Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=O)[CH2:25][C:26](=O)[CH3:27])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.[CH:53]1([NH:57][NH2:58])[CH2:56][CH2:55][CH2:54]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:22])([F:23])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:57]([CH:53]2[CH2:56][CH2:55][CH2:54]2)[N:58]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 308d, (2S,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as brown oil. MS (ESI): m/z=549.8 [M+H]+.
Reaction SMILES: C(O)(C)C.FC(F)(F)C([NH:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12])=O.[OH-].[K+]>C(O)C>[NH2:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)C(NC(=O)C(F)(F)F)c1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: CC(C)(O)C(N)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
180 mL of isopropanol and 180 mL of ethanol were added to 36.0 g of the 1-(trifluoroacetylamino)-1-(1-naphthyl)-2-methyl-2-propanol obtained, and 63 g of an aqueous solution of 22% by weight of potassium hydroxide was added-dropwise thereto over 30 minutes at room temperature. The inner temperature of the mixture was raised to 50° C. and, at the same temperature, the mixture was stirred for 2 hours to effect reaction. The reaction mixture was concentrated, and 500 mL of chloroform and 180 mL of water were added to the resulting concentrated residue to carry out extraction treatment. The organic layer obtained was washed with 100 mL of water and the organic layer obtained was dried over dehydrated sodium sulfate and then concentrated. The resulting concentrated residue was dried at an inner temperature of 30° C. under reduced pressure to obtain 28.0 g of brown, viscous and oily 1-amino-1-(1-naphthyl)-2-methyl-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#[C:22][CH3:23])[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#[C:22][CH3:23])[CH2:18][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CC#CCC(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC#CCC(CNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 3-chloroaniline (4.33 mL, 40.9 mmol), the product from Step K (ca. 41 mmol), and crushed 4 Å molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen was added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction was stirred for one hour, then warmed to room temperature. After 3 hours, the solution was poured into EtOAc and washed with water, sat. NaHCO3 soln. and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(OB(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O.C(O)C>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
After obtaining the supported metal nanoparticles, the catalytic activity was examined using a very popular cross coupling reaction—Suzuki reaction, which is commonly used in the pharmaceutical industry, as shown in FIG. 8. Still referring to FIG. 8, Iodobenzene (0.5 mmol), phenyl boric acid (0.8 mmol) and K2CO3 (1.0 mmol) were added to a 4 mL mixture of a water:ethanol (1:1) solution. Then, the supported nano-Pd on XAD-4 (100 mg) was added, and the reaction mixture was heated to 60° C. for 12 hours. The supported catalyst was recovered by filtration, and the filtrate was extracted by ether. The evaporation of ether furnished the crude product, which was purified by regular flash column chromatography, as known to those of ordinary skill in the art, to yield pure biphenyl in 90% yield. The supported metal nanoparticles could be reused three times without significant activity loss.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[S:17])[C:14]3=[C:18]([CH3:22])[N:19]=[C:20]([CH3:21])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+].Br.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1.ClCCl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[C:14]3=[C:18]([CH3:22])[N:19]=[C:20]([CH3:21])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCc1cccnc1
Reactant: COc1ccc(-c2nn3c(C)nc(C)c3c(=S)[nH]2)cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2nc(SCc3cccnc3)c3c(C)nc(C)n3n2)cc1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of Example 27A (50 mg, 0.16 mmol) in 5 ml of DMSO is added to 5 ml of a saturated sodium hydrogencarbonate solution. 80 mg (0.32 mmol) of 3-picolyl bromide hydrobromide are then added and the reaction mixture is stirred at 60° C. overnight. After cooling, the batch is poured onto 50 ml of dichloromethane and washed with water (3×50 ml). The organic phase is dried (sodium sulphate) and the solvent is removed in vacuo. The crude material obtained is purified by flash chromatography (eluent dichloromethane/methanol 20:1).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:3]=1.[C:11](=O)([O:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)[O:12]C1C=CC([N+]([O-])=O)=CC=1>C1COCC1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2([NH:10][C:11](=[O:12])[O:22][CH:23]3[CH:28]4[CH2:27][CH2:26][N:25]([CH2:30][CH2:29]4)[CH2:24]3)[CH2:9][CH2:8]2)[CH:3]=1
Reactant: CC(C)(N)c1csc(Br)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN2CCC1CC2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(NC1(c2csc(Br)c2)CC1)OC1CN2CCC1CC2
Yield: 49.5 %

