Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:16]([CH3:18])([CH3:17])[CH:15]2[C:19]([OH:21])=[O:20])[CH:7]=1.[O:22]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CCOCC>[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:16]([CH3:17])([CH3:18])[CH:15]2[C:19]([O:21][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:30]=2)=[O:20])[CH:7]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)O)C12C=C(Cl)c1ccccc12
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC1(C)C(C(=O)OCc2cccc(Oc3ccccc3)c2)C12C=C(Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
Pyridine (1.68 g) and thionyl chloride (2.5 g) are added to a mixture of 3'-chloro-3,3-dimethyl-spiro[cyclopropane-1,1'-indene]-2-carboxylic acid (5.0 g; 0.02 mole) and ether (50 ml). After two hours at room temperature, pyridine (1.68 g) and m-phenoxybenzyl alcohol (4.0 g) are added and the reaction mixture stirred at room temperature overnight. The reaction mixture is then washed with water, the ether fraction dried over magnesium sulfate and evaporated to dryness. The residue is purified on a dry column (silica gel; 20% methylene chloride:hexane) to afford 3.0 g of title compound, a yellow-orange liquid. The sample is 90-95% pure by NMR, and shows an ester carbonyl stretch at 1730 cm-1 in IR.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)[CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(O)C.[Pd]>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH:24]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:36][C:37]([OH:39])=[O:38])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCCN2CCN(CC(=O)OC(C)(C)C)CCCN(CC1)CC(Cc1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Nc1ccc(CC2CN3CCCN(CC(=O)O)CCN(CCCN(CC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 145.7 %

Procedure:
To a solution of 51 (0.42 g, 0.58 mmol) in ethanol (50 mL) was added 10% Pd/C (0.13 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated under vacuum to give an oily residue which was triturated with Et2O to provide yellow solid 28 (0.39 g, 98% yield) (2 equiv TFA calculated on the basis of mass).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[S:37]([CH3:36])(=[O:39])=[O:38])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (198.3 mg) obtained in Example 23-4 was dissolved in anhydrous dichloromethane (4.0 ml) and added with triethylamine (0.142 ml) and methanesulfonyl chloride (0.060 ml), and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (192.0 mg) as a colorless oily substance.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]1[Cl:23])(C)(C)C.Cl.C=O.N>C(O)C>[Cl:23][C:11]1[N:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:14]2=[C:13]([C:15]#[N:16])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C#N)c(-c2ccccc2)c1Cl
Agent: C=O
Agent: Cl
Agent: N
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)c(Cl)n2c1CNCC2
Temperature: 90 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a suspension of 66.9 g (193 mmol) of tert-butyl{2-[2-chloro-4-cyano-3-phenyl-1H-pyrrol-1-yl]ethyl}carbamate in 150 ml of ethanol are added slowly 688 ml (2670 mmol) of aqueous 4N hydrochloric acid solution and the mixture is heated to 90° C. Evolution of gas is rapidly observed, and after 1 hour, the medium is clear. 6.44 g (71.5 mmol) of paraformaldehyde are then added and heating is continued for a further 4 hours. After cooling, the reaction medium is basified slowly by adding aqueous ammonia, the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a yellow solid, which is triturated in acetonitrile and then isolated by filtration. The filtrate is concentrated under reduced pressure and the solid residue obtained is triturated in acetonitrile and then isolated by filtration. The two batches of solid are combined to give 30.6 g of 6-chloro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in the form of a beige-coloured powder after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](=O)[CH3:14].[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([NH:19][CH2:18][CH:17]([OH:16])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=1)[CH3:14]
Reactant: COC(=O)c1ccc(CC(C)=O)c(Cl)c1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared as in Example 1b from 1-(2-chloro-4-carbomethoxyphenyl)propan-2-one (2.32 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.1 g). The compound crystallised from hexane m.p. 82°-94° as a 40:60 mixture of diastereoisomers. τ(CDCl3) 8.85 (3H,d,J=6 Hz), 6.8-7.6 (5H,m+2H replaceable by D2O), 6.1 (3H,s), 5.3 (1H,m), 2.7 (1H,d,J=8 Hz), 2.3-2.6 (4H,m), 2.1 (2H,d,J=8 Hz), 1.95 (1H,s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12](=[O:15])[CH2:13]Br)=[CH:4][C:3]=1[Cl:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:13][N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[OH:15])=[CH:4][C:3]=1[Cl:16]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1C(F)(F)F
Reactant: c1ccc(CNCCCCCCOCCc2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2ccccn2)Cc2ccccc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 43.6 %

Procedure:
