:6]([O:13][CH:19]([B:21]([OH:23])[OH:22])[CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:33]12([OH:44])[CH2:41][CH:37]([C:38]1([CH3:40])[CH3:39])[CH2:36][CH2:35][C:34]2([OH:43])[CH3:42]
Reactant: OCc1ccccc1
Reactant: CC1(O)CCC2C[C@]1(O)C2(C)C
Reactant: CC(Cl)B(O)O
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(OCc1ccccc1)B(O)O
Product: CC1(O)CCC2CC1(O)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
n-BuLi (1.6 N, 13.8 mL) was added to a solution of benzyl alcohol (2.3 mL, 22 mmol) in THF (60 mL) at −78 ° C. followed by DMSO (1.6 mL, 22 mmol). The solution was allowed to warm to room temperature and stir for 1 h. The solution was recooled to 0° C. and a solution of Pinacol (1-chloroethyl)boronate (2.06 g, 11 mmol) in THF (60 mL) was added. The solution was stirred at room temperature for 1 h and then heated at 60° C. for 5 h. The contents of the flask are poured into 0.2 N HCl (300 mL). The layers were separated and the aqueous layer was washed with ether (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. To this solution was added (s)-pinanediol (1.87 g, 11.0 mmol) and the solution was stirred for 1 day and concentrated to yield an oil. This oil was purified by silica gel column chromatography using 10% ethyl acetate/90% hexane as an eluent. The appropriate fractions are pooled and the solvent evaporated to yield 2.66 g (77% yield) of a pale yellow oil. 1H-NMR (CDCl3) δ 7.30 (m, 5H), 4.57 (s, 2H), 4.32 (d, 1H), 3.45 (dq, 1H), 2.39-1.82 (m, 6H), 1.41 (s, 3H), 1.40 (dd, 3H), 1.29 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: [C:1]12([C:11](O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH:51]=[C:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:53]=[C:46]12.FC(F)(F)C(O)=O.C1NCCN2C=C(C(OCC)=O)C=C12>CN(C=O)C>[C:1]12([C:11]([N:50]3[CH2:49][CH2:48][N:47]4[CH:51]=[C:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:53]=[C:46]4[CH2:45]3)=[O:12])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1cc2n(c1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(c1)CCN(C(=O)C13CC4CC(CC(C4)C1)C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial containing 1-adamantanecarboxylic acid (0.05 g, 0.283 mmol) was added HATU (0.11 g, 0.283 mmol), triethylamine (0.11 mL, 0.772 mmol) and DMF (1.5 mL). The solution was allowed to stir at rt for 30 minutes before ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate Intermediate 5 (0.05 g, 0.257 mmol) was added to the solution. The solution was then allowed to stir at rt overnight and then evaporated. To the resulting residue was added DCE (3 mL) and water (1 mL). After separation, the aqueous phase was extracted with DCE (2×3 mL). The combined organic phases were concentrated to give a crude ethyl 2-(1-adamantylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate as a solid.
Reaction SMILES: C([NH:8][C:9]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:12]2[O:13][CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]=1[CH3:31])C1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[CH2:14][O:13][C:12]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[C:9]([NH2:8])=[C:10]([CH3:31])[C:11]2=3)=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1c(NCc2ccccc2)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCCC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(N)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCCC2
Yield: 76 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-amine synthesized in Reference Example 289, the title compound was synthesized in the same manner as in Reference Example 30. Yield 76%. Melting point: 106-107° C. (hexane-ethyl acetate).