Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[N:21]=[CH:22][N:23]([CH2:24][CH2:25][O:26][CH2:27][C:28]#[CH:29])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.[O-]C1C=CC=CC=1.[Na+]>COCCOCCOC>[O:9]([C:11]1[C:20]2[N:21]=[CH:22][N:23]([CH2:24][CH2:25][O:26][CH2:27][C:28]#[CH:29])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#CCOCCn1cnc2c(Cl)nc3ccccc3c21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: COCCOCCOC
Product: C#CCOCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Temperature: 110 °C
Reaction time: 15.5 h
Yield: 44.6 %

Procedure:
A dried round bottom flask was charged with a stir bar, sodium hydride (8.15 g, 203.9 mmol) and anhydrous 2-methoxylethyl ether (diglyme, 100 mL) while under a nitrogen atmosphere and at ambient temperature. Phenol (20.7 g, 220.2 mmol) was added in several portions as a solid and the resulting solution stirred under a nitrogen atmosphere until gas evolution ceased. 4-chloro-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (46.6 g, 163.1 mmol) was added neat and the solution was heated to 110° C. After 15.5 hours, a preformed solution of sodium phenoxide (phenol 5 g, 53.1 mmol and sodium hydride 1.91 g, 47.8 mmol) in diglyme (20 mL) was added to the reaction solution and heating was increased to 165° C. The reaction was judged complete after 1 hour at 165° C. After cooling to less than 70° C., the volatiles were removed under reduced pressure and the resulting brown solid was partitioned between chloroform and saturated aqueous sodium carbonate. The aqueous fraction was extracted with chloroform; the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile with a small amount of dimethyl formamide to provide 25 g of 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([OH:28])[CH:22]=2)=[O:18].[O:29]1[CH2:32][CH:31](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:28][CH:31]1[CH2:32][O:29][CH2:30]1)[CH:22]=2)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(O)cc5[nH]4)c3N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(OC6COC6)cc5[nH]4)c3N)ccc2[nH]1
Temperature: 80 °C
Reaction time: 144 h
Yield: 28.8 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl)-methanone (21 mg, 0.056 mmol), toluene-4-sulfonic acid oxetan-3-yl ester (19 mg, 0.084 mmol), and potassium carbonate (13 mg, 0.095 mmol) were dissolved in anhydrous N,N-dimethylformamide (DMF), and heated at 80° C. with stirring under a nitrogen atmosphere for six days. After cooling to room temperature, the reaction mixture was combined with water, and extracted with an ethyl acetate/methanol (10/1) solution. The organic layer was isolated, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/3) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-(oxetan-3-yloxy)-1H-indol-2-yl]-methanone as a yellow solid (6.9 mg, 29%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C:3]1=[O:17].[O:18]=[C:19]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]2)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1>>[OH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][C:35]([N:32]2[CH2:33][CH2:34][CH:29]([N:28]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:18])[CH2:30][CH2:31]2)=[O:36])[C:3]1=[O:17]
Reactant: N[C@@H]1CCCCN(Cc2cccc(O)c2)C1=O
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Product: O=C(N[C@@H]1CCCCN(Cc2cccc(O)c2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3R)-3-amino-1-(3-hydroxybenzyl)azepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 16. MS 492.2599 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1)([O-])=O.FC1C=CC([N+]([O-])=O)=CC=1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:16]2[CH:17]=[CH:18][C:13]([NH2:10])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCCN1CCCC1
Agent: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(OCCCN2CCCC2)cc1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-propan-1-ol, and 4-nitrophenol or 1-fluoro-4-nitrobenzene as starting materials.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([OH:38])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([O:38][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
133 g (1.95 mol) of imidazole and 164 g (1.09 mol) of tert-butyldimethylchlorosilane are added, under an argon atmosphere, to an ice-cold solution of 124 g (238 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 800 ml of DMF. After 17 h at RT, the reaction mixture is poured onto 1.9 l of ice-water and extracted 3× with 0.8 l of ethyl acetate on each occasion. The organic phases are washed with water, sat. NaHCO3 solution, water, 10% citric acid solution, water and, finally, saline, dried with Na2SO4 and evaporated. The residue is dissolved in 700 ml of methanol and 175 ml of THF, and 175 g of K2 CO3 in 820 ml of water are added to this solution, which is then stirred at RT for 1 h. The resulting emulsion is partially evaporated on an RE, and the residue is diluted with ice-water, and this mixture is acidified to pH 4 with 10% citric acid solution while stirring vigorously. The mixture is extracted 3× with ethyl acetate, and the organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane→hexane/ethyl acetate 95:5→9:1→2:1→1:1) results in the title compound: TLC Rf (E)=0.15; tRet (II)=22.7 min.