Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:45])C1C=CC(CO)=CC=1>>[CH3:34][O:35][C:36](=[O:45])[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][C:20]2[C:19]([C:9]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]4[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=4[N:10]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3ccccc3)c2cc1F
Product: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 1-benzyl-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 6, intermediate) and 4-hydroxymethyl-benzoic acid methyl ester (CAS Reg. No. 6908-41-4). Brown sticky solid (15%). MS (Turbo Spray): m/z=386.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)c1ncccc1Br
Product: CC(C)S(=O)(=O)c1ncccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared as described in step D of Example 803 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 3-bromo-2-(isopropylsulfonyl)pyridine. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.7, 1.7, 1H), 8.57 (d, J=1.4, 2H), 7.80 (dd, J=7.8, 1.6, 1H), 7.59 (dd, J=7.8, 4.6, 1H), 7.46 (m, 1H), 7.39 (dd, J=7.9, 1.8, 1H), 7.32 (dd, J=11.1, 1.7, 1H), 5.17 (s, 2H), 4.26 (hept, J=6.9, 1H), 1.32 (d, J=6.9, 6H).
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.NN.Cl>CCO>[NH2:10][C:9]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=[C:4]([CH3:5])[C:6]=1[C:7]#[N:8]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Product: COc1ccc(-n2nc(C)c(C#N)c2N)cc1
Temperature: 105 °C
Yield: 90.8 %

Procedure:
To a stirred solution of 2-(1-ethoxyethylidene) malononitrile (1.00 g, 6.66 mmol) in EtOH (8 mL) was added (4-methoxyphenyl)hydrazine (1.29 g, 9.32 mmol). (Prior to use the hydrazine its HCl salt was washed with NaHCO3/CH2Cl2. The organic phase was concentrated and used directly.) The solution was heated to 105° C. in the microwave for 20 min. CH2Cl2, was added and the organic phase was washed with 1M HCl and the organic extract was washed with aqueous NaHCO3. The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.38 g, 85%) which was used as such in the next step. The procedure was adapted from J. Med. Chem. 2004, 47, 5894-5911.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:16])(=[O:4])[CH3:3].[NH2:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[C:20]([Cl:32])[CH:19]=1>>[ClH:16].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22](=[O:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([Cl:32])[CH:19]=1)(=[O:4])[CH3:3]
Reactant: Nc1ccc(C(=O)c2ccccc2)c(Cl)c1
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Agent: Cl
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(C(=O)c4ccccc4)c(Cl)c3)c2c1
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline hydrochloride was reacted with 4-amino-2-chlorobenzophenone to give 6-acetoxy-4-(4-benzoyl-3-chloroanilino)quinazoline hydrochloride salt in 47% yield, m.p. >250° C.;
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[N:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13](I)([CH3:15])[CH3:14]>C(#N)C>[CH:13]([N:10]1[N:9]=[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]2=[N:11]1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1cccc2[nH]nnc12
Reactant: CC(C)I
Solvent: CC#N
Product: CC(C)n1nc2cccc([N+](=O)[O-])c2n1
Temperature: 50 °C

