Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:33]([CH3:45])[CH:32]=3)=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]3[N:49]=[C:50]([CH3:52])[N:51]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[C:33]([CH3:45])[CH:32]=3)=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]3[N:49]=[C:50]([CH3:52])[N:51]=[C:24]23)[CH2:19][CH2:18]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)c(C)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogen carbonate (1.21 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-methylbiphenyl-2-carbonitrile (0.41 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.26 g, 58%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([CH:32]=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][CH:29]([CH:32]=[CH2:1])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCC1CCC(C=Cc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(C=CC3CCC(CCCCC)CC3)cc2)CC1

Procedure:
Potassium tert-butoxide (1.0 eq, 0.44 g, 3.62 mmol) was added slowly with stirring for 3 minutes to 32 ml of solution including methyltriphenylphosphonium bromide (1.2 eq, 1.55 g, 4.33 mmol) dissolved in THF. Then, the solution was stirred for 30 minutes at a room temperature and THF solution (35 ml) of trans-4-{4-[2-(4-pentyl-cyclohexyl)ethenyl]phenyl}cyclohexane carbaldehyde (1.32 g, 3.62 mmol) obtained in Example 4-2 was added slowly dropwise for 10 minutes to reaction mixture, and then was stirred at a room temperature for 24 hours. The white precipitate was filtered under reduced pressure and the filtrate was washed by water (100 ml) and extracted with ether (20 ml×1 time) The aqueous layer was extracted by chloroform (20 ml×3 times). The organic layer was collected, washed by water (30 ml×2 times) and salt water (brine, 20 ml×1 time), dried by anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane, Rf=0.36). The remnant was dissolved in chloroform (3 ml), and cold ethanol (8 ml) was added dropwise by pipette and stirred with glass rod to recrystallize 1.02 g (77%) of 1-[2-(4-pentyl-cyclohexyl)ethenyl]-4-(4-vinyl-cyclohexyl)benzene.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:37]1
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 4-(2,4-difluorobenzyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=478.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.30 (m, 4H), 2.36 (m, 4H), 2.67 (t, 2H, J=6.8 Hz), 3.47 (s, 2H), 4.22 (t, 2H, J=6.8 Hz), 6.58 (d, 1H, J=3.6 Hz), 6.72 (m, 1H), 7.06 (dt, 1H, J=8.4 Hz and 2.0 Hz), 7.14 (d, 1H, J=3.2 Hz), 7.20 (m, 2H), 7.42 (dd, 1H, J=15.2 Hz and 8.0 Hz), 754 (br s, NH2), 7.93 (s, 1H). Anal. calculated for (C24H24F2N80+0.5 H2O): C, 59.13; H, 5.17; F, 7.79; N, 22.98; O, 4.92. Found C, 58.84; H, 4.97; N, 22.63.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([F:50])=[CH:29][C:30]([Cl:49])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[Cl:49][C:30]1[C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:46][CH2:47]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:48][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5]3)[CH:7]=2)=[C:28]([F:50])[CH:29]=1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c(Cl)cc3F)c2)CC1
Yield: 71.8 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (100 mg, 0.50 mmol), oxalyl chloride (55 μL, 0.62 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (160 mg, 73%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:39]=[C:38]([Br:40])[C:21]3[N:22]=[CH:23][N:24]([CH2:25][C:26]4[CH:31]=[C:30]([NH:32][C:33](=[O:36])CBr)[CH:29]=[CH:28][C:27]=4[F:37])[C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[SH:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48].[CH2:51](Cl)Cl>>[CH3:50][O:49][C:47](=[O:48])[CH2:46][CH2:45][SH:44]([C:33](=[O:36])[NH:32][C:30]1[CH:29]=[CH:28][C:27]([F:37])=[C:26]([CH2:25][N:24]2[C:20]3[CH:19]=[C:18]([S:15]([C:13]4[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:43])=[NH:9])[S:11][C:12]=4[S:41][CH3:42])(=[O:16])=[O:17])[CH:39]=[C:38]([Br:40])[C:21]=3[N:22]=[CH:23]2)[CH:31]=1)[CH3:51]
Reactant: ClCCl
Reactant: COC(=O)CCS
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3cc(NC(=O)CBr)ccc3F)c2c1
Product: COC(=O)CC[SH](C)C(=O)Nc1ccc(F)c(Cn2cnc3c(Br)cc(S(=O)(=O)c4cc(C(=N)NC(=O)OC(C)(C)C)sc4SC)cc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of [(4-{7-bromo-3-[5-(2-bromo-acetylamino)-2-fluoro-benzyl]-3H-benzoimidazole-5-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester ((Example 191: step a) 0.014 g, 0.017 mmol) in CH2Cl2 (2 mL) was treated with methyl 3-mercaptopropionoate (2.50 μL, 0.025 mmol) and stirred at room temperature 30 min. The reaction was diluted with CH2Cl2 and washed with water (1×10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 3-[(3-{4-bromo-6-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazol-1-ylmethyl}-4-fluoro-phenylcarbamoyl)-methylsulfanyl]-propionic acid methyl ester (0.011, 85%) as a tan solid. C31H33BrFN5O8S4: 814.04 (M+1) found 814.70.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(C)C(=O)O
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3C(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate (Example 92b) and isobutyric acid as brown solid (39%). MS 400 (MH+).
Reaction SMILES: [H-].[Na+].[Cl-].[CH2:4]([O:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:38]1[C:42]2([CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>CN(C)C=O.CCCCC>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[C:45]2[CH2:46][CH2:47][C:42]3([O:41][CH2:40][CH2:39][O:38]3)[CH2:43][CH2:44]2)=[CH:36][CH:37]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: C(=C1CCC2(CC1)OCCO2)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 47.6 %

