Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([CH:30]1[CH2:35][C:34](=O)[O:33][C:31]1=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC=CC=1>O>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][N:21]2[C:34](=[O:33])[CH2:35][CH:30]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:31]2=[O:32])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCCCCCCCC1CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
A mixture of 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (12.1 g, 41.1 mmol), 2-octylsuccinic anhydride (9.0 g, 41.1 mmol) and 20 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The solvent was removed under vacuum while heating the reaction mass. 18.7 g of a very viscous, clear yellow liquid was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:3]([OH:5])=[O:4].C(O)(=O)C>O>[O:11]=[C:9]1[NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][CH2:8]1
Reactant: N[C@@H](CCCC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC[C@@H](C(=O)O)N1
Yield: 45 %

Procedure:
A mixture of (S)-2-amino-hexanedioic acid (50 g, 310.25 mmol), acetic acid (100 mL), and water (400 mL) water was refluxed for 3 h. The unchanged starting amino acid was filtered off (24 g) and the filtrate evaporated, dissolved in hot water (50 mL) and then cooled. A crystalline precipitate formed which was filtered to provide the title intermediate (20 g, 45% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCCl
Reaction time: 10 h
Yield: 243.5 %

Procedure:
A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Shanghai Bangcheng Chemical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) in 2500 mL of N,N-dimethylformamide was added drop-wise with an N,N-dimethylformamide solution of 1-bromo-3-chloropropane (795.9 g, 1.4 mol) while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice water slowly with vigorous stirring. The precipitate was filtered, washed with water, and dried to give 827.2 g solid. Yield: 93.8%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4](Cl)[N:3]=1.C(O)(C)C.O.[NH2:31][NH2:32]>O>[NH2:1][C:2]1[N:3]=[C:4]2[NH:31][N:32]=[CH:23][C:5]2=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[N:7]=1
Reactant: NN
Reactant: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c2cn[nH]c2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
In a disposable sealed tube was added 2-(2-Amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (96.0 mg, 0.25 mmol, 1.0 eq.), isopropanol (2.0 mL), and hydrazine monohydrate (0.02 mL, 0.35 mmol, 1.4 eq.). The reaction was sealed and heated to 80° C. After 2 hrs, the reaction was spiked with 0.01 mL of hydrazine monohydrate, resealed, and allowed to continue stirring at 80° C. overnight. The reaction was then cooled to RT and the resulting yellow precipitate was filtered and rinsed with cold EtOH to give crude 2-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide. The crude precipitate was then sonicated in 1.0 mL H2O, filtered, rinsed with an additional 1 mL H2O, and lyophilized overnight to give pure 2-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a pale yellow solid (30 mg, 34%). LC/MSD (HP Series 1100 MSD): Expected MW: 351, Observed M+H, 352.1, Retention time: 1.19 min. ANALYTICAL HPLC: >90%, Retention time: 3.58 min (8 minute run). 1H-NMR (d6-DMSO): 12.5 (br s, 1H), 10.42 (s, 1H), 8.15 (s, 1H), 7.80 (m, 2H), 7.59 (t, 1H), 7.41 (d, 1H), 6.01 (br s, 2H), 4.40 (rotamer d, 2H) ppm.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]1[NH:13]C(=O)OC(C)(C)C>O1CCOCC1.CO>[CH3:2][O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]1[NH2:13].[ClH:1]
Reactant: CO[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO[C@@H]1Cc2ccccc2[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.048 g, 1.2 mmol, 60% dispersion in mineral oil) was added to a mixture of the above intermediate in N,N-dimethylformate (2.3 mL) under N2. The mixture was stirred at r.t. for 10 min., and methyl iodide (0.075 mL, 1.2 mmol) was added. The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-30%) to afford tert-butyl (1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate [LCMS (M+Na)+: 286.1]. 2 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl (1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate in methanol (1 mL). The reaction mixture was stirred at r.t. overnight. The volatiles were removed under reduced pressure to afford the desired product as HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH2:28][O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C>C(#N)C>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH:32][CH:27]([CH2:26][NH:25][CH2:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Reactant: NCC1=Nc2ccccc2OC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1ccc2[nH]cc(CCCNCC3COc4ccccc4N3)c2c1
Yield: 52.1 %

Procedure:
To a solution of 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.52 g, 1.5 mmol) and 3-aminomethyl-1,4-benzoxazine (0.25 g, 1.5 mmol) [prepared in accordance with the procedure set forth in Ind. J. Chem., 13:462-467 (1975)] in acetonitrile (15 mL) was added triethylamine (0.42 mL, 3.0 mmol) at room temperature. The reaction mixture was allowed to reflux 18 h, cooled and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/methanol/NH4OH, 98/2/0.5) to afford 265 mg (52%) of the free base.
Reaction SMILES: CO.N1CC[CH2:6][CH2:5][CH2:4]1.Cl.Cl.[CH3:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:22])=[NH:19])=[CH:14][CH:13]=1>CC(C)=O>[CH2:24]([NH:23][C:21]1[NH:20][C:18]([NH:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([CH3:11])=[CH:33][CH:32]=2)=[N:19][C:5]([CH3:6])([CH3:4])[N:22]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(C)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C)cc2)N1
Yield: 47.2 %

