Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][N:33]1[C:37]([CH3:38])=[C:36]([CH:39]=O)[CH:35]=[N:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:32][N:33]1[C:37]([CH3:38])=[C:36]([CH2:39][NH:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=3)[CH2:6][CH2:7]2)[CH:35]=[N:34]1
Reactant: Cc1c(C=O)cnn1C
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CN[C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)cnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) and 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (23 mg, 0.19 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 1 h. NaBH(OAc)3 (200 mg, 0.95 mmol) was then added to the reaction mixture and stirred for another 16 h. The reaction mixture was diluted with 1M Na2CO3 to pH 9-10 and the organic phase was separated. The aqueous phase was extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 54 mg (52%) of the title compound as a pale yellow foam, m/z 549.7 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH2:35][C:36](O)=[O:37])[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:3]1[C:2]([N:1]2[C:36](=[O:37])[CH2:35][N:30]([CH3:29])[CH2:31][C:32]2=[O:33])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[N:4]=1
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl
Reactant: CN(CC(=O)O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))-amino]ethyl}amine, and 2 mmol of methyliminodiacetic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]-4-methylpiperazine-2,6-dione.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([Cl:11])[Cl:10])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:3]=1.[Cl:16]C1N=C(Cl)C=C(C(Cl)(Cl)Cl)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]([Cl:16])([Cl:10])[Cl:11])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:13])[Cl:14])[N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reactant: Clc1nc(OC(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Product: Clc1nc(OC(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Yield: 83 %

Procedure:
According to the gas chromatogram, the filtrate (113.8 g) consisted of 83% of the title compound, 4% of 2-chloro-4-dichloromethoxy-6-trichloromethylpyrimidine and 9% of 2,4-dichloro-6-trichloromethylpyrimidine. The total yield of the title compound was 87.6% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.[Zn](C)[CH3:30]>C1COCC1.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:21][C:19]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:20]
Reactant: C[Zn]C
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3ccccc23)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1 (94 mg, 0.237 mmol) and PdCl2(dppf) (18 mg, 0.047 mmol) in THF (1 ml) at room temperature was added ZnMe2 in toluene (1.2 M, 0.4 mL). The reaction mixture was stirred at 50° C. for 2 h. A second portion of ZnMe2 (0.6 mL) and PdCl2(dppf) (18 mg) was added. The reaction was heated at 50° C. for 3 h, cooled and quenched by sat. aqueous NaHCO3. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated. Purification by reverse-phase HPLC (C-18 column, 5-90% MeCN in H2O with both containing 0.05% TFA) provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.0 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.13 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.60 (d, J=7.6, 1H), 7.30 (dd, J=2.4, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 4.45 (s, 2H), 3.92-3.84 (m, 1H), 3.61-3.57 (m, 1H), 2.51 (s, 3H), 2.17-2.12 (m, 2H), 1.82-1.79 (m, 2H), 1.54-1.23 (m, 4H). HRMS (ES) [M+1]+ calcd for C23H25N3O2: 376.2020, Found: 376.2010.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[C:18]([S:25](O)(=[O:27])=[O:26])=[CH:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:29][CH3:30])[C:4]1=[O:5])[CH3:2].[NH3:31]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[C:18]([S:25]([NH2:31])(=[O:27])=[O:26])=[CH:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:29][CH3:30])[C:4]1=[O:5])[CH3:2]
Reactant: N
Reactant: CCn1c(=O)c2c(nc(/C=C/c3cc(OC)ccc3S(=O)(=O)O)n2C)n(CC)c1=O
Product: CCn1c(=O)c2c(nc(/C=C/c3cc(OC)ccc3S(N)(=O)=O)n2C)n(CC)c1=O
Yield: 6 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (2.30 mmol) of Compound 16 obtained in Example 15 and 0.7 ml of conc. aqueous ammonia. The resulting crude crystals were purified by high performance liquid chromatography (column: YMC-pack, SH-365-10, 30 i.d.×500 mm, eluent: 40% acetonitrile/water, flow rate: 40 ml/min) to give 55 mg (yield 6%) of Compound 17 as a pale yellow powder.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C>ClCCl>[CH2:22]([C:19]1[N:18]=[C:17]([CH:16]=[CH:15][C:9]2[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=2)[O:21][N:20]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: -42.5 °C
Reaction time: 0.29 h

