Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH2:9]C(O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CO>C(#N)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1cc(F)cc(CC(=O)O)c1[N+](=O)[O-]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Yield: 103.2 %

Procedure:
To the crude 3-Amino-5-fluoro-2-nitro phenyl acetic acid (3.6 g, 16.8 mmol) was added Cu2O (10.1 g, 70.6 mmol) in 120 mL of acetonitrile along with 50 uL of methanol and the suspension was refluxed for 12 hours. The reaction mixture was filtered through Celite and the Celite pad washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to give 2.95 g of material which by 1H NMR was 80% pure. ESIMS [M+Na]−193; 1H NMR (500 MHz, DMSO) δ 6.67 (s, 2H), 6.56 (dd, J=11, 2.8 Hz, 1H), 6.39 (dd, J=11, 2.8 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.N(OCCC(C)C)=O.[ClH:19]>C(O)(=O)C.S(=O)(=O)(O)O.[Cu]Cl>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Cl
Reactant: Nc1ccnc2[nH]ccc12
Agent: Cl[Cu]
Agent: CC(C)CCON=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Clc1ccnc2[nH]ccc12
Temperature: 12 °C
Reaction time: 3 h

Procedure:
750 mg (5.63 mmol) of 4-amino-1H-pyrrolo[2,3-b]pyridine (from example XVII) are dissolved in a mixture of 67.5 ml of glacial acetic acid and 0.67 ml of concentrated sulfuric acid. The mixture is cooled to 12° C. 3.67 ml (3.20 g, 117 mmol) of isopentyl nitrite are slowly added dropwise, and the mixture is stirred at 12° C. for 3 hours. This solution is then added to a suspension (temperature: 50° C.) of 6.07 g (61.4 mmol) of copper(I) chloride in 34 ml of concentrated hydrochloric acid, and the mixture is then heated at 80-90° C. for 30 min. The mixture is cooled to RT and stirred overnight. For work-up, the reaction solution is concentrated and made alkaline using 1N aqueous sodium hydroxide solution, the precipitated copper salts are filtered off with suction through kieselguhr and the mixture is extracted 3× with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24]2[C:23](=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: O=C1C=CCCC1
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc(Cl)c(C(O)C3=CCCCC3=O)c2)cc1
Yield: 91 %

Procedure:
The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAc in hexane as eluent, gave pure Baylis-Hillman adduct in 91% yield (3.13 g).
Reaction SMILES: [C:1]1([C:7]2([NH:10][C:11]3[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=[C:13]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[CH:12]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][C:34](OC(C)=O)=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([N:30]1[CH2:31][CH2:32][N:27]([C:23]2[CH:22]=[C:21]([NH:20][C:13]3[CH:12]=[C:11]([NH:10][C:7]4([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:9][CH2:8]4)[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cnc(Nc2cccc(N3CCNCC3)c2)cc1NC1(c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2cccc(Nc3cc(NC4(c5ccccc5)CC4)c(C(N)=O)cn3)c2)CC1

Procedure:
To a solution of 4-(1-phenylcyclopropylamino)-6-(3-(piperazin-1-yl)phenylamino)nicotinamide (30 mg, 0.07 mmol) in DCM was added Ac2O (0.0066 mL, 0.07 mmol) and DIPEA (0.024 mL, 0.14 mmol), the mixture was concentrated and purified by preparative HPLC to give 6-(3-(4-acetylpiperazin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide. MS found for C27H30N6O2 as (M+H)+ 471.4. UV: λ=251.8 nm. 1H NMR: (CD3OD) δ 8.14 (s, 1H), 7.27 (m, 4H), 7.12 (dd, J=8.8, 1.2 Hz, 2H), 6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.72 (s, 1H), 6.56 (dd, J=7.6, 1.2 Hz, 1H), 6.11 (s, 1H), 3.68 (m, 4H), 3.17 (m, 2H), 3.09 (m, 2H), 2.15 (s, 3H), 1.38 (m, 4H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.[F:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]2)=[N:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([C@H:7]([C@@H:5]3[O:6][C:2]([CH3:1])([CH3:16])[O:3][C:4]3=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C@H:26]([CH3:30])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Reactant: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Product: CC(C)C[C@H](C(=O)N1CCN(c2ncc(F)cn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O