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CO>[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:25][CH2:26]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (80 mg, 0.170 mmol), N,N-dimethylglycine (18 mg, 0.170 mmol) and diisopropylethylamine (0.089 mL, 0.509 mmol) in DMF (1 mL) is added TBTU (55 mg, 0.170 mmol) and the reaction mixture is stirred at room temperature for 1 hour. Methanol (0.5 mL) is added and the reaction mixture purified by silica gel chromatography (gradient of 0-10% 2M NH3 in methanol/dichloromethane) to give 7-cyclopentyl-2-{5-[4-(2-dimethylamino-acetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, which is further purified by trituration with acetonitrile, as an off white solid (69 mg, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:21]([N:24]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])[C:25]2[S:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1I)#[N:2].[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:48]1[CH:53]=[CH:52][N:51]=[N:50][CH:49]=1)CCC>CN(C)C=O.[Cu]I>[C:1]([C:3]1[CH:4]=[C:5]([S:21]([N:24]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])[C:25]2[S:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:48]1[CH:53]=[CH:52][N:51]=[N:50][CH:49]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 30 °C

Procedure:
A mixture of 3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 429, 33.07 g, 47.08 mmol) in dimethylformamide (140 mL) was treated with copper (I) iodide (1830 mg, 9.60 mmol) and cesium fluoride (14.4 g, 94.2 mmol). The mixture was sparged with nitrogen for 15 minutes. Then 4-(tributylstannyl)pyridazine (19.1 g, 51.8 mmol) dissolved in dimethylformamide (10 mL) was added and the reaction heated to 30° C. The reaction was cooled, poured onto water (1 L) and extracted with diethylether (4×450 mL). The combined extracts were washed with water (6×500 mL), dried over magnesium sulfate and evaporated to furnish an orange foam. This residue was purified using column chromatography (using a gradient of 100% heptane with 2% triethylamine to 40:60 ethylacetate:heptane with 2% triethylamine) to furnish the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([N:72]1[CH2:73][CH2:74][N:69]([CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:70][CH2:71]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-phenyl-propionic acid (3 g, 11.3 mmol) was dissolved in DMF (100 mL), and PyBOP (5.9 g, 11.3 mmol) and Hünig's base (3.36 g, 25.99 mmol) were added, followed by 1-benzyl-piperazine (2 g, 11.3 mmol). Stirring at rt was continued for 8 h, followed by the addition of EtOAc (400 mL). The mixture was washed with 1 N aq. HCl (300 mL), sat. aq. sodium hydrogencarbonate solution (300 mL) and brine (300 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4.375 g (91%) of [(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester. LC-MS: tR=0.80 min; [M+H]+=424.34.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:37]4[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=4)[C:31]#[N:32])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(CC3CCCCC3)C2=O)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.064 mmol) in 1,4-dioxane (1.5 mL), Cs2CO3 (2 N, 0.5 mL) and 3-cyanophenylboronic acid (19 mg, 0.128 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-(cyclohexylmethyl)-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (9.74 mg, 31%). 1H-NMR (MeOD): 1.02 (m, 5H), 1.62 (m, 6H), 2.03 (m, 1H), 2.24 (m, 1H), 3.30 (m, 1H), 3.44 (m, 1H), 5.91 (m, 1H), 6.97 (m, 1H), 7.16 (m, 1H), 7.25 (m, 1H), 7.35 (m, 3H), 7.46 (m, 2H), 7.56 (m, 1H), 7.71 (m, 2H)
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[N:19]=3)[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]4[CH2:24][CH2:25]4)=[O:22])[N:19]=3)[CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2n1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cn1
Yield: 44.7 %

Procedure:
A mixed solution of N-{6-[(6-nitropyridin-3-yl)oxy]imidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (184 mg, 0.542 mmol), reduced iron (173 mg, 2.95 mmol) and ammonium chloride (315 mg, 5.89 mmol) in ethanol (2 mL) and water (0.5 mL) was stirred at 80° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and filtered through celite. Water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-÷ethyl acetate/methanol=95/5) to give the title compound (75 mg, 45%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([N+:26]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:10]=1.O.O.[Sn](Cl)Cl.[N:40]#[C:41]Br.C(OCC)(=O)C>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:41]([NH2:40])=[N:26][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:10]=1
Reactant: CC(C)(C)CNc1nc(-c2[nH]c(-c3c(F)cccc3Cl)nc2-c2ccccc2)ccc1[N+](=O)[O-]
Reactant: N#CBr
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)Cn1c(N)nc2ccc(-c3[nH]c(-c4c(F)cccc4Cl)nc3-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Dissolve {6-[2-(2-chloro-6-fluoro-phenyl)-5-phenyl-3H-imidazol-4-yl]-3-nitro-pyridin-2-yl}-(2,2-dimethylpropyl)-amine (240 mg, 0.50 mmol) in 100% ethanol (10 mL) and add tin(II) dichloride dihydrate (564 mg, 2.50 mmol, 5.0 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly with saturated aqueous NaHCO3. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad with water and ethyl acetate washes. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SO4, filter, and concentrate under reduced pressure. Add 10% aqueous ethanol and cyanogen bromide (106 mg, 1.00 mmol, 2.0 equiv) to the resulting solid and stir overnight. Quench the reaction with saturated aqueous NaHCO3 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer three times with saturated aqueous NaCl, dry with Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOH)/CH2Cl2 to provide 5-[2-(2-Chloro-6-fluoro-phenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine as a yellow-green solid (196 mg, 60% yield).
