Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[O:19])[C:9]=2[CH:20]=1.O>C(O)C.[OH-].[Na+]>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH:10]([OH:19])[C:9]=2[CH:20]=1
Reactant: CSc1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In operations carried out in a manner similar to that described in Example VI, 0.5 gram (13 millimoles) of sodium borohydride was added to a solution of 0.8 gram (3.2 millimoles) of 3-methylthio-5H-dibenzo[a,d]cyclohepten-5-one in 20 milliliters of ethanol to which 1 drop of 40 percent sodium hydroxide had been added and the resulting mixture stirred overnight at room temperature. Thereafter, water was added to the reaction mixture, the aqueous mixture subjected to reduced pressure to remove the ethanol, the remaining aqueous solution extracted with ether, the ether solution washed successively with water and saturated sodium chloride, and then dried over magnesium sulfate. The dried solution was subjected to reduced pressure to obtain the 3-methylthio-5H-dibenzo[a,d]cyclohepten-5-ol intermediate as a white solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([N+]([O-])=O)[CH:18]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8])([O-])=O.C1(C)C=C(C)C=C(C)C=1C(OC1C=CC=CN=1)=O.C(OC1C=CC=CN=1)(=O)C(C)(C)C.C(OC1C=CC=CN=1)(=O)C1C=CC(OC)=CC=1>>[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:8])[C:6]1[CH:5]=[CH:4][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Oc1ccccn1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)(C)C(=O)Oc1ccccn1
Agent: COc1ccc(C(=O)Oc2ccccn2)cc1
Agent: Cc1cc(C)c(C(=O)Oc2ccccn2)c(C)c1
Product: O=C(Oc1ccccn1)c1ccccc1

Procedure:
Other products prepared by this procedure are 2-(3,5-dinitrobenzoyloxy)pyridine (88%), 2-mesitoyloxypyridine (86%), 2-pivaloyloxypyridine (93%), and 2-p-anisoyloxypyridine (100%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH2:12](Cl)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH:13]=[CH2:12]
Reactant: C=CCCl
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A 500 mL flask is charged with isatin (50 g, 339 mmol), allyl chloride (33.8 g, 441 mmol), potassium carbonate (93.9 g, 679 mmol), and DMF (100 mL). The mixture is stirred at 70° C. for 14 hours (complete conversion by TLC), and then diluted with DMF. After filtration over a pad of cellite and removal of the solvent, the product remained as red crystals (68 g) which are used directly in the next step. 1HNMR (CDCl3, 300 MHz) δ 4.34 (dtr, 1H, 3J=5.3 Hz, 4J=1.8 Hz, NCH2CHC═CH2); 5.27 (dm, 1H, 3J=10.3 Hz, NCH2CHC═CHcis); 5.30 (dm, 1H, 3J=17.0 Hz, NCH2CHC═CHtrans); 5.82 (ddtr, NCH2CHC═CH2); 6.87 (d, 1H, 3J=7.9 Hz, H-7); 7.09 (br tr, 1H, 3J=7.3 Hz, H-5); 7.55 (dtr, 1H, 3J=8 Hz, H-6); 7.57 (d m, 1H, 3J=7.3 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 42.82 (NCH2); 111.11 (C-7); 117.77 (C-9); 118.80 (CH═CH2); 123.96 (C-5); 125.50 (C-4); 130.51 (CH═CH2); 138.48 (C-6); 150.96 (C-8); 158.02 (C-2); 183.29 (C-3).
Reaction SMILES: C([O:3][CH:4](OCC)/[CH:5]=[CH:6]/[C:7]1[C:8]2[S:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:9]=2[C:10]([NH2:13])=[N:11][CH:12]=1)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[NH2:13][C:10]1[C:9]2[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)=[CH:15][S:16][C:8]=2[C:7](/[CH:6]=[CH:5]/[CH:4]=[O:3])=[CH:12][N:11]=1
Reactant: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Nc1ncc(/C=C/C=O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 106 %