Procedure:
To a hot, stirred solution (50° C) of 20.0 g. of 4-nitrobenzotriazole in 600 ml. of acetonitrile is added 4.2 g. of sodium hydroxide pels and 20.0 g. of isopropyl iodide. The solution is then heated to reflux for 30 hours, filtered and the solvent removed by evaporation to yield an oil. The oil is extracted with concentrated hydrochloric acid (3 × 200 ml.) to leave behind a solid material. The solid is washed with water and air dried to yield crude 2-isopropyl-4-nitrobenzotriazole. The analytical sample is recrystallized from petroleum ether, m.p. 65°-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(Cl)nc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a solution of 2-chloro-5-hydroxypyridine (50 g, 0.386 mol) and potassium carbonate (80 g, 0.579 mol) in N,N-dimethylformamide (300 mL) was added p-methoxybenzyl chloride (66.5 g, 0.425 mol), and the mixture was stirred at 80° C. for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with methanol to give the title compound (61.3 g, 64%) as a white solid.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1)=O.O>CO.[OH-].[Na+]>[NH2:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([CH:13]=[O:14])=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc(C)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(N)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)-acetamide in MeOH (30 mL) and 1 N NaOH (30 mL) was stirred at RT overnight. To the suspension was added 100 mL of water and the solid was filtered, washed with water, and dried. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (heptane/EtOAc=4:1) to give the title compound. MS: m/z 150 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(CCCN)c1ccccn1
Reactant: CSc1ncc(CCc2ccccc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(CCc2ccccc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.81 g) and 2-methylthio-5-phenylethylpyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 26 hr. After stripping, the residue was crystallised twice from ethanol and finally from acetone to give 2-[3-(N-methyl-N-pyrid-2-ylamino)propylamino]-5-phenylethylpyrimid-4-one, 0.68 g (46%) mp 134°-136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:27](=[O:28])[CH2:26][Cl:25])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C(Cl)CCl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)CCl)C1O
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethylamine and 20 ml of methylene chloride was added with 74 μl (0.935 m mol) of chloroacetyl chloride with stirring at the room temperature, followed by further stirring for 30 minutes. After the completion of the reaction, the precipitated crystals were separated by filtration to obtain 201 mg (yield: 76%) of the intended compound.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][CH:20]=[N:19][C:18]=3[C:22]([F:25])([F:24])[F:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Li]CCCC.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:32][C:20]1[S:21][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:18]([C:22]([F:23])([F:24])[F:25])[N:19]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3scnc3C(F)(F)F)c(C)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C(F)(F)F)c(C)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-trifluoromethyl-thiazol-5-yl)-imidazo[1,2-b]pyridazine (915 mg, 2.48 mmol) in 40 mL of THF under N2 atmosphere al −78° C., BuLi (1.86 mL 1.6 M in hexane, 2.98 mmol) is slowly added. The mixture is stirred at −78° C. for 30 minutes. Then, a solution of CBr4 (989 mg, 2.98 mmol) in 3 mL of THF is added, and the mixture is stirred at −78° C. for 45 minutes. The reaction is quenched by addition of NH4Cl saturated solution (50 mL), extracted with Et2O (2×50 mL), dried over MgSO4, and concentrated in vacuo. Crude product is purified by flash chromatography on silica gel (eluent CH2Cl2) to obtain 685 mg of the title compound (Yield: 62%). 1H NMR (CDCl3): δ0.86 (t, J=7.5 Hz, 6H), 1.82 (m, 4H), 2.45 (s, 3H), 2.51 (s, 3H), 3.27 (m, 1H), 6.74 (s, 1H). ESIMS: m/z 447, 449 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@@H:13]([OH:25])[C@H:14]2[NH2:24])[CH2:6]1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:24][C@@H:14]1[C@H:13]([OH:25])[CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@:20]1([CH3:23])[C@H:7]([CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]1)[CH2:8][CH2:9]3
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@H](N)[C@H](O)C[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](N)[C@H](O)C[C@@H]12
Yield: 80.5 %