1-[4-Amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromoethanone (2.1 g), N-[6-[2-(2-pyridinyl)ethoxy]hexyl]benzenemethanamine (2.20 g) and N,N-diisopropylethylamine (0.94 g) were stirred together in tetrahydrofuran (45 ml) for 24 h at room temperature under nitrogen. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (80 ml) and sodium borohydride (0.63 g) was added portionwise to the solution at 0° under nitrogen. The mixture was stirred for 1 h and then 2N hydrochloric acid (40 ml) was added. The solvent was evaporated in vacuo, the residue partitioned between 8% sodium bicarbonate solution (150 ml) and ethyl acetate (100 ml). The organic phase was separated, and the aqueous phase re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with toluene-ethanol-triethylamine (98:2:1) afforded the title compound as a yellow oil (1.59 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.CO.O1CCCC1.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[CH:37]=[C:36]([CH3:38])[CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol) and 1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (90.8 mg, 0.367 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.40 mmol), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration. The obtained slightly yellow solid was suspended in methanol (3 mL), and the mixture was stirred at 70° C. for 10 min. The suspension was collected by filtration, and the obtained solid was washed with methanol to give the title compound (122 mg, 72%) as a slightly yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH:4]([CH:5](OC(=O)C)[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]=1[CH3:33])=[O:18].C(OCC)C.CCCCC>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:34])[CH:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:22]=1[CH3:33])=[O:18]
Reactant: CC(=O)OC(C1C(C(=O)OCc2cccc(-c3ccccc3)c2C)C1(C)C)C(Cl)(Cl)C(F)(F)F
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1c(COC(=O)C2C(C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a solution of 38.4 mg (0.074 mmol) of the stereoisomer [RF 0.39 (CH2Cl2 /hexane=1/1)] of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoro-propyl)cyclopropanecarboxylate obtained in Example 11 and dissolved in 0.3 ml of DMF, 6 mg of zinc powder was added, and the mixture was stirred at 60° C. for 2.5 hours. After an addition of 2 ml of diethyl ether and 2 ml of pentane to the mixture, the inorganic salt was filtered off through a silica gel short column. The silica gel was washed with diethyl ether, and the organic layers were combined and concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/2) to obtain 29.8 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[C:11]([CH3:12])=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[O:9][N:8]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([NH:29][C:30]([C:22]2[C:17]([S:14]([NH:13][C:10]3[O:9][N:8]=[C:7]([CH3:6])[C:11]=3[CH3:12])(=[O:15])=[O:16])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccn2)c1C
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ncccc2C(=O)Nc2ccccc2)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
nBuLi (1.8 ml, 2.34M) was slowly added to a solution of N-(3,4-dimethyl-5-isoxazolyl)pyridine-2-sulfonamide (500 mg, 2.0 mmol) in THF (14 ml) at -78° C. The mixture was stirred at -78° C. for 1 hour. Phenylisocyanate (3.55 mg, 2.9 mmol) was then added slowly and the mixture was allowed to warm room temperature. The reaction was quenched with H2O and the volatiles were removed under reduced pressure. The aqueous residue was extracted with EtOAc (2×50 ml). The aqueous layer was acidified with concenrated HCl to pH 4(~50 ml) and extracted with EtOH (2×50 ml). The combined organic layer was dried (MgSO4), filtered and evaporated to give a yellow oil, which was purified by HPLC to give an 88% yield with a m.p. of 199°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[CH2:7][CH2:6][CH2:5]2.C1C=CC=CC=1.C(O)C.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CCOCC.[Pt]>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccccc1N1CCCc2cc(Br)ccc21
Agent: [Pt]
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: Nc1ccccc1N1CCCc2cc(Br)ccc21
Yield: 54.4 %

Procedure:
A Parr hydrogenation bottle was charged with 6-bromo-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (16.7 g, 0.050 mole), 1% platinum-on-carbon (1 g), benzene (100 ml) and ethanol (100 ml). The mixture was shaken under an initial hydrogen pressure of 58 psi until uptake ceased. The mixture was then filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was taken up in hot ether (150 ml), filtered, and the filtrate was treated with a hot solution of maleic acid (6.4 g, 0.055 mole) in ether (500 ml). The solution was boiled down to about 300 ml and allowed to cool. The supernatant was decanted from an oil, which separated. The supernatant was concentrated and the process was repeated several times to give 11.4 g (55%) of product. Recrystallization from ethyl acetate afforded the analytical sample, mp 113°-116° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=4)=[N:16][N:17]([CH3:19])[CH:18]=3)=[O:12])=[C:4]2[N:3]=1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:26][C:22]1[CH:21]=[C:20]([C:15]2[C:14]([NH:13][C:11]([C:10]3[CH:9]=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH:31][CH2:30][CH:27]5[CH2:29][CH2:28]5)=[N:3][C:4]=34)=[O:12])=[CH:18][N:17]([CH3:19])[N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cccc(Cl)c2)n1