Procedure:
A mixture of Example 360A (170 mg, 0.38 mmol), p-toluenesulfonic acid (10 mg), acetone (9 mL), and water (1 mL) was stirred for 1.25 hours and concentrated. The residue partioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried (MgSO4), filtered, and concentrated to provide the desired product (150 mg). 1H NMR (DMSO-d6, 400 MHz) δ 9.66 (d, 1H), 8.32 (s, 1H), 7.89 (d, 1H), 7.68 (s, 1H), 7.47 (m, 4H), 7.20 (t, 1H), 7.14 (m, 4H), 6.65 (dd, 1H); MS m/e 373.3 (M+H)+, 371.1 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[N:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[N:26]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nn(C)c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1-Methyl-1H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=486.4.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][C@H:29]([OH:33])[C@@H:30]([OH:32])[CH3:31])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.O1CCOCC1>CO.[Pd]>[OH:33][C@H:29]([C@@H:30]([OH:32])[CH3:31])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: C[C@H](O)[C@@H](O)COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](O)[C@@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
2-[4-(Benzyloxycarbonyl)piperazin-1-yl]-4-[(2S,3S)-(2,3-dihydroxybutan-1-yl)oxy]quinazoline (5.1 g) is dissolved in methanol (90 ml)--dioxane (10 ml), and thereto is added 10% palladium/carbon (0.5 g), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 16 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give 4-[(2S,3S)-(2,3-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (3.3 g).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:32]([CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)=[O:33])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1CCOCC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with tetrahydro-pyran-4-carboxylic acid in analogy to experiment A1 to give (2S,4R)-1-(tetrahydro-pyran-4-carbonyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 474.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([N:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 24 h under reflux conditions to give the title compound as yellow oil. MS: m/e=451.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(N)c1
Reaction time: 72 h
Yield: 97.3 %

Procedure:
10% Palladium on activated carbon (1.0 g, 9.4 mmol, 0.15 eq) is added at room temperature to a stirred solution of 4-methoxy-2-nitro-phenylamine (10.0 g, 59.5 mmol, 1.0 eq) in methanol (70 mL). The mixture is hydrogenated for 72 hours, then filtered through decalite. Solvent is removed to afford 4-methoxy-benzene-1,2-diamine as a dark brown oil (8.0 g, 97% yield).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])=[CH:20][CH:19]=1.BrB(Br)Br>>[NH2:26][C@@H:24]([C:21]1[CH:20]=[CH:19][C:18]([C:4]2[C:5]3[C:6]4[CH:17]=[CH:16][S:15][C:7]=4[C:8](=[O:14])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[OH:2])=[CH:23][CH:22]=1)[CH3:25]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: Cc1cc(O)c(-c2ccc([C@@H](C)N)cc2)c2c1[nH]c(=O)c1sccc12
Yield: 54.1 %

Procedure:
Following General Procedure F, (R)-tert-butyl 1-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (43 mg, 0.095 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) to afford the desired product (18 mg, 51%) as a grey solid: 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.52 (s, 3H), 7.65 (dd, J=13.3, 6.8 Hz, 3H), 7.30 (d, J=8.2 Hz, 2H), 7.06 (s, 1H), 5.87 (d, J=5.4 Hz, 1H), 4.64-4.45 (m, 1H), 2.50 (s, 3H), 1.63 (d, J=6.8 Hz, 3H); ESI MS m/z 480 [C27H33N3O3S+H]+; HPLC 98.6%, tR=8.42 min.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.[O:11]=[C:12]1[CH2:17][C:16](=O)[CH2:15][CH:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:3][C:16]1[CH2:15][CH:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12](=[O:11])[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C=C(Cl)CC1c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of phosphoryl chloride (3.53 g.) and dimethylformamide (1.68 g.) at 0° C was added a cooled solution of ethyl 2,4-dioxo-6-p-tolylcyclohexanecarboxylate (6.2 g.) a dione of formula II prepared as in Example 1, in dichloromethane (60 ml.). After keeping at 0° C for 30 minutes the mixture was poured into excess 2N-Na2CO3 solution and extracted with ether. After washing the ether extracts with water and drying over magnesium sulphate, evaporation of the solvents gave crude ethyl 4-chloro-2-oxo-6-p-tolyl-3-cyclohexenecarboxylate (a halide of formula IV) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccc(C=O)cc2)cc1
Yield: 84.9 %

Procedure:
A mixture of 4-methoxyphenol (1.0 g, 0.00806 mol), 4-bromobenzaldehyde (1.49 g, 0.00805 mol), CuO (0.64 g, 0.00805 mol), potassium carbonate (1.11 g, 0.00803 mol) in pyridine (100 mL) was refluxed for 60 h. The reaction mixture was filtered into ice/water and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), concentrated and chromatographed with CH2Cl2 to afford 1.56 g (85%) of 4-(4-methoxyphenoxy)benzaldehyde.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22](C(O)=O)[CH:21]=[CH:20][C:19]=12>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22]([C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH:21]=[CH:20][C:19]=12
Reactant: O=C(O)c1ccc2cncn2c1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc2cncn2c1
Temperature: 90 °C