Procedure:
The title compound was prepared following the procedure of Example 4 (step a), but starting from (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid and 5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine. The crude was purified by chromatography on silica using a gradient of EtOAc: cHex (0/10 to 4/6). The title compound was isolated as a yellow oil (413 mg, 75%). TLC (EtOAc:cHex 3:7) Rf=0.25; 1H NMR (DMSO-d6) δ: 8.16 (s, 2H), 4.85-5.0 (m, 0.6H), 4.41-4.52 (m, 3.4H), 4.23 (m, 0.4H), 3.46-3.67 (m, 0.6H), 2.80-3.20 (m, 4H), 1.70-1.79 (m, 1H), 1.056 (m, 3H), 1.38 (s, 6H), 1.13-1.32 (m, 2H), 0.90 (m, 6H). HPLC (Condition A) Rt: 4.26 min (HPLC purity: 96.1%). LC/MS: M+(ESI): 409.6.
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C>[N+:7]([C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:9])=[O:8]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1sc2ccccc2c1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1sc2ccccc2c1Nc1ccccc1
Yield: 95.9 %

Procedure:
A mixture solution of 3-bromo-2-nitrobenzo[b]thiophene (14 g, 54 mmol), aniline (14 ml, 154 mmol) and triethylamine (11 ml, 79 mmol) in DMF (150 ml) was heated at 120° C. for 30 min before quenching with water. The solid was isolated by filtration, washed with water and recrystallized from DCM/hexane to yield 2-nitro-N-phenylbenzo[b]thiophen-3-amine (14 g, 96%) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.CSC.B>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1ccc(CC2OCCO2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a cooled (0° C.) solution of 4-((1,3-dioxolan-2-yl)methyl)benzoic acid (1.02 g, 4.92 mmol) in anhydrous THF (63.5 mL), a solution of borane dimethylsulfide complex (2.0 M in THF, 12.29 mL, 24.59 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 5 minutes and then the coolant removed. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was cooled to 0° C. and methanol (1 mL) was added. The reaction mixture was diluted with water and saturated aqueous sodium hydrogen carbonate and then extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (magnesium sulphate) filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in iso-hexane to afford the title compound (0.936 g, 98%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]\[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]\[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 97.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-Butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (80.7 mg, 98%).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:25]O.O1CCCC1>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[O:18][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CO
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)COC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), ethyl glycolate 4.04 g, 0.039 mole), 70 ml of tetrahydrofuran, 230 ml of n-hexane and one drop of methanesulfonic acid was refluxed for 2 hours. On completion of the reaction, 2 drops of tetramethylguanidine was added to discharge the blue color. The reaction mixture was filtered hot and the filtrate was cooled. An oily layer formed which was removed and stripped free of solvent; the remaining filtrate was also stripped, leaving an oil. Both samples of oil were combined and chilled. A waxy solid formed which, on repeated trituration with petroleum ether, gave a white solid. Recrystallization from a mixture of petroleum ether/acetone gave a white solid, mp 63°-67.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1)[CH2:11][C:9]1[NH:8][CH:7]=[CH:6][N:10]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound (130 mg) obtained in Example 125-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour. Then, the solution was cooled to 0° C. The solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.4 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:12]2)=[C:5]([F:29])[CH:4]=1)#[N:2].C(OCC)C.[ClH:35]>O1CCOCC1>[ClH:35].[F:29][C:5]1[CH:4]=[C:3]([CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCCOc3ccc(C#N)cc3F)CC(C1)O2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCCN2CC3CNCC(C2)O3)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 7-[3-(4-cyano-2-fluorophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (9.15 g, 22.5 mmol; see step (ii) above) was taken in 15 mL of dioxane, to which was added 75 mL of diethyl ether saturated with HCl gas. The resulting mixture was stirred for 1 h at RT under a nitrogen atmosphere before solvent was decanted and the precipitated solid washed with dry diethyl ether (4 times) and dried under vacuum. This gave 9 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[CH:4][NH:5][CH:6]=1.Cl.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:7]([NH:17][CH2:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])=[O:9])=[CH:4][NH:5][CH:6]=1
Reactant: Cc1c[nH]cc1C(=O)O
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1c[nH]cc1C
Yield: 43.1 %

Procedure:
Using 7.63 g (60 mmol) of 4-methyl-3-pyrrolecarboxylic acid, 15.4 g (100 mmol) of β-alanine ethyl ester hydrochloride, 14 ml (100 mmol) of triethylamine, 17.3 g (90 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 100 ml of methylene chloride, 5.80 g of the title compound were obtained in a similar manner as in Example 2 (yield: 26%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=2)[CH:10]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:21]1([NH:20][C:18]2[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=[C:14]([C:11]3[CH:10]=[C:9]([CH2:8][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[S:13][CH:12]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CBr)c3)nc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CN4CCCC4)c3)nc12
Temperature: 50 °C
Yield: 50.5 %