Procedure:
To a cooled solution of 0.06 mL of boron tribromide (0.6 mmol) in 2 mL dichloromethane, 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-nonyl-[1,2,4]oxadiazole (compound of Example 33; 0.1 g, 0.27 mmol) dissolved in 8 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45 to −40° C. for 15-20 min and allowed to attain a temperature of 25° C. to 30° C. over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After the completion of the reaction, the reaction mixture was quenched in 20 mL of chilled 5% sodium bicarbonate solution at a temperature below 20° C. (pH 8-9). 10 mL of ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].C1(=O)O[CH2:12][CH2:11][O:10]1>>[OH:10][CH2:11][CH2:12][O:7][C:1](=[O:8])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: CC/C=C/CC(=O)O
Reactant: O=C1OCCO1
Product: CCC=CCC(=O)OCCO

Procedure:
For instance, we treated trans-3-hexenoic acid (a low molar mass model compound for HTBN) with ethylene carbonate in the presence of a phase transfer catalyst to yield 2-hydroxyethyl-3-hexenoate. More specifically, trans-3-hexenoic acid (about 1.14 grams; about 0.001 moles, commercially available from Aldrich Chemical Co., Milwaukee, Wis.), ethylene carbonate (about 0.97 grams; about 0.001 moles) and phase transfer catalyst were added to a 25 ml reaction flask containing a magnetic stirrer. The mixture was stirred at elevated temperature conditions to effect the hydroxyethylation reaction of the hexenoic acid. The reaction yields were estimated from the 1H NMR spectrum of the crude product mixture.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[C:6]1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([N:5]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[C:6]1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(CC)ccc1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCCn1c(CC)ccc1C(=O)c1cccc(N)c1
Yield: 61.6 %

Procedure:
A solution of 11.9 g (39 mmol) of 1-butyl-2-(3'-nitrobenzoyl)-5-ethylpyrrole in 100 ml of methanol was hydrogenated at 45 p.s.i. in the presence of 3 g of 10% palladium-charcoal catalyst for 1 hour. The catalyst was then separated by fltration and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using hexane-acetone (95:5) as eluant, to produce 6.5 g (60%) of 1-butyl-2-(3'-aminobenzoyl)-5-ethylpyrrole, the pure title compound, which was recrystallized from hexane. M.P. 71°-7° C.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-pyrimidinyl)amino)ethoxy]benzaldehyde (1.7 g) and 2,4-thiazolidinedione (0.7 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 189-90° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11]C=[CH:9][C:8]=2OC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[S:17]1CCC(NN)CC1>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][S:17][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: NNC1CCSCC1
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Product: N#Cc1cnn(C2CCSCC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-(tetrahydro-2H-thiopyran-4-yl)hydrazine provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.44 (s, 1H), 4.71 (s, 2H), 3.84-3.76 (m, 1H), 2.80-2.63 (m, 4H), 2.24-2.10 (m, 4H). MS: (M+H m/z 209.1).
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:3](=[O:5])[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[F:1])[CH3:13]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)C(F)c1ccccc1
Product: CCOC(=O)[C@H](C)NC(=O)C(F)c1ccccc1

Procedure:
Following General Procedure BF above, and using α-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.75 in 1:1 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:14]([CH3:19])[CH:13]=1
Reactant: CC1CCN(CCN)CC1
Reactant: Cc1cc(Br)ccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(Br)ccc1NCCN1CCC(C)CC1