Procedure:
To a stirred solution of 2-(5-bromothiophen-3-yl)propan-2-amine (0.366 g, 1.66 mmol) in THF (10 mL) was added 4-nitrophenyl quinuclidin-3-yl carbonate (0.571 g, 1.95 mmol) and a few granules of 4-(dimethylamino)pyridine. The mixture was refluxed overnight, concentrated and partitioned between ethyl acetate (50 mL) and aqueous NaHCO3 (50 mL). The organic layer was washed again with aqueous NaHCO3 (1×50 mL), dried (Na2SO4) and concentrated. The resulting dirty yellow gum was purified by flash chromatography using a chloroform/methanol/ammonia gradient to afford quinuclidin-3-yl (1-(5-bromothiophen-3-yl)cyclopropyl)carbamate as an off-white solid (0.305 g, 49%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>ClCCl.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3cccc(F)c3)ccc21
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 97% of theory, C26H25FN6O3 (488.5); Rf value: 0.13 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=489; (M+Na)+=511; (M+2Na)++=267.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24]1([CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH:23][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCCc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCCc2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 4-phenylbutyryl chloride, gave 5-formyl-6-methoxy-3′-nitro-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccnc1Br
Yield: 48 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, 2-bromopropane (0.53 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-isopropyloxy pyridine (300 mg, yield: 48%) was obtained as an oil phase.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[C:15]([CH:17]1[CH2:19][CH2:18]1)#[CH:16].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CC#N.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:17]1([C:15]#[C:16][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[NH2:12])[CH2:19][CH2:18]1
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: C#CC1CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C#CC2CC2)c(N)c1
Yield: 95.1 %

Procedure:
bromo-4-methylsulfonyl-2-nitrobenzene (1.5 g, 5.36 mmol), ethynylcyclopropane (0.7 g, 10.72 mmol), K2CO3 (1.5 g, 10.72 mmol) in CH3CN (30 ml), Pd(ACN)2Cl2 (55.5 mg, 0.21 mmol) and X-phos (128 mg, 0.27 mmol) under N2 were heated at 45° C. for 3 h. EA extractive work up and preparative TLC (PE:EtOAc=5:1) gave the title compound (1.2 g).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36]O)=[NH:35])=[CH:32][N:31]=1>>[F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:36]=[C:34]([C:33]4[CH:38]=[CH:39][C:30]([NH2:29])=[N:31][CH:32]=4)[N:35]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) (201 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (110 mg, 43%). MS (ISP) 518.1 [(M+H)+]; mp 250° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)Cl.ClCCl>[Br:16][C:15]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: BrBr
Reactant: c1cnc2cc(-c3ccncc3)nn2c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Brc1c(-c2ccncc2)nn2cccnc12
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To 2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidine (0.30 g) in 15 mL chloroform was added dropwise a solution of 86 μL bromine in 1 mL chloroform. After 1.5 hours. at ambient temperature, the mixture was diluted with dichloromethane, washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to afford 386 mg (92% yield) product as a tan solid. MS showed a M+1 molecular ion of m/z 277.4 by positive APCI.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
A mixture of platinum oxide (1.0 g) in ethanol (37.5 ml) and glacial acetic acid (12.5 ml) were mixed under nitrogen with 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (20 g, 0.0926 mol) in ethanol (187.5 ml) and glacial acetic acid (62.5 ml). The reaction mixture was then hydrogenated at 60 psi until the reaction was complete by tlc. The catalyst was removed by fitration and the solvent evaporated in vacuo to give a yellow solid which was dried at 60° C. in vacuo (EP 722941).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:55][CH:56]1[CH2:60][CH2:59][C:58](=[O:61])[O:57]1)(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH3:35])[CH2:55][CH:56]4[CH2:60][CH2:59][C:58](=[O:61])[O:57]4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C1CCC(COS(=O)(=O)C(F)(F)F)O1
Reactant: CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCC(=O)O1)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in CH3CN (5 mL) was added DIEA (70 mg, 0.54 mmol) and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate (66.5 mg, 0.27 mmol). The resulting solution was stirred overnight at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 37 mg (31%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 24) [M+H]+=657.2, RT=1.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.2, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.24-5.17 (m, 2H), 4.58-4.54 (m, 1H), 4.41-4.38 (m, 1H), 3.98-3.95 (m, 1H), 3.16-3.03 (m, 1H), 2.69-2.55 (m, 4H), 2.46-2.44 (m, 2H), 2.26 (s, 3H), 2.24-2.16 (m, 1H), 1.88-1.83 (m, 1H), 1.79-1.71 (m, 2H), 1.48-1.44 (m, 1H), 1.29-1.21 (m, 1H).