Procedure:
To a suspension of sodium hydride (729 mg 60% in mineral oil) in N,N-dimethylformamide containing one drop of pentane is added (4-benzyloxybenzyl)triphenylphosphonium chloride (7.52 g). The mixture is stirred for 40 min, then 1,4-dioxaspiro[4.5]decan-8-one (2.37 g) is added. The mixture is stirred for one hour at room temperature, the suspension turning from red to green. The mixture is poured into ice (250 g) and extracted with ethyl acetate (4 times 100 mL). The organic extracts are pooled, washed with saturated aqueous solution of sodium chloride (3 times 50 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography over silica gel using a gradient heptane/ethyl acetate from 90/10 to 60/40 to give 2.43 g of 8-(4-benzyloxybenzylidene)-1,4-dioxaspiro[4.5]decane as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:57]([CH3:64])([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19]([N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:31][CH2:30][N:29]([C:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([CH3:64])[CH3:63])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of 140 mg (0.20 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 29a), 60.8 mg (0.44 mmol) K2CO3 and 45 μL (0.30 mmol) ethyl 2-bromo-2-methyl-propionate in 1.8 mL DMF was shaken at 50° C. for 12 h and then for 48 h at RT. The precipitate was filtered off and the filtrate was purified by HPLC without working up; the fractions containing the product were combined, evaporated down i. vac., the residue was made alkaline with saturated NaHCO3 solution, the precipitate was suction filtered, washed with 20 mL water and dried at 40° C.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:36][N:37]=5)=[CH:27][C:26]=4[NH:43][C:44]4[C:45]5[CH:53]=[CH:52][C:51]([CH:54]([CH3:56])[CH3:55])=[N:50][C:46]=5[N:47]=[CH:48][N:49]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[S:34][C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:36][N:37]=3)=[O:42])=[CH:27][C:26]=2[NH:43][C:44]2[C:45]3[CH:53]=[CH:52][C:51]([CH:54]([CH3:56])[CH3:55])=[N:50][C:46]=3[N:47]=[CH:48][N:49]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ncc(C(C)(C)C)s4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ncc(C(C)(C)C)s4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 65 °C
Yield: 65.3 %