Procedure:
40 ml of methanol, 80 ml of acetone and 16 ml (16.2 mmol) of piperidine were added to 3.0 g (7.7 mmol) of N1-(4-methylbenzyl)-N5-octyl-biguanide dihydrochloride, and the mixture was refluxed for 23 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform, methanol and acetic acid (9:0.5:0.5)). 50 ml of ethanol and 50 ml of water were added to the resulting colorless resinous solid, and the pH of the mixture was adjusted to 11 to 12 with 5N sodium hydroxide. The mixture was refluxed for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with water, and dried well under reduced pressure to obtain 1.3 g of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([OH:29])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:34]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([O:29][CH3:34])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 250 mg (0.578 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) in MeOH (3 mL) was added thionyl chloride (78.0 μl, 1070 μmol) dropwise at 0° C. After being stirred at 25° C. for 14 h, the reaction was diluted (EtOAc), basified (sat NaHCO3), extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=2)(=[O:25])=[O:24])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:27]=[C:26]([S:23]([NH:22][CH2:21][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:25])=[O:24])[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)c(Cl)c2)(c2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NCC1(c2ccc(I)cc2)CCNCC1)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of 4-[(3-chloro-4-fluoro-benzenesulfonylamino)-methyl]-4-(4-iodo-phenyl)-piperidine-1 carboxylic acid tert-butyl ester (0.09 g, 0.16 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added TFA (0.5 mL, to give a 25% v/v solution). The mixture was stirred at room temperature for 3 h. TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×10 mL), diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 solution (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and dried under high vacuum for 1 h to give 3-chloro-4-fluoro-N-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-benzenesulfonamide as a reddish solid (0.021 g, ˜0.04 mmol). MS: 509/511 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Cl.CN(C)CCCN=C=NCC.[CH:37](O)=[O:38]>O1CCCC1.C(Cl)Cl>[CH:37]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:38]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-3-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (171 mg) and formic acid (34 μL) in dry tetrahydrofuran (6 mL) is stirred at ambient temperature for one hour, diluted with methylene chloride (10 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 186-187° C.
Reaction SMILES: Br[C:2]1([CH3:19])[O:6][C:5]([CH3:17])([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)[O:4][C:3]1=[O:18].CN(C)C=O.C(OC(C)C)(C)C>>[CH2:19]=[C:2]1[O:6][C:5]([C:7]23[CH2:14][CH:13]4[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]4)[CH2:16]2)[CH2:8]3)([CH3:17])[O:4][C:3]1=[O:18]
Reactant: CC1(Br)OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
16.5 g (0.05 mol) of the obtained 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one was placed in a 100 ml egg-plant type flask, and 73.1 g (1.0 mol) of N,N-dimethylformamide was added thereto, followed by intensively stirring at 40° C. for 2 hours. After completion of the stirring, the mixture was transferred into a 500 ml separatory funnel, and 200 g of isopropyl ether was added thereto, followed by fully shaking. Thereafter, the obtained mixture was left at rest, so as to separate the mixture into two layers. And then, the N,N-dimethylformamide phase that was a lower layer was removed. The isopropyl ether phase that was a upper layer washed with water to remove N,N-dimethylformamide dissolved therein. Thereafter, isopropyl ether was removed, so as to obtain white crystals. The obtained white crystals were recrystallized from hexane, so as to obtain 10.9 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one at a purity of 99.8% (Formula (19), yield: 88%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:30]S(C(C)(C)C)=O)([C:24]2[N:25]([CH3:29])[CH:26]=[N:27][CH:28]=2)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)=[CH:5][C:4]=1[F:37])#[N:2].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:30][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:37])[CH:5]=1)([C:24]1[N:25]([CH3:29])[CH:26]=[N:27][CH:28]=1)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1