Procedure:
Hydrolysis of 17α-amino-5α-androstane-3β,16α-diol 3-acetate (4.8 g) with sodium hydroxide (4 N) and ethanol at reflux temperature gave 17α-amino-5α-androstane-3β,16α-diol (3.4 g). Crystallisation from ethanol yielded an analytical sample, m.p. 220°-225° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N1C=CC=CC=1.[CH3:18][O:19][CH2:20][CH2:21][OH:22].Cl>CN(C1C=CN=CC=1)C.ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:22][CH2:21][CH2:20][O:19][CH3:18])(=[O:3])=[O:2]
Reactant: COCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To tosyl chloride (50.0 g, 0.263 mol) at 0° C. and under nitrogen were added anhydrous dichloromethane (80 ml), anhydrous pyridine (23 ml, 24.3 g, 0.29 mol), 2-methoxyethanol (21.0 ml, 20.0 g, 0.263 mol) and a catalytic quantity of DMAP. After 10 minutes the mixture was warmed to room temperature, at which it was stirred for 16 hours. Dichloromethane (100 ml) and 1 M aqueous hydrochloric acid (50 ml) were added. The organic layer was isolated and washed with 1 M aqueous hydrochloric acid (4×30 ml) and water (4×30 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (51.68 g, 85%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[C:5]([NH:7][NH:8][C:9]([C:11]1[N:15]([C:16]2[CH:17]=[C:18]([CH2:21][NH:22][C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[S:19][CH:20]=2)[N:14]=[C:13]([C:35]([F:38])([F:37])[F:36])[CH:12]=1)=O)=[O:6].CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[C:5]1[O:6][C:9]([C:11]2[N:15]([C:16]3[CH:17]=[C:18]([CH2:21][NH:22][C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH3:25])[S:19][CH:20]=3)[N:14]=[C:13]([C:35]([F:36])([F:37])[F:38])[CH:12]=2)=[N:8][N:7]=1
Reactant: COc1ccccc1C(=O)NNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nnc(-c2cc(C(F)(F)F)nn2-c2csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c2)o1
Yield: 101.3 %

Procedure:
A solution of compound 16 (73 mg, 0.120 mmol) in DMF (1.0 mL) and DIC (0.1 mL, 0.642 mmol) was heated to 100 degrees for 13 hours. The reaction was concentrated down to a brown gum and then applied onto a 12M Biotage column and eluted with 0-5% methanol and dichloromethane to give 72 mg of a semi-purified compound. This material was further purified by preparative HPLC (C18 Aquasil 20×250 mm; 40-85% methanol in water in 45 minutes at 10 mL/min) to give compound 17 (20.3 mg, 29%) as a white crust. LRMS (ESI): calc. 592.2; found 493.2 (MH-Boc)+, 593.3 (MH)+.
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH2:14])[S:11][N:10]=1)[C:6]([NH2:8])=[O:7].[CH:15](O)=[O:16].C(OC(=O)C)(=O)C>>[F:1][CH2:2][O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH:14][CH:15]=[O:16])[S:11][N:10]=1)[C:6]([NH2:8])=[O:7]
Reactant: O=CO
Reactant: NC(=O)C(=NOCF)c1nsc(N)n1
Solvent: CC(=O)OC(C)=O
Product: NC(=O)C(=NOCF)c1nsc(NC=O)n1
Yield: 61.4 %

Procedure:
To a suspension of 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl) acetamide (anti-isomer) (3.51 g, 16 mmol) in 99% formic acid (14.73 g, 320 mmol), acetic anhydride (4.90 g, 48 mmol) was added, and the mixture was reacted at 40° C. for 50 hrs, and then cooled to below 10° C. to separate crystals. The crystals were collected by filtration and washed with cold methanol (10 ml) on Nutsche. The crystals in DMF (16 ml) were heated to dissolve and the resulting solution was dispersed in methanol (32 ml), and then cooled, filtered and dried to give 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl) acetamide (syn-isomer) (2.43 g, yield: 61.4%). The content obtained by HPLC: 99.0% (anti-isomer: 0.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine (compound 446) (75 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. The solution was brought to 0° C., trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 4 hr. The reaction solution was brought to 0° C., was stirred and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 61%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:17]1
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O.[Cu]I>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]([CH3:13])[C:8]([O:12][C:19]2[N:18]=[N:17][C:16]([Cl:15])=[C:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=2)=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: COC(=O)Cc1cc(C)c(O)c(C)c1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1cc(C)c(Oc2cc(C(C)C)c(Cl)nn2)c(C)c1
Temperature: 90 °C
Yield: 67.2 %