Procedure:
3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tertbutyl)acetal are added to 570 mg (3.52 mmol) of imidazo[1,5-a]pyridine-6-carboxylic acid [described in Bioorg. Med. Chem. Lett., (2002), 12(3), 465-470] in a mixture of 5 ml of dimethylformamide and 5 ml of toluene and the mixture is heated at 90° C. for 6 hours. 3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tert-butyl)acetal are again added to the reaction medium and the mixture is heated at 90° C. for a further 4 hours. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through a bed of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). After evaporation, 580 mg of a beige powder are obtained. Melting point: 77° C.; 1H NMR (d6-DMSO): 1.59 (9H, s), 7.71 (1H, d), 7.36 (1H, s), 7.58 (1H, d), 8.56 (1H, s), 9.03 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([OH:29])=[CH:24][C:23]=1[CH3:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[OH:29][C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[CH3:1])=[C:23]([CH3:30])[CH:24]=1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2c(C)cc(O)cc2C)c1C
Temperature: 60 °C
Reaction time: 14.5 h

Procedure:
In an atmosphere of nitrogen, a mixture of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 4-bromo-3,5-dimethylphenol, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred for 14.5 hours with heating at 60° C. to obtain methyl 4′-hydroxy-2,2′,6′-trimethylbiphenyl-3-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4][CH:3]1[CH3:45].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH:5]3[CH2:6][CH2:7][C:2](=[O:1])[CH:3]([CH3:45])[CH2:4]3)=[CH:10][CH:11]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)C(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)C(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 3-{4-[(4-hydroxy-3-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.50 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.38 g, 77%).
Reaction SMILES: [NH2:1][CH:2]([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH:41]([Cl:45])[C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH:41]([Cl:45])[C:42]([NH:1][CH:2]([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:38][CH3:39])=[O:43]
Reactant: CCC(N)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)C(Cl)Cl)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Yield: 67 %

Procedure:
2,2-Dichloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide was obtained from treating[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.049 g, 0.09 mmol, Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2-Dichloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide (0.039 g, 67%) as an oil. ES-LCMS m/z 642 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([CH:11]=[C:12]([CH3:14])[N:13]=3)[N:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1.[CH2:15]([CH:17]([C:20]1[C:21]2[N:22]([C:27](I)=[C:28]([CH3:30])[N:29]=2)[N:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:18][CH3:19])[CH3:16]>>[CH:1]1([C:4]2[C:5]3[N:6]([C:11]([C:27]4[N:22]5[N:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH:17]([CH2:15][CH3:16])[CH2:18][CH3:19])[C:21]5=[N:29][C:28]=4[CH3:30])=[C:12]([CH3:14])[N:13]=3)[N:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cn2nc(C)cc(C3CC3)c2n1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C5CC5)cc(C)nn34)c(C)nc12
Yield: 43.9 %

Procedure:
Using a procedure analogous to Example 16B, 8-cyclopropyl-2,6-dimethyl-imidazo[1,2-b]pyridazine (76.5 mg, 0.41 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.14 g, 0.41 mmol) give the title compound (71.6 mg, 0.18 mmol, 43%). 1H NMR (CDCl3): δ 0.91 (t, J=7.1 Hz, 6H), 1.05-1.11 (m, 2H), 1.24-1.30 (m, 2H), 1.75-1.93 (m, 4H), 2.41 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 2.65-2.75 (m, 1H), 3.33-3.45 (m, 1H), 6.64 (s, 1H), 6.67 (s, 1H) ppm. ES-MS (m/z): calcd for C24H30N6 (M+H)+: 403.6. found: 403.3.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.[ClH:11].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[ClH:11].[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:19][NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][N:3]=1
Reactant: NNc1ccccc1
Reactant: Cc1ncc(C=O)c(N)n1
Agent: Cl
Solvent: CO
Product: Cc1ncc(C=NNc2ccccc2)c(N)n1
Yield: 99.8 %

Procedure:
In 333 ml of methanol was dissolved 8.6 g of 2-methyl-4-amino-5-formylpyrimidine. To the solution was added gradually 10.6 g of phenyl hydrazine hydrochloride. As the reaction proceeded, crystals precipitated out. Five hours later, the crystals were collected by filtration and dried under reduced pressure to obtain 16.5 g (93%) of 1-(2-methyl-4-aminopyrimidyl)methylidene-2-phenylhydrazine hydrochloride. Physical properties of 1-(2-methyl-4-aminopyrimidyl)methylidene-2-phenylhydrazine hydrochloride are as follows:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:23]([C:20]2([C:17]3[N:13]4[CH2:14][CH2:15][S:16][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:30])[CH2:11][C:12]4=[N:19][N:18]=3)[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccccc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), phenylboronic acid (61 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (197 mg, 78%) as a light yellow solid.