Reaction SMILES: [CH3:1]N(C)C(CC)CN(C)C.N#N.CCO.[Li]C(CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.CI>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:1])[CH:23]=1
Reactant: CCC(CN(C)C)N(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: N#N
Agent: [Li]C(C)CC
Solvent: CI
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3I (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at −80° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g).
Reaction SMILES: C(OP(CC1C=CC(N[N:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])=CC=1)(=O)OCC)C.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1.C(#N)CC#N.O.[NH2:45][NH2:46]>>[CH2:34]([O:33][P:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([NH:23][N:17]=[C:18]2[C:19]([NH2:20])=[N:46][N:45]=[C:21]2[NH2:22])=[CH:38][CH:37]=1)(=[O:36])[O:30][CH2:31][CH3:32])[CH3:35]
Reactant: CCOP(=O)(Cc1ccc(NN=C(C#N)C#N)cc1)OCC
Reactant: NN
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: O
Solvent: N#CCC#N
Product: CCOP(=O)(Cc1ccc(NN=C2C(N)=NN=C2N)cc1)OCC

Procedure:
{4-[N′-(3,5-Diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic acid diethyl ester was prepared using [4-(N′-dicyanomethylenehydrazino)benzyl]phosphonic acid diethyl ester (0.16 g, 0.5 mmol) which was derived from diethyl 4-aminobenzylphosphonate (0.243 g, 1.0 mmol) and malononitrile (1.5 mmol) in a manner similar to that described in Example 2, and hydrazine hydrate. The title compound was purified by flash chromatography and isolated as a golden solid (0.116 g, 66%); 1H NMR (ppm, 200 MHz, DMSO-d6) δ 1.20 (t, 6H), 3.23 (d, 2H), 3.95 (q, 4H), 6.0 (brs, 4H), 7.28 (d, 2H), 7.60 (d, 2H), 10.70.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[OH:5][C:6]1[CH:7]=[C:8]([O:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:9]=[C:10]2[C:15]=1[CH:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][C:12]([CH3:21])([CH3:20])[CH2:11]2.[CH3:34]O>>[C:1]([O:5][C:6]1[CH:7]=[C:8]([O:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:24])[CH:9]=[C:10]2[C:15]=1[CH:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][C:12]([CH3:21])([CH3:20])[CH2:11]2)(=[O:2])[CH3:34]
Reactant: CO
Reactant: C[O-]
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)CC(C)(C)CC2CC(=O)O
Agent: [Na+]
Agent: [Na]
Product: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1C(CC(=O)O)CC(C)(C)C2
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of sodium methoxide prepared from 0.2 g. sodium metal and 32 ml. methanol is added a solution of 0.20 g. (0.53 mmole) of the lactone of 2-[8-hydroxy-3,3-dimethyl-6-(5-phenyl-2-pentyloxy)tetralin-1-yl]acetic acid and the mixture is stirred for 30 minutes. The methanol is evaporated in vacuo, the residue is cooled in ice and a cold solution of 6.4 ml. acetyl chloride in 12.8 ml. ethyl acetate is added and the resulting mixture stirred 15 minutes. The mixture is concentrated to dryness in vacuo, the residue taken up in fresh ethyl acetate, washed with water, brine and dried (MgSO4) to yield 0.30 g. yellow oil. The oil is purified on a silica gel column using mixtures of methylene chloride and methanol as eluant to afford 110 mg. (47%) of title compound. 1H-NMR (CDCl3) ppm (delta): 0.8 (s, 3H), 1.03 (s, 3H), 1.23 (d, 4H), 1.7 (m, 6H), 2.3 (s, 3H), 2.5 (m, 4H), 2.9 (m, 1H), 3.13 (m, 1H), 4.2 (m, 1H), 6.4 (s, 2H), 7.13 (s, 5H).