Procedure:
A solution of (3,5-dimethyl-4-hydroxy-phenyl)-acetic acid methyl ester (6a) (12.5 g, 0.064 mol) in anhydrous dimethyl sulfoxide (256 mL) under argon at room temperature was treated with 3,6-dichloro-4-isopropyl pyridazine (7) (18.43 g, 0.096 mol) followed by anhydrous potassium carbonate (17.69 g, 0.12 mol) and copper (I) iodide (6.09 g, 0.032 mol). The reaction mixture was heated to 90° C. for 24 h. At this time, the reaction was cooled to room temperature and was poured onto a 1N aqueous hydrochloric acid solution (200 mL) and ice. The aqueous layer was diluted with water (100 mL) and extracted with ethyl acetate (2×500 mL). The aqueous layer was made basic (pH=8) by the addition of a 1N aqueous sodium hydroxide solution. The water layer was extracted again with ethyl acetate (1×500 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography using silica gel eluted with 5-15% ethyl acetate in petroleum ether to afford [4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid methyl ester (8a) (15 g, 67%) and a minor amount of isomer as a white solid; EI(+)-HRMS m/z calcd for C18H21ClN2O3 (M+) 348.1241, found 348.1237. Molecular Weight=348.8327; Exact Mass=348.1241
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]1([C:17]2([CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[O:21][CH2:20][CH2:19][O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:17]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:18][CH2:19][CH2:20][O:21]2)[C:4](=[O:9])[O:3]1
Reactant: O=C(Cl)CCCC1(c2ccccc2)OCCO1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCC2(c3ccccc3)OCCO2)C(=O)O1
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
Step AAH (3): To a soln of 2,2-dimethyl-1,3-dioxane-4,6-dione (329 mg, 2.281 mmol) in dichloromethane (10 mL) was added DMAP (405 mg, 3.32 mmol). After stirring for 10 min, a solution of 4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl chloride (2.07 mmol) in dichloromethane was added at 0° C. under nitrogen. The mixture was stirred at rt for 3 his. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was sequentially washed with 1.0 N aqueous HCl, 1.0 N aqueous NaOH, and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to 2,2-dimethyl-5-(4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl)-1,3-dioxane-4,6-dione (700 mg, 1.93 mmol, 93% yield).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][N:6]=1)=[NH:4].[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:37])[C:26]=1[O:27][CH2:28][C@@H:29]([OH:36])[CH2:30][NH:31][C:32](=[O:35])[CH2:33][OH:34])[C:21](O)=O)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][N:6]=3)[N:4]=2)[CH:24]=[C:25]([CH3:37])[C:26]=1[O:27][CH2:28][C@@H:29]([OH:36])[CH2:30][NH:31][C:32](=[O:35])[CH2:33][OH:34])[CH3:17]
Reactant: CCc1cc(C(=O)O)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: Cc1cc(C(=N)NO)ncc1CC(C)C
Product: CCc1cc(-c2nc(-c3cc(C)c(CC(C)C)cn3)no2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 34.4 %

Procedure:
The title compound (32 mg) is prepared by coupling and cyclizing N-hydroxy-5-isobutyl-4-methyl-pyridine-2-carboxamidine (40 mg, 193 μmol) with 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid (60 mg, 193 μmol) as described in Example 1; LC-MS: tR=0.95 min, [M+H]+=482.86.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27]([NH:29][C@@:30]([CH2:42][CH3:43])([CH2:33][O:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][OH:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCOCC>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C@:30]([CH2:42][CH3:43])([CH2:33][O:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][OH:32])=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCCCCC(=O)OC[C@@](CC)(CO)NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(=O)OC[C@](CC)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
Molecular sieve 4A (117 g) and pyridinium dichromate (117 g, 311 mmol) were added to a solution of (2R)-2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanol (66.7 g, 210 mmol) obtained in Reference example 2 (2a) in methylene chloride (700 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mixture and the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-5:1) to obtain the title compound (45.9 g, yield: 69%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:15]Br.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[C:13]([Br:15])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: BrBr
Reactant: CC(C)Cn1cnc2cc(N)ccc21
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(Br)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isobutyl-5-aminobenzimidazole (2.4 g, 13 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5%) NH, sat'd MeOH/CH2Cl2) to provide 1.2 g (4.5 mmol, 35%) of the product.