Reaction SMILES: BrC1C=C[C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[N:37]1C=C[N:40]=[CH:39][C:38]=1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[N:40][CH:39]=[CH:38][N:37]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cnccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cnccn4)ccc3c1)n2C1CCCCC1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-pyrazin-2-yl-ethanone (32 mg, 0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (15 mg, 10% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:33]1[CH2:32][CH:31]2[CH:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:19])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
N,N'-carbonyldiimidazole (1.13 g) is added to a solution, cooled to +5° C., of [2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetic acid (1.85 g) in dry dichloromethane (30 cc). The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenylperhydro-4-isoindolone hydrochloride (2.29 g) and triethylamine (1.9 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours, then washed with water (2×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (30:70 by volume) and collecting 125-cc fractions. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-{[2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetyl}-7,7-diphenylperhydro-4-isoindolone (2.8 g) in the form of a white meringue-like product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1)[CH3:14].[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>COCCOC>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
Dissolve 290 ml (2.069 mol) diisopropylamine in 3.6 liters DME and precool to −78° C. Add 820 ml (2.05 mol) n-butyllithium (2.5 M solution in hexane) dropwise in the space of approx. 20 min (temperature<−60° C.). After 15 min at −60° C., add a solution of 435 g (1.864 mol) (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.4 liters DME dropwise (temperature<−60° C.). Stir the mixture for a further 30 min at −60° C., before adding a solution of 189.5 ml (1.864 mol) benzaldehyde in 1.4 liters DME (time approx. 20 min, temperature −60° C.). Heat the mixture over a period of 4 h to RT, before adding 7 liter satd. ammonium chloride solution. Extract the reaction mixture with ethyl acetate. After phase separation, wash the organic phase with satd. ammonium chloride solution, dry, and concentrate by vacuum evaporation. Dissolve the residue in 7 liters dioxan and 5 liters methanol, and add 6 liters 1 N hydrochloric acid. Stir the mixture overnight at RT, then, after adding 11 liters satd. sodium chloride solution, extract with 6.5 liters ethyl acetate. Wash the organic phase with water and with satd. sodium chloride solution, dry, and concentrate by vacuum evaporation. Dissolve the residue in 2 liters diisopropyl ether, add seed crystals and stir for 2 h. The precipitated solid is filtered with suction, washed with 300 ml diisopropyl ether and petroleum ether and dried under vacuum. Concentrate the mother liquor, and after storing for 2 days at 4° C., again filter off the precipitated solid with suction, wash with approx. 100 ml diisopropyl ether and petroleum ether and dry under vacuum. On combining the two solids, 154.9 g (34% of theor.) of the target product is obtained.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[Br:8][CH2:9][C:10](Cl)=[O:11].C(N(CC)CC)C>C(OCC)C>[Br:8][CH2:9][C:10]([O:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:11]
Reactant: CC(O)CC(=O)O
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(CC(=O)O)OC(=O)CBr
Temperature: 5 °C
Yield: 70 %

Procedure:
5 g (0.048 mol) of 3-hydroxybutyric acid and 0.062 mol of bromoacetyl chloride were dissolved in 100 ml of diethyl ether. This solution was stirred in an ice bath, and while maintaining the solution at a level of not higher than 5° C., 20 ml of diethyl ether containing 5.35 g (0.053 mol) of triethylamine was dropwise added over a period of 30 minutes. After the dropwise addition, the mixture was stirred at room temperature for 10 hours. Then, triethylamine hydrochloride was filtered off from the reaction solution, and the filtrate was washed three times with distilled water. The ether solution thereby obtained was dried over anhydrous sodium sulfate, and then diethyl ether was distilled off. As a result, a slightly yellow desired compound was obtained in a yield of 70%.