Reactant: NCC1CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2cnn3ccc(NCC4CC4)nc23)c(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of the above crude 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, cyclopropylmethylamine (0.1 mL, 1.0 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in ethanol (5 mL) was heated at 120° C. by microwave irradiation. After 30 minutes, the reaction mixture was concentrated to dryness, and the resultant crude product was purified by reverse phase HPLC and lyophilized to give 95.7 mg (64%) of N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)-5-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=422.1; 1H NMR (500 MHz, DMSO) δ 9.62 (s, 1H), 8.58 (d, J=7.6, 1H), 8.20 (s, 1H), 8.14 (s, 2H), 7.75-7.59 (m, 2H), 7.46 (t, J=7.8, 1H), 7.42-7.34 (m, 1H), 6.41 (d, J=7.6, 1H), 3.90 (s, 3H), 2.62-2.54 (m, 2H), 0.76 (s, 1H), 0.38-0.24 (m, 2H), −0.14 (m, 2H).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:44][O:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[CH2:53][CH2:52][C@H:51]2[NH2:57])=[O:47]>ClCCl.C(OCC)(=O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([NH:57][C@H:51]2[C:50]3[C:54](=[CH:55][CH:56]=[C:48]([C:46]([O:45][CH3:44])=[O:47])[CH:49]=3)[CH2:53][CH2:52]2)=[O:12])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=C(O)c1cnn2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cnn3cccnc13)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.25 g, 1.533 mmol, 1 eq) was dissolved in dichloromethane (20 ml), and the mixture was cooled to 0° C. Then DIPEA (0.65 ml, 2.833 mmol, 2.5 eq), EDCI (0.34 g, 1.84 mmol, 1.2 eq) and HOBT (29 mg, 0.307 mmol, 0.2 eq) were added in succession and stirring was carried out for 15 min at RT. The reaction solution was cooled to 0° C. again, (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.34 g, 1.533 mmol, 1 eq), dissolved in dichloromethane (10 ml), was added, and the mixture was stirred for 16 h at RT. After monitoring by thin-layer chromatography, the reaction solution was diluted with ethyl acetate, washed in succession with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution (in each case 20 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 2:1) and the desired product (R)-methyl 3-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydro-1H-indene-5-carboxylate (B-07) was thus obtained. Yield: 85%
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[F:22][C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:29][C:26]1[CH:25]=[CH:24][C:23]([F:22])=[N:28][CH:27]=1)[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1ccc(F)nc1)OCC
Temperature: 100 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
Bromoacetaldehyde diethyl acetal (6.75 ml, 44.9 mmol) and cesium carbonate (30.9 g, 95.0 mmol) were added to an N,N-dimethylacetamide solution (60 ml) of 6-fluoropyridin-3-ol (3.0 g, 24.9 mmol, purity: at most 94%), and stirred under a nitrogen atmosphere at 100° C. for 15 hours. The reaction solution was cooled with ice, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=17:1 to 6:1) to obtain 5-(2,2-diethoxyethoxy)-2-fluoropyridine (5.67 g, yield: 99%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:28]N1C(=O)CCC1=O>ClCCl>[C:24]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[C:9]1[Cl:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Solvent: ClCCl
Product: CC(C)(C)n1c(Cl)c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pyrrolo[2,3-d]-pyrimidine (0.20 g), N-chlorosuccinimide (80 mg) and dichloromethane (5 ml) was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (95:5) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 7-(tert-butyl)-6-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo-[2,3-d]pyrimidin-4-ylamine, m.p. 136.8-137.8° C.
Reaction SMILES: C[Mg]Cl.[CH3:4][Zn]C.[CH2:7]([C@@H:10]1[CH2:14][C:13](=[O:15])[CH:12]=[CH:11]1)[CH2:8][CH3:9]>CCOCC.C1(C)C=CC=CC=1.C1COCC1>[CH3:4][C@H:11]1[C@H:10]([CH2:7][CH2:8][CH3:9])[CH2:14][C:13](=[O:15])[CH2:12]1
Reactant: C[Zn]C
Reactant: CCC[C@H]1C=CC(=O)C1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC[C@@H]1CC(=O)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Methylmagnesium chloride (7.1 ml of a 3M solution in ether, 21.3 mmol) was added slowly to a stirred solution of dimethylzinc (5.3 ml of a 2M solution in toluene, 10.6 mmol) in THF (80ml) under argon at 0° C. After 30 minutes the mixture was cooled to −78° C. and 2 (1.2 g, 9.7 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield 4 as a solution in toluene which was purified by column chromatography (SiO2, pentane-ether, 1:0 to 9:1 to give the cyclopentanone 4 (0.86 g, 63%). νmax(CDCl3)/cm−1 1733 (C═O).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][CH3:44]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:36](=[O:45])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43][CH3:44])=[N:3][C:4]([CH3:27])=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccccc1SC
Reactant: COCN(c1cc(Cl)c(C)nc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)c(C)nc1C(=O)c1ccccc1SC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (255 mg, 0.5 mmol) in anhydrous THF (3 mL) was added 2 M isopropylmagnesiumchloride in THF (600 μL, 1.2 mmol) at −40° C. It was then warmed to 0° C. and stirred at the same temperature for 1 h and then N-Methoxy-N-methyl-2-methylsulfanyl-benzamide (422 mg, 1.00 mmol) was added in and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO) to provide 4-chloro-N-[5-chloro-6-methyl-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. Mass spectrum m/z: 601.4 (M+Na).