Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[O:4][N:3]=1.[NH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[C:16]([NH2:18])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:1][C:2]1[C:6]([CH2:7][NH:10][C:11]2[N:15]=[CH:14][NH:13][C:12]=2[C:16]([NH2:18])=[O:17])=[C:5]([CH3:9])[O:4][N:3]=1
Reactant: NC(=O)c1nc[nH]c1N
Reactant: Cc1noc(C)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1CNc1nc[nH]c1C(N)=O
Yield: 96.7 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 17(e) using 3,5-dimethylisoxazole-4-carbaldehyde (0.50 g, 4.0 mmol), 5-amino-imidazole-4-carboxamide (0.50 g, 4.0 mmol), acetic acid (0.23 mL, 4.0 mmol) and sodium cyanoborohydride (0.30 g, 4.8 mmol) with the exception that after stirring o.n., more sodium cyanoborohydride (0.04 g, 0.6 mmol) was added and the reaction mixture refluxed for 2 h. The reaction mixture was then concentrated in vacuo and the crude product was triturated with ethyl ether and the solid removed by filtration. The filtrate was concentrated to give the title compound (0.91 g, 97% yield). This material was used in the next step without further purification. MS (ESI) m/z 236 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[NH:10][NH2:11].[C:12](#[N:15])[CH:13]=[CH2:14]>C1COCC1.[OH-].[Na+]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:10]([CH2:14][CH2:13][C:12]#[N:15])[NH2:11]
Reactant: NNc1cc2ccccc2[nH]1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CCCN(N)c1cc2ccccc2[nH]1

Procedure:
To a solution of 2-indolyl hydrazine (1.47 g.) in THF (100 ml.) was added acrylonitrile (0.75 g.) and five drops of 2N sodium hydroxide solution. The reaction mixture was heated under reflux for eight hours and then concentrated in vacuo. The residue was dissolved in ethanol, treated with activated charcoal, filtered and cncentrated again to give 3-[1-(2-indolyl)hydrazino]propanenitrile, crystallized from ether-ethanol, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)[CH2:6][CH2:5][N:4](C([O-])=O)[CH2:3]1.CCOC(C)=O.[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[F:18][C:15]([F:16])([F:17])[C:14]([C:11]1[CH:10]=[N:9][C:8]([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[CH3:1])=[N:13][CH:12]=1)([OH:20])[CH3:19]
Reactant: C[C@H]1CN(C(=O)[O-])CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 80 °C

Procedure:
A 100 mL round-bottomed flask was charged with ((3S)-3-methyl-4-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (1.12 g, 2.87 mmol), 10 mL of EtOAc, and 3 mL of 4N HCl in dioxane. The mixture was heated at 80° C. for 3 h. The resulting white precipitate was collected by filtration to give 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (1.05 g)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:26]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
To a solution of 24.8 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered, and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 36.8 g (0.15 mol) of 3,5-dichlorobenzenesulfonyl chloride in 70 mL of CH2Cl2 dropwise quickly over five minutes. The addition funnel was rinsed with an additional 30 mL of CH2Cl2, and the cloudy yellow mixture was allowed to warm to room temperature with stirring overnight. The mixture was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, then brine, then dried (MgSO4), filtered, and concentrated to a yellow oil which crystallized on standing. The material was recrystallized three times from ethyl acetate/hexanes to give 39.3 g (0.116 mol, 77%) of N-(3,5-dichlorobenzenesulfonyl)-Proline methyl ester (MW=338) as white needles (TLC on silica vs. 2:1 hexanes/ethyl acetate, Rf=0.51). M/z=339.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]([N+:20]([O-])=O)([CH3:19])[CH:3]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O>[Zn].C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[C@@H:3]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:20]1
Reactant: CC(C)(C(CC(=O)c1ccccc1)c1cccnc1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(C)N[C@@H](c2ccccc2)C[C@@H]1c1cccnc1
Reaction time: 1 h

