Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37]>C(Cl)Cl>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:37]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCCN(C)C
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)CCN(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N,N′-trimethylethylenediamine (47 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 534 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:26][N:27]2[C:31]([CH3:32])=[CH:30][N:29]=[CH:28]2)[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:26][N:27]2[C:31]([CH3:32])=[CH:30][N:29]=[CH:28]2)[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CC(Cn2cncc2C)c2ccc(F)cc2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cncn1CC(Cc1ccc(C(=O)O)c(-c2ccccc2)c1)c1ccc(F)cc1

Procedure:
Product from step B in solution in methanol (25 ml) was treated at reflux for 2 hours with NaOH 2N (5.8 ml). After evaporation to dryness and neutralisation at pH6 with 6N HCl, the resulting solid was filtered and purified on reverse phase silica eluting with MeOH/(NH4)2CO3 buffer (2 g/l, pH7) 40/60 to give 4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-propyl]-2-phenyl-benzoic acid.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH:2]3[C:14]4[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=4[C:8]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=4)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCN(C(c3ccccc3)c3ccccc3)CC1)c1ccccc1-2
Reaction time: 20 h
Yield: 23.4 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (1.0 g, 4.26 mmol) was suspended in 10 ml of dry tetrahydrofuran, while cooling in an ice bath. 1-(Diphenylmethyl)piperazine (1.1 g, 4.26 mmol) dissolved in 10 ml of dry tetrahydrofuran was added over 10 min., thereafter triethylamine (0.59 ml, 4.26 mmol) in 3 ml tetrahydrofuran was added. The ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran to give 1.36 g of the crude product which was recrystallized two times from acetic acid to yield 0.45 g (20%) of the title compound as a hydrochloride. M.p. 212°14 216° C. 1H-NMR (DMSO-d6, δ): 2.5-3.3 (m, 8H), 4.64 (s, 1H), 5.62 (d, 1H), 7.1-7.9 (m, 14H), 11.25 (s, 1H), 11.74 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=O)C>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[NH:20]1[CH:21]=[C:17]([C:7]23[CH2:6][CH2:5][C:4](=[O:3])[CH:15]2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]3)[N:18]=[CH:19]1
Reactant: CCOC(=O)CCC1(c2c[nH]cn2)Cc2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Titanium tetrachloride (5.5 ml) was added dropwise to a stirred suspension of zinc powder (6.5 g) in dry tetrahydrofuran (300 ml) with ice cooling under a nitrogen atmosphere. The mixture was heated at reflux for one hour. 3-[2-(1H-Imidazol-4-yl)-1-oxoindan-2-yl]propionic acid ethyl ester (3.0 g) in 100 ml of dry tetrahydrofuran was then added to the refluxing mixture during 4 hours. After a further 2 hour reflux period, the reaction mixture was cooled to room temperature, quenched by cautious addition of 30 ml of methanol and the pH of the mixture was adjusted to 8-9 with aqueous sodium hydroxide solution. The slurry was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was stirred in aqueous hydrochloric acid at room temperature for 2 hours. Work-up of the reaction mixture gave the crude product, which was purified by flash chromatography using methylene chloride/methanol (97:3) as eluent. The yield was 1.2 g, m.p. 234-236° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38]O)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][Br:20])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
To a stirring solution of 550 mg (2.09 mmol, 1.3 equiv) of triphenylphosphine in 10 mL of acetonitrile at 0° C. is added 0.1 mL (1.93 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 383 mg (1.61 mmol) of (1-Benzyl-1H-indazol-3-yl) methanol, prepared as in Intermediate 15, in 5 mL of acetonitrile is added over 2 min. The resulting solution is stirred 1 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 305 mg of the title compound as a white solid: 1H NMR (CDCl3, 300 MHz) δ7.82 (d, 1H), 7.40-7.16 (m, 8H), 5.59 (s, 2H), 4.90 (s, 2H); Rf =0.75 in hexane/EtOAc 2/1.
Reaction SMILES: [Ag:1].[C:2]([CH:5]([CH:7]([C:9]([O-:11])=[O:10])[OH:8])[OH:6])([O-:4])=[O:3].[Na+].[Na+]>>[C:2]([CH:5]([CH:7]([C:9]([O-:11])=[O:10])[OH:8])[OH:6])([O-:4])=[O:3].[Ag+2:1]
Reactant: [Ag]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Product: [Ag+2]

Procedure:
This example illustrates the preparation of the silver coating solution that is used in Examples 5 and 6. Three (3) ml of a sodium tartrate solution (tartaric acid disodium salt dehydrate, obtained from Aldrich) dissolved in 20 ml distilled water) was added to 3 ml of a silver nitrate solution (silver nitrate dissolved in 10 ml distilled water) at 22° C. A white precipitate of silver tartrate formed rapidly. Concentrated ammonium hydroxide, 28% ammonia (obtained from EM Science), was added dropwise to the solution until the silver tartrate dissolved completely to give a clear solution of ammoniacal silver tartrate with a pH of approximately 12.
Reaction SMILES: [CH2:1]([P:14](=[O:25])([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[P:2](=[O:13])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7].C=O.[CH2:28](NCC)C>CO>[C:1]([P:2](=[O:13])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7])([P:14](=[O:25])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH2:28]
Reactant: CCNCC
Reactant: CCCCOP(=O)(CP(=O)(OCCCC)OCCCC)OCCCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCC)OCCCC)P(=O)(OCCCC)OCCCC
Yield: 65.8 %