Procedure:
5.00 g (35.00 mmol) of 2-(4-methylpiperidin-1-yl)ethylamine was added under argon to a mixture of 10.39 g (35.00 mmol) of 4-bromo-1-iodo-2-methylbenzene, 0.33 g (1.75 mmol) of CuI, 30.0 g (141.00 mmol) of potassium phosphate, and 4.34 g (70.00 mmol) of ethylene glycol in 35 mL of isopropanol and the mixture was refluxed for 15 hours. The reaction mixture was evaporated down in vacuo and the residue taken up in EtOAc. The organic phase was washed with 5% aqueous ammonia, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, EtOAc). Yield: 1.20 g (11% of theoretical); C15H23BrN2 (M=311.261); calc.: molpeak (M+H)+: 311/313 (Br); found: molpeak (M+H)+: 311/313 (Br); HPLC-MS: 4.24 minutes (method B).
Reaction SMILES: [OH-].[Na+].[N:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12]([O:14]CC)=[O:13])[CH:4]=1>C(O)C>[N:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: CCOC(=O)c1cnn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2ccccc12
Yield: 76.7 %

Procedure:
A 2.5 N aqueous solution of sodium hydroxide (36 mL) was added to a solution of ethyl pyrazolo[1,5-a]pyridine-3-carboxylate (Preparation 22a, 4.3 g, 22.6 mmol) in ethanol (70 mL) and the resulting reaction mixture was heated to reflux for 1 h. After evaporation of the ethanol, the reaction mixture was acidified with 15% aqueous hydrochloric acid solution. The solid formed was filtered, washed with water and diethyl ether and dried to give the title compound (2.81 g, 77%) as a pale pink solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([C:25]1[CH:26]=[CH:27][C:28]([Br:31])=[N:29][CH:30]=1)(=[O:24])[CH3:23]>C1COCC1>[Br:1][CH2:23][C:22]([C:25]1[CH:30]=[N:29][C:28]([Br:31])=[CH:27][CH:26]=1)=[O:24]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(Br)nc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 206.1 %

Procedure:
Add pyridinium tribromide (7 g, 22 mmol) to a solution of 5-acetyl-2-bromo-pyridine (4 g, 20 mmol) in THF (100 mL) at room temperature. Stir the mixture for 16 h at ambient temperature under a nitrogen atmosphere. Quench the mixture with saturated aqueous NaHCO3 (50 mL, pH at 7.8). Extract the mixture with EtOAc (150 mL). Wash the organic layer with brine (50 mL) and concentrate in vacuo to obtain the desired intermediate as a dark brown oil (11.5 g) that was used without further purification. MS (ES+) m/z: 280.0 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH2:16][CH2:17][CH2:18][N:14]3[C:13](=[O:19])[C:12]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:28][O:29][CH2:30][C@@H:31]([NH2:33])[CH3:32]>C1(C)C=CC=CC=1>[CH3:28][O:29][CH2:30][C@@H:31]([NH:33][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH2:16][CH2:17][CH2:18][N:14]3[C:13](=[O:19])[C:12]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:8]=[CH:7][N:6]=1)[CH3:32]
Reactant: Cc1ccccc1Oc1c(-c2ccnc(S(C)(=O)=O)n2)n2n(c1=O)CCC2
Reactant: COC[C@H](C)N
Solvent: Cc1ccccc1
Product: COC[C@H](C)Nc1nccc(-c2c(Oc3ccccc3C)c(=O)n3n2CCC3)n1
Temperature: 115 °C