Procedure:
A solution of the product of Example 161E (123.4 mg, 0.1558 mmol) in 1,4-dioxane (4 mL) was treated with a solution of lithium hydroxide monohydrate (13 mg, 0.3 116 mmol) in water (2 mL) at ambient temperature, then heated at 65° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (30 mL), adjusted the aqueous pH to 6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 4% methanol/methylene chloride afforded the title compound (58 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.28 (s, 9 H) 1.34 (d, J=6.99 Hz, 6 H) 3.17-3.34 (m, 1 H) 5.64 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.80 (s, 1 H) 6.82 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.46 Hz, 1 H) 7.88-7.98 (dd, 1 H) 8.11 (s, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 12.47 (s, 1 H); MS (ESI+) m/z 570 (M+H)+, (ESI−) m/z 568 (M−H)−.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.FC(F)(F)C(O)=O.[NH2:61][C@H:62]([C:74]([NH:76][C:77]12[CH2:86][CH:81]3[CH2:82][CH:83]([CH2:85][CH:79]([CH2:80]3)[CH2:78]1)[CH2:84]2)=[O:75])[CH2:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65].Cl>C(OCC)(=O)C>[C:77]12([NH:76][C:74]([C@@H:62]([NH:61][C:29](=[O:30])[CH2:28][NH:27][C:25]([CH:24]([CH2:23][CH2:22][CH:19]3[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]3)[CH2:32][CH2:33][CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:38][CH2:39]3)=[O:26])[CH2:63][C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[O:75])[CH2:78][CH:79]3[CH2:85][CH:83]([CH2:82][CH:81]([CH2:80]3)[CH2:86]1)[CH2:84]2
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)NC23CC4CC(CC(C4)C2)C3)CC1
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
Isobutyl chloroformate (1.7 g, 12.4 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (6.9 g, 11 mmol) in 150 ml of ethyl acetate and N-methylmorpholine (5 g, 49.5 mmol). A white suspension is obtained. After stirring for 10 minutes, a solution of benzyl (3S)-3-amino-4-(1-adamantylamino)-4-oxobutanoate trifluoroacetate (6.9 g, 11.2 mmol) in 20 ml of ethyl acetate is added. Stirring is continued at room temperature for 18 hours. 2N hydrochloric acid is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 6.6 g of a beige-coloured solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:37]([NH:44][CH2:45][CH2:46]N)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH2:37]([NH:44][CH2:45][CH2:46][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: NCCNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCNCc3ccccc3)cc21
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring at for 18 hours, the reaction was treated with N1-benzyl-ethane-1,2-diamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to MeOH/CH2Cl2 to provide compound 11g-5 as an oil in 100% yield.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:3]([NH2:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl.[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](=N)OCC)=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]2[NH:1][CH:2]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH:3]([C:4]3[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=3)[N:11]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=N)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(C(N)C(N)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C2NC(c3ccc(Cl)cc3)=NC2c2ccc(Cl)cc2)cc1
Yield: 63.5 %

Procedure:
A solution of 4-[1,2-diamino-2-(4-chloro-phenyl)-ethyl]-benzonitrile (81 mg, 0.298 mmol) and ethyl 4-chloro-benzimidate hydrochloride (55 mg, 0.249 mmol) in ethanol (5 mL) was heated at 72° C. for 5 h. The solvent was removed, and the residue was taken in methylene chloride (10 mL). The reaction mixture was washed with 1 N sodium hydroxide solution (1 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0.5% methanol in methylene chloride yielded 4-[2,5-bis-(4-chloro-phenyl)-4,5-dihydro-3H-imidazol-4-yl]-benzonitrile (62 mg, 76%). HR-MS (EI, m/z) calculated for C22H15N3Cl2 (M+) 391.0643, observed 391.0648.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(O[C:24]([N:26]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:47])[N:32]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[N:38])=[O:25])(C)(C)C.[CH3:56][CH2:57][CH2:58][CH2:59]CC.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:56][CH2:57][CH2:58][CH2:59][C:24](=[O:25])[N:26]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:47])[N:32]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[N:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Yield: 74 %

Procedure:
N-(tert-Butoxycarbonyl )-O-benzylhydroxylamine (1.43 g, 6.40 mmol) was alkylated with (6) (3.00 g, 5.68 mmol) using NaH (80%, 0.19 g, 6.33 mmol) in DMF (100 mL), following the procedure used for (4). Column chromatography on silica gel with 4:1 hexane/EtOAc yielded 3.0 g (74%) of (7) as an oil: NMR δ 1.50 (s, 9 H), 1.40-1.85 (m, 12 H), 2.20-2.50 (m, 6 H), 3.27-3.70 (m, 6 H), 4.75 (s, 6 H), 7.33 (s, 15 H). Anal. (C41H54N4O7) C, H, N.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[CH:28]=[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]2=[N:21]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[CH:28]=[C:23]2[CH:24]=[N+:25]([O-:9])[CH:26]=[CH:27][C:22]2=[N:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cccc(Cl)c1-n1cc2cnccc2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A dried solution of mCPBA (7.2 mmol) in DCM (20 mL) was added to a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (1.28 g, 4.8 mmol) in DCM (30 mL) under nitrogen. The reaction mixture was stirred for 1 hour, warmed to room temperature, and stirred for a further 2 hours. Sodium thiosulfate (sat. aq.) was added and the layers were partitioned. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous magnesium sulfate, and concentrated to under reduced pressure. The residue was purified by silica gel flash chromatography (5-10% methanol in DCM) to afford the title compound as a white solid (1.22 g, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (dd, J=1.8, 0.9 Hz, 1H), 8.84 (d, J=1.0 Hz, 1H), 7.95 (dd, J=7.5, 1.8 Hz, 1H), 7.84 (dt, J=7.5, 1.0 Hz, 1H), 7.81-7.78 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H).