Procedure:
6.95 g (17.4 mmol) of tetra-n-butyl methylenebisphosphonate, 2.61 (86.8 mmol) of paraformaldehyde and 1.27 g (17.4 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 46 hours. After the methanol is eliminated as described above in Example I, 4.72 g of tetra-n-butyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:31][C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Oc1ccc2ccccc2c1
Product: COc1cc(Nc2cncc(Oc3ccc4ccccc4c3)n2)cc(OC)c1OC
Yield: 38 %

Procedure:
Using Method X, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 2-naphthol, 78 mg of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:26][C:27]1[C:28]([CH3:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[CH3:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([NH:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]([OH:34])[C:28]=2[CH3:35])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C)c1N
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(C)ccc(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (intermediate III(k)) (400 mg, 1.5 mmol, 1.1 eq) in CH2Cl2 (8 mL) was added (COCl)2 (585 mg, 4.6 mmol, 3.3 eq) and DMF (3 drops). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent and the residue obtained was dissolved in THF (8 mL) and added dropwise to a solution of 3-amino-2,4-dimethylphenol (intermediate X(c)) (192 mg, 1.4 mmol, 1.0 eq) and NaHCO3 (587 mg, 7.0 mmol, 5.0 eq) in THF (6 mL) at 0° C. After the addition was complete the reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 10:1 to 5:1, then DCM: MeOH, 20:1) to give the title compound as a yellow solid (436 mg 82%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O>>[CH:18]([N:13]1[C:12]([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1cccs1
Product: CC(C)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 36.2 %