Procedure:
A solution of 44.7 g. of 4-methyl-4-nitro-3-(3-pyridyl)-valerophenone in 420 ml. of glacial acetic acid is heated at 60° C. with stirring and treated portionwise with 44.7 g. of zinc dust. After 1 hour, an additional 44.7 g. of zinc dust are added and the reaction mixture is left to react for an additional hour. The cooled reaction mixture is filtered, the filter residue washed with glacial beingnabled acetic acid and the filtrate evaporated under reduced pressure. The residue is taken up in 400 ml. of water and made alkaline with potassium carbonate. The reaction mixture is extracted three times with 200 ml. of ethyl acetate each time, the organic phase is washed twice with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue is crystallized with isopropyl ether and there is obtained a product with a melting point of 60°-61° C. The mother liquors are chromatographed on a 50-fold amount of silica gel with ether/diethylamine (95.5) and, after crystallization with isopropyl ether, there is obtained trans-3-(2,2-dimethyl-5-phenyl-3-pyrrolidinyl)-pyridine, with a melting point of 57°-58° C. A methanolic solution of the base product is treated with a methanolic solution of oxalic acid to obtain pH 6. The obtained crystals are washed with ether and the oxalate of the product with a melting point of 224°-225° C. is obtained.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].O[C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C1CCC(N=C=NC2CCCCC2)CC1>CC#N.C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:26]([O:28][C:41]1[CH:42]=[CH:43][CH:44]=[CH:34][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (50 mg, 0.11 mmol) and ethyl 2-hydroxybenzoate (19 mg, 0.11 mmol) in CH3CN/THF (1:1, 0.5 mL) at −10° C. was added DCC (12 mg, 0.11 mmol) and DMAP (1 mg). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EtOAc-PE, 0-20%) to afford ethyl 2-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate (40 mg, 67%) as colorless oil. Mass calculated for C37H51NO5=589.80; found: [M+H]+=590.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:43]1C(C)=CC=CC=1C>C(Cl)Cl.[OH-].[NH4+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:43])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(N)=O)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 100 mg, 0.19 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (100 μL, 0.20 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (44 μL, 0.38 mmol) was added. The reaction continued to stir at 0° C. for 20 min. Concentrated aqueous ammonium hydroxide (4 drops) was added. The ice bath was removed and the reaction continued to stir at 25° C. for 20 min. The reaction was diluted with ethyl acetate (20 mL), washed with water (2×5 mL), saturated aqueous brine solution (1×5 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 4-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzamide (49 mg, 49%) as an off white powder: ESI-LRMS m/e calcd for C26H29ClN4O4S [M+] 528.16, found 529.19 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.35-1.92 (m, 8H, 4×CH2), 2.11-2.26 (m, 1H, CH), 3.23 (s, 3H, SO2CH3), 3.65 (t, J=7.6 Hz, 1H, CH), 5.18 (s, 2H, NCH2), 6.08 (br.s., 2H, NH2), 6.74 (d, J=2.0 Hz, 1H, Ar), 7.15 (d, Jo=8.1 Hz, 2H, Ar), 7.37 (d, J=2.0 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.72 (d, Jo=8.1 Hz, 2H, Ar), 7.98 (d, Jo=8.1 Hz, 1H, Ar), 8.79 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)CCCC.Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[C:4]([CH3:36])=[CH:3][C:2]([N:43]4[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(Cl)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Temperature: 150 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
A mixture of 0.530 g (1.02 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 1.4 from Example 1, 0.266 g (2.05 mmol) of 1-(2-hydroxyethyl)piperazine (CAS 103-76-4) and 0.14 ml (1.0 mmol) of triethylamine in 5 ml of pentanol is stirred for 2 days at 150° C. The reaction medium is diluted with 20 ml of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The brown oil obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.220 g of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol in the form of an amorphous powder which is used in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[Cl:16][C:17]1[C:18]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C(Cl)Cl.CCOCC.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].C(Cl)Cl>[ClH:16].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[C:18]2[CH2:26][CH2:25][NH:24][CH2:23][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(Cl)ncnc2C1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2c1CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.091 g, 0.111 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.815 g, 3.71 mmol), tert-butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.000 g, 3.71 mmol), and potassium carbonate (2.050 g, 14.83 mmol) in 12 mL of dioxane and 4 mL water was heated to 110° C. for one hour. The reaction mixture was then diluted with DCM, the organics were dried over MgSO4 and concentrated. The crude residue was treated with HCl (4N in dioxane) (9.27 ml, 37.1 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was diluted with ether, and the resulting solids were filtered off and dried yielding 4-(2-methoxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (1.333 g, 3.86 mmol, 104% yield) as a gray solid with minor impurities. (M+H)+=310.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:41][CH3:42])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:6]=1.[H-].[Na+].I[CH3:47]>C1COCC1>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:41][CH3:42])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:47])[C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:6]=1
Reactant: CI
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(Nc2cccc(C)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(N(C)c2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-{[ethyl-(4-m-tolylamino-benzenesulfonyl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.080 g, 0.13 mmol) in THF (2 mL) under N2 was added sodium hydride (60% in mineral oil; 0.016 g, 0.39 mmol), and the mixture was stirred for 30 minutes at room temperature. Iodomethane (0.02 mL, 0.39 mmol) was added, and the reaction was stirred at room temperature for 4 hours. Analytical LCMS indicated that some starting material remained, so additional sodium hydride (60% in mineral oil; 0.008 g, 0.20 mmol)) and iodomethane (0.01 mL, 0.20=01) was added, and the reaction was stirred for 30 minutes and then taken directly to the hydrolysis step as a solution in THF.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([NH2:16])=[O:15])[CH2:8][CH2:7]2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([NH2:16])=[O:15])[CH2:8][CH2:7]2
Reactant: NC(=O)C1CCc2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)C1CCc2cc(N)ccc2O1
Yield: 99.9 %