Procedure:
To a solution of 3-(2-methanesulfonyl-pyrimidin-4-yl)-2-o-tolyloxy-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 3, (0.11 g, 0.28 mmol) in toluene (4 mL) is added (S)-1-methoxy-2-propylamine (0.10 g, 1.13 mmol). The reaction mixture is heated to 115° C. for 24 h. The solvent is removed in vacuo and the resulting residue is purified by preparative HPLC to afford 52 mg of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=5.1 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 7.16 (d, J=5.4 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 4.29-4.21 (m, 1H), 4.17 (t, J=7.2 Hz, 2H), 4.01 (t, J=7.2 Hz, 2H), 3.50 (dddd, J=9.3, 9.3, 4.5, 4.5 Hz, 2H), 3.42 (s, 3H), 2.69 (dt, J=7.2 Hz, 2H), 2.46 (s, 3H), 1.31 (d, J=6.6 Hz, 3H); ESI+ MS: m/z (rel intensity) 396.2 (90, M++H); Anal Calcd for C21H25N5O3: C, 63.78; H, 6.37; N, 17.71. Found: C, 63.63; H, 6.20; N, 17.05.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=O)C1CCN(c2nc(Cl)nc3[nH]ccc23)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.744 mmol), isonipecotamide (95 mg, 0.742 mmol) and triethylamine (0.300 mL, 2.15 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. The precipitates were collected and dried on vacuum to give 1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (205 mg). MS 280.3 and 282.3 (M+H, Cl pattern).
Reaction SMILES: C[C:2]1[O:3][C:4](=O)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.FC(F)(F)[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>CCOC(C)=O.CCCCCC>[C:17]1([N:18]2[CH:4]=[C:5]3[C:6]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[N:7][C:2]2=[O:3])[CH:19]=[CH:20][CH:21]=[CH:15][CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1nc2ccccc2cn1-c1ccccc1
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of 2-methyl-4H-Benzo[d][1,3]oxazin-4-one (12; 1.0 g, 6.2 mmol) and 3-trifluoromethylaniline (13, R═H, 0.77 mL, 6.2 mmol, 1.0 eq) were heated at 160° C. (oil bath) for 12 hours. The reaction was cooled to room temperature and the resulting solid was subjected to chromatography on silica gel with 20-50% EtOAc/hexane. Product-containing fractions were pooled and evaporated to yield 1.08 g mg (56%) of 14 as a yellow solid: 1H NMR (CDCl3): 8.27 (d, 1H), 7.29-7.28 (m, 7H), 2.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)[CH:6]=1.P(Br)(Br)[Br:17]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:17][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]2)=[CH:9][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Cn2cc(Cl)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cnn(Cc2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of (4-((4-chloro-1H-pyrazol-1-yl)methyl)phenyl)methanol (0.375 g, 1.68 mmol) in methylene chloride (7 mL) at 0° C. under a nitrogen atmosphere was treated with PBr3 (0.456 g, 1.68 mmol) and the mixture was warmed to rt and stirred for 1 h. After this time, the mixture was diluted with saturated aqueous sodium bicarbonate and ice and then extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0.342 g, 91%) as a white solid. MW=285.57. 1H NMR (CDCl3, 500 MHz) δ 7.46 (s, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.19 (d, J=8.1 Hz, 2H), 5.24 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[OH:24][CH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:25][OH:24])[CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(CO)c4)c(C(=O)O)s3)c2cc1OC
Yield: 1.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-hydroxymethylphenylboronic acid (22.9 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-hydroxymethyl-phenyl)-thiazole-5-carboxylic acid (0.8 mg, 2.0%) as a white solid. MS 412 m/z (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:27][NH2:28].C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:17])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][CH2:27][C:26]([F:33])([F:25])[C:29]([F:32])([F:31])[F:30])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)C(F)(F)F
Yield: 81.1 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.94 g (0.013 mol) of 2,2,3,3,3-pentafluoropropylamine, 1.81 ml (0.013 mol) of triethylamine in 30 ml of DMF were reacted at 50° C. for 64 hours, affording 5.36 g of oil. This oil was purified by HPLC using 1% ethyl acetate/cyclohexane as eluting solvent to give 1.82 g of oil which was kugelrohr distilled at 41 Pa, pot temperature 95° C., to give 1.55 g (23.4%) of product as a clear oil, n25D 1.4351.