Reactant: COc1cccc(CCNCCCC(NS(=O)C(C)(C)C)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1cncc1C(N)(CCCNCCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-propane-2-sulfinic acid [1-(4-cyano-3-fluoro-phenyl)-4-[2-(3-methoxy-phenyl)-ethylamino]-1-(3-methyl-3-H-imidazol-4-yl)-butyl]-amide (0.075 g, 0.1427 mmol) was dissolved in CH2Cl2 (7 mL) with cooling in an ice-H2O bath, then treated with BBr3 (1 mL of a 1M solution in CH2Cl2, 1 mmol). After 15 min., H2O (3 mL) was added and the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH and stirred at ambient temperature for 15 min. Concentration to dryness gave the title compound which was used without further purification. MS (M+1) 408.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][CH2:25]Br)[N:22]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[CH3:31][NH:32][CH3:33]>C(#N)C>[CH3:31][N:32]([CH3:33])[CH2:25][CH2:24][CH2:23][N:21]1[N:20]=[N:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:30])[C:6]=3[CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=2)=[N:22]1
Reactant: CNC
Reactant: CCCc1c(COc2ccc(-c3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Solvent: CC#N
Product: CCCc1c(COc2ccc(-c3nnn(CCCN(C)C)n3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
5-[4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl]-2-(3-bromopropyl)-2H-tetrazole (2.8 g, 0.006 mol) was dissolved in acetonitrile and cooled to 10 approximately 0° C. Dimethylamine (anhydrous, excess) was cooled in the reagent bottle before it was opened then added to the cool acetonitrile solution. The solution was maintained at approximately 0° C. with an ice bath while it was stirred (approximately 5 hours). The reaction mixture was then concentrated in vacuo. Water was added and the resultant solution was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and dried over sodium sulfate. The dried ethyl acetate layers were concentrated and the resultant residue was chromatographed by HPLC (preparatoryscale, silica gel column, eluted isocratically with a mixture of 9.5 : 0.5 methylene chloride:methanol to which 0.05% of diethylamine had been added to yield 2.3 g, 88.5% yield of the title product: m.p. 89°-91° C.; n.m.r.: (300 MHz, CDCl3) δ: 1.0 (t, 2H); 1.6 (m, 2H); 2.1 (t, 2H); 2.2 (s, 6H); 2.3, (t, 2H); 2.4 (t, 2H); 2.6 (s, 3H); 2.7 (t, 2H); 4.7 (t, 2H); 5.2 (s, 2H); 7.1 (2d, 3H); 7.6 (d, 1H); 8.1 (d, 2H); 12.7 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.CCN(CC)CC.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:18]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCCc1ccc(Br)cc1)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a mixture of 2-(4-bromophenyl)ethanol (1.00 g, 4.97 mmol, 1.00 equiv) and Et3N (0.763 ml, 0.554 g, 5.47 mmol, 1.10 equiv) in a round-bottom flask in THF (20 ml) was added benzoyl chloride (0.589 mL, 0.713 g, 5.07 mmol, 1.02 equiv). The reaction mixture was stirring for 4 h at 23 ° C. and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:1 (v/v) to afford 1.50 g of the title compound as a colorless solid (99%). Rf=0.7 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.00 (d, J=7.2 Hz, 1H), 7.58-7.54 (m, 1H), 7.45-7.42 (m, 4H), 7.16 (d, J=8.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 3.04 (t, J=6.4 Hz, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 166.6, 137.1, 133.1, 131.8, 130.8, 130.3, 129.7, 128.5, 120.6, 65.2, 34.8.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[NH:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH2:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:36][NH:35][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC(=O)OC(C)(C)C)ccn34)c12
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylicacid (250 mg, 0.550 mmol) in DMF (5 mL) was added tert-butyl hydrazinecarboxylate (80.0 mg, 0.605 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (116 mg, 0.605 mmol), 1H-benzo[c/][1,2,3]triazol-1-ol hydrate (92.7 mg, 0.605 mmol) and triethylamine (66.8 mg, 0.660 mmol). The reaction mixture was stirred overnight and concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) provided tert-butyl 2-(3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carbonyl)hydrazinecarboxylate (188 mg), to which was added TFA/DCM (2 mL/3 mL). The mixture was stirred for 30 minutes and concentrated to give the product as the TFA salt (156 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:41][C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 0.908 ml benzyl bromoacetate and 3.571 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:11]2[CH2:12][C:8]3([CH2:9][CH2:10]2)[CH:4]([CH2:5][CH2:6][C:7]3=[O:13])[C:3]1=[CH2:14].C(O)=O>CCCCC>[CH3:14][C:3]1[C:2]([CH3:1])([CH3:15])[CH:11]2[CH2:12][C:8]3([CH2:9][CH2:10]2)[C:4]=1[CH2:5][CH2:6][C:7]3=[O:13]
Reactant: C=C1C2CCC(=O)C23CCC(C3)C1(C)C
Solvent: O=CO
Solvent: CCCCC
Product: CC1=C2CCC(=O)C23CCC(C3)C1(C)C

Procedure:
350 mg of 7,7-dimethyl-6-methylene-tricyclo[6.2.1.01,5 ]undecan-2-one (see example 1) were heated at 40° for 5 days in the presence of 20 ml of 98% formic acid. After the usual treatments of extraction, washing, drying and evaporation, there were isolated 330 mg of crude material (purity 90%). The pure compound was obtained after cristallization in n-pentane.