Procedure:
The title compound (46 mg) was prepared according to Example 189 using 208 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 187 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C14H19N3S, 261.13. found, m/z 262.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.70-7.69 (m, 1H), 7.25-7.23 (m, 1H), 7.15-7.14 (m, 1H), 4.65 (br s, 2H), 4.55-4.49 (m, 1H), 3.8-3.6 (m, 2H), 3.23-3.10 (m, 2H), 2.93-2.83 (m, 2H), 1.44-1.36 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:18]([N:19](C)[C:20](=O)C)=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[N:24](C)[C:25](=O)C>CS(C)=O>[Cl:8][C:9]1[C:18]([NH:19][CH3:20])=[CH:17][C:12]([C:13](=[O:14])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])=[CH:11][C:10]=1[NH:24][CH3:25]
Reactant: COC(=O)c1cc(N(C)C(C)=O)c(Cl)c(N(C)C(C)=O)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1cc(C(=O)CS(C)(=O)=O)cc(NC)c1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 3.8 g. of sodium hydride (50% suspension in oil) and 11.2 g of dimethylsulfone in 40 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. 9.4 G. of methyl 4-chloro-3,5-bis-(N-methylacetamido)benzoate were then added, and the mixture was stirred at 80° C. for 3 hours. The solution was diluted with 200 ml. of ice water, the precipitated material extracted with ethyl acetate, the ethyl acetate solution purified over aluminum oxide, evaporated and the residue recrystallized from methanol, there being obtained 4'-chloro-3',5'-bis(methylamino)-2-methylsulfonylacetophenone having a melting point of 165°-167° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:28][N:29]([CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([CH2:36][N:29]([CH2:28][C:24]3[NH:23][CH:27]=[CH:26][N:25]=3)[CH2:30][C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[CH:38][CH:39]=2)=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(N)cc1)Cc1ncc[nH]1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
The compound (150 mg) obtained in Example 34-3 was dissolved in DMF (3.0 ml) and then added with the compound (140 mg) synthesized in Example 2-2. To the mixture solution, HOBt (79.0 mg) and PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (681 mg) were added, followed by stirring at room temperature for 18 hours. After completion of the reaction, PS-carbodiimide was filtrated and DMF in the filtrate was then distilled off. The residue was added with chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The residue was brought into an anhydrous state using anhydrous sodium sulfate and then concentrated. Subsequently, the concentrated product was purified through column chromatography (chloroform/methanol), thereby obtaining the subject compound (105 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7]2.[H][H]>[Pd].C(O)C>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:10]1[C:11]2[C:6](=[CH:5][C:4]([NH2:17])=[CH:3][C:2]=2[F:1])[CH2:7][CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN1CCCc2cc(N)cc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (340 mg, 1.27 mmol) was weighed into a round bottom flask equipped with a stir bar. Ethanol (8 mL) was added, followed by Pd (10 wt. % on activated carbon). The flask was fitted with a balloon of hydrogen, evacuated of air and backfilled with hydrogen. The reaction mixture was stirred for 2 h at room temperature under balloon pressure. The reaction mixture was then filtered through a pad of celite and the pad washed with methanol. The filtrate was concentrated, then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in dichloromethane. Yield: 270 mg, 89%. ESI-MS: 238 (MH+, 100), 193 (37), 147 (31).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]2=[N:18]1.N1C=CC=CC=1.[C:34](Cl)(=[O:38])[C:35]([CH3:37])=[CH2:36]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:34](=[O:38])[C:35]([CH3:37])=[CH2:36])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]2=[N:18]1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc2nn(-c3cc(OCCCO)cc(C(C)(C)C)c3O)nc2c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCOc1cc(-n2nc3ccc(OC)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer, a thermometer and an addition funnel which was protected from moisture with a drying tube were placed 37.16 g (0.1 mol) of the benzotriazole of Example 3, 800 mL of dry toluene and 17 mL (0.21 mol) of dry pyridine. A solution of 13 mL (0.128 mol) of methacryloyl chloride (freshly distilled) in 10 mL of toluene was added to the mixture over 30 minutes. The reaction mixture was stirred overnight at room temperature (<25° C.). A white precipitate (pyridinium chloride) was separated by filtration and washed with toluene. The filtrate and washings were combined, washed with 1N hydrochloric acid, water, aqueous sodium bicarbonate and water successively, then dried with anhydrous sodium sulfate and evaporated. The residue (ca. 41 g) was dissolved in a mixture of 1 L of methanol and 500 mL of methylene chloride by heating in a water bath at 45° C. The resulting solution was filtered to remove a small amount of insoluble materials and diluted with 250 mL of methanol. The solution was cooled slowly at room temperature, in a refrigerator and finally then placed in a freezer where the temperature was reduced to about -5° C. The resulting crystals were separated by filtration, washed with 250 mL of cold methanol/methylene chloride (90/10 v/v) and dried in vacuo to give 38.4 g of 99.7% pure product m.p. 114°-116° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1.[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O>O1CCCC1>[CH3:15][O:16][C:17]1[N:22]=[C:21]([NH:23][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[OH:24])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(N)n1
Reactant: O=Cc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(NCc2ccccc2O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
512 mg (2.41 mmol, 1.5 eq) of sodium triacetoxyborohydride are added to a solution of 200 mg (1.61 mmol, 1 eq) of 6-methoxypyridin-2-ylamine (starting material 1) and 236 mg (2.41 mmol, 1 eq) of 2-hydroxybenzaldehyde (starting material 2) in 20 ml of tetrahydrofuran. The solution is stirred at room temperature for 48 h. It is evaporated and the residue is taken up in 100 ml of dichloromethane and then extracted with a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined and dried over sodium sulphate. The residue is chromatographed on silica gel (5/95 ethyl acetate/heptane). 2-[(6-methoxypyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid. Melting point=103° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31](Cl)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: COCCn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 60% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (71 mg, 76%) as a white foam: [α]30589=−90.0° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.19 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.61 (t, J=5.1 Hz, 2H, OCH2), 3.95 (m, 1H, ArCHCO), 4.12 (t, J=5.1 Hz, 2H, NCH2), 6.42 (d, J=2.0 Hz, 1H, Ar), 7.55 (d, J=2.0 Hz, 1H, Ar), 7.62 (d, Jo=8.1 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.1 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[NH:30][C:29]([C:31]5[N:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].C1C=C[C:46]2[N:51](O)[N:50]=[N:49][C:47]=2[CH:48]=1.N1C=C(C(O)=O)N=N1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.C(O)(=O)C>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]5[NH:30][C:29]([C:31]6[N:36]=[CH:35][CH:34]=[CH:33][N:32]=6)=[N:28][N:27]=5)[CH2:24][CH2:25]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[C:48]([C:47]5[N:49]=[N:50][NH:51][CH:46]=5)=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: On1nnc2ccccc21
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Agent: O=C(O)c1c[nH]nn1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2cc3c(ccn4c(-c5c[nH]nn5)nnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5ncccn5)[nH]4)CC3)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 11-3 (0.2 g, 0.36 mMol), HOBT (0.05 g, 0.4 mMol), and 1H-1,2,3-triazole-4-carboxylic acid (0.05 g, 0.4 mMol) in anhydrous DMF (2 mL) was added DIEA (0.18 mL, 1.1 mMol) followed by EDC (0.08 g, 0.4 mMol). The solution was heated in the microwave reactor for 30 minutes at 80° C. Solution was then treated with 0.5 mL of acetic acid and was heated to 80° C. in the microwave reactor for 10 min. Upon cooling to room temperature, the solution was passed through a syringe filter and purified on a C18 reverse phase HPLC to give 11-4 as a solid. Mass (M+1) calculated: 632.2742 observed: 632.274