Procedure:
A mixture of compound from example 61 (6.75 g, 30.0 mmol), absolute ethanol (700 mL) and 10% activated palladium on carbon (1.35 g) was placed under a hydrogen balloon for 24 h. The product was filtered through celite and the solvent was evaporated to afford the title compound (5.76 g, 100%). Rf=0.4 (methylene chloride:methanol 95:5); MS (FAB) m/z 193 (MH+).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:53])[CH2:7][N:8]([CH2:47][C:48]([O:50]CC)=[O:49])[C:9](=[O:46])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:30])[O:28]C)[CH:13]=[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]C)=[O:43])[CH:11]=1)C>>[C:6]([CH2:7][N:8]([C:9](=[O:46])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:30])=[O:28])[CH:13]=[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH:11]=1)[CH2:47][C:48]([OH:50])=[O:49])([OH:53])=[O:5]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCCCCCC(=O)OC)cc(OCCCCCCCCCCC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCOc1cc(OCCCCCCCCCCC(=O)O)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[3,5-bis[(11-methoxy-11-oxoundecyl)oxy]benzoyl]glycine ethyl ester gave N-(carboxymethyl)-N-[3,5-bis[(10-carboxydecyl)oxy]benzoyl]glycine, mp 134°-140°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CS(C)=O>[CH:35]1([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: BrC1CCCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Temperature: 85 °C
Yield: 60 %

Procedure:
Methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (500 mg, 1.62 mmol, prepared in Synthetic Intermediate III(c)) was dissolved in 5 mL DMSO and NaHMDS (2.4 mL, 2.4 mmol, 1.0 M in THF) was added followed by bromocycloheptane (446 uL, 3.25 mmol). The reaction was heated overnight at 85° C. The reaction was quenched with TFA and purified by HPLC to give methyl 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (393 mg, 60%). (M+H)+=405.
Reaction SMILES: [N:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:20][C:21]1[CH:22]=[C:23]([C:30]([NH:32][NH2:33])=[O:31])[C:24]2[CH:25]=[N:26][NH:27][C:28]=2[CH:29]=1>CN(C)C=O.CO.ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:30]([NH:32][NH:33][C:8](=[O:10])[CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:31])[C:24]2[CH:25]=[N:26][NH:27][C:28]=2[CH:29]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: NNC(=O)c1cc(Br)cc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)NNC(=O)c1cc(Br)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 103 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (0.841 g, 2.212 mmol) was dissolved in N,N-dimethylformamide (5 ml) then treated with 4-morpholinylacetic acid (0.304 g, 2.092 mmol) and then N,N-diisopropyethylamine (0.386 ml, 2.212 mmol). The clear solution was stirred at 20° C. for 10 mins then to this was added 6-bromo-1H-indazole-4-carbohydrazide (0.513 g, 2.011 mmol) as a partial solution in N,N-dimethylformamide (8 ml). The clear solution was stirred at 20° C. for 72 h under nitrogen. It was then reduced in volume to −1 ml, diluted with methanol (5 ml) and loaded onto an aminopropyl cartridge which had been pre-conditioned with methanol. The fully-loaded cartridge was left to stand for 2 h then eluted with methanol and the eluant evaporated to give an orange oil. This was diluted with dichloromethane (3 ml) and loaded onto a silica (10 g) cartridge. This was eluted with a gradient of methanol and ethyl acetate to give the title compound as a beige solid (0.792 g).
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7][N:8]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:21]([NH:23][NH2:24])=O>ClC1C=CC=CC=1Cl>[NH2:17][C:18]1[CH:19]=[C:20]([C:21]2[N:8]3[CH2:7][CH2:6][CH:5]([C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=4)[CH2:4][C:3]3=[N:24][N:23]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(C(=O)NN)cc1N
Reactant: COC1=NCCC(c2ccc(C#N)cc2)C1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nnc3n2CCC(c2ccc(C#N)cc2)C3)cc1N
Temperature: 150 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of 4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile (compound 347.3, 5.00 g, 23.36 mmol, 1.00 equiv) in 1,2-dichlorobenzene (100 mL) was added 3-amino-4-methylbenzohydrazide (compound 347.4, 4.63 g, 28.0 mmol, 1.20 equiv). The resulting solution was stirred overnight at 150° C. in an oil bath. After cooling to ambient temperature, the resulting mixture was purified using silica gel column chromatography with dichloromethane/methanol (1:0˜100:1) as eluent to furnish 2.40 g (31%) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:11]2[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)#[N:2].C(O)C>[C].[Pd].O1CCCC1>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:11]2[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)#[N:2]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#CCCCC#N)cc23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCCCCC#N)cc23)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.7 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (3.03 g, 6.13 mmol), copper iodide (176 mg, 0.920 mmol) and hex-5-ynenitrile (2.86 g, 30.7 mmol) in tetrahydrofuran (30 ml)-triethylamine (10 ml) was added dichlorobistriphenylphosphinepalladium (431 mg, 0.613 mmol), and the mixture was stirred under an argon atmosphere at 80° C. for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give black crystals. The crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, yield 84%) as white crystals. Subsequently, tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, 5.17 mmol) and 10% palladium-carbon (550 mg) were suspended in a mixed solvent of ethanol (200 ml)-tetrahydrofuran (35 ml) and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl {[6-(5-cyanopentyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.37 g, yield 92%) as white crystals.