Procedure:
Potassium carbonate (30 mg, 0.20 mmol) was added to 5-(5-(bromomethyl)thiophen-3-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (25 mg, 0.07 mmol) dissolved in DMF (0.7 mL). Pyrrolidine (6 μL, 0.07 mmol) was added and the reaction was heated to 50° C. for 1.25 h. Water (3 mL) was added and the orange precipitate was filtered and dried in vacuo to give 7-(cyclopropylamino)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (13 mg, 54%) which was used without further purification. LCMS (ES): >85% pure, m/z 368 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a mixture of 2-nitroaniline (1.38 g) and triethylamine (1.67 ml) in dichloromethane (30 ml) were added 4-nitrobenzoyl chloride (1.85 g) and the solution was stirred at ambient temperature for 4 hours. The solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and brine, and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with n-hexane to give 2-nitro-N-(4nitrobenzoyl)aniline (1.82 g).
Reaction SMILES: Cl.C([O:9][NH:10][C:11](=[O:41])[CH:12]([N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]1)=[O:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:9][NH:10][C:11](=[O:41])[CH:12]([N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][OH:40])[CH2:36][CH2:37]1)=[O:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14]
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)NOCc2ccccc2)C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)NO)C(C)C)cc1

Procedure:
To a solution of N-benzyloxy-2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide hydrochloride (0.39 grams, 0.63 mmol) in methanol (30 mL) was added 5% palladium on barium sulfate (0.19 grams). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 2.25 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated to a tan foam which was chromatographed on silica gel eluting with 15% methanol in chloroform containing 0.5% ammonium hydroxide. Clean fractions containing the desired product were taken up in saturated sodium bicarbonate solution. The resulting mixture was extracted several times with ethyl acetate and the combined extracts were concentrated to afford N-hydroxy-2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}-(4-methoxybenzenesulfonyl)amino]-3-methyl-butyramide as an oil. The hydrochloride salt (0.20 grams, 61%) was formed using anhydrous hydrochloric acid in cold (0° C.) methanol. MS: 487 (M+1). Analysis calculated for C21H34N4O7S.circle-solid.HCl.circle-solid.0.5H2O: C, 47.41; H, 6.82; N, 10.53. Found: C, 47.41; H, 7.11; N, 9.91.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:18](OS(C)(=O)=O)/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(OC(N[C@@H](CC1C=CC=CC=1)[C@@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C.CCCCCC>C(OCC)(=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)/[CH:18]=[CH:19]/[C@H:20]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:21]([O:23][CH3:24])=[O:22])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cl[Mg]C1CCCCC1
Agent: COC(=O)/C=C/[C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H](/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 82 %

Procedure:
Using the procedure of Example 8 but replacing benzylmagnesium chloride with cyclohexylmagnesium chloride (2.0M solution in ether) and replacing the resultant compound of Example 7 with the resultant compound of Example 14 provided, after chromatography on silica gel using 6:1 hexane:ethyl acetate, the desired compound (Rf 0.65, 2:1 hexane:ethyl acetate) in 82% yield. 1H NMR (CDCl3) δ 0.6-1.7 (br envelope, 11 H), 1.41 (s, 9 H), 2.69 (m, 1 H), 2.75 (dd, J=14, 7 Hz, 1 H), 2.89 (dd, J=14, 5 Hz, 1 H), 3.66 (s, 3 H), 4.41 (m, 2 H), 5.44 (AA', 2 H), 7.1-7.3 (m, 5 H). Mass spectrum: (M+H)+ =402.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[S:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[S:54][C:50]([CH:47]([CH3:49])[CH3:48])=[CH:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 5-isopropylthiophene-2-carboxylic acid (0.07 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated to give the subtitled compound as a clear gum. Yield 0.23 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([N:14]2[C:18](=[O:19])[CH2:17][S:16][C:15]2=[O:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([CH:36]=O)=[CH:33][CH:34]=3)[CH:29]=[N:28]2)=[C:24]([C:40]([F:43])([F:42])[F:41])[CH:23]=1>>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32](/[CH:36]=[C:17]4/[C:18](=[O:19])[N:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[C:15](=[O:20])[S:16]/4)=[CH:33][CH:34]=3)[CH:29]=[N:28]2)=[C:24]([C:40]([F:41])([F:43])[F:42])[CH:23]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(N2C(=O)CSC2=O)CC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1

Procedure:
((5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione was prepared from 4-(2,4-dioxo-thiazolidin-3-yl)piperazine-1-carboxylic acid tert-butyl ester and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F.