Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH2:30][Cl:31].CN(C=O)C>CC(C)=O>[Cl:31][CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(-c2ccc(O)cc2)c2sccc2c1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(OCCCCl)cc2)c2sccc2c1=O
Yield: 98 %

Procedure:
A solution of the product of step 3 (858 mg, 3 mmol), K2CO3 (1.24 g, 3.0 eq.), and 3-bromo-1-chloropropane (0.3 mL, 1.05 eq.) in acetone:DMF (25 mL:3 mL) was heated to 80° C. overnight. The mixture was then filtered, washed with acetone, and concentrated to dryness to afford the product of step 4 (1.17 mg, 98% yield): Mp 92-4° C.; MS m/z 363 (M+H).
Reaction SMILES: C12(C[O:12]C3C=CC(C#N)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[CH:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH:30]1[CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=1[CH:49]1[CH2:51][CH2:50]1)[CH2:36]2>>[CH:31]12[CH2:37][CH:35]3[CH2:34][CH:33]([CH2:38][CH:29]([CH2:36]3)[CH:30]1[CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]([NH2:46])=[O:12])=[CH:43][C:42]=1[CH:49]1[CH2:51][CH2:50]1)[CH2:32]2
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1ccc(OCC2C3CC4CC(C3)CC2C4)c(C2CC2)c1
Product: NC(=O)c1ccc(OCC2C3CC4CC(C3)CC2C4)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 38 step 3 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with 4-(adamantan-2-ylmethoxy)-3-cyclopropylbenzonitrile, the title compound was obtained as a colorless solid (0.62 g, 95%): MS (ES+) m/z 326.3 (M+1);
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[N:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:33][O:32][C:29]1[N:28]=[N:27][C:15]([C:13]2[O:12][C:11]([CH3:24])=[C:10]([CH2:9][OH:8])[CH:14]=2)=[CH:31][CH:30]=1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(CO)c(C)o2)nn1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 3-chloro-6-methoxypyridazine (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (40% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (1.3 g, 86%) as a white crystal.
Reaction SMILES: C[N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1.[NH2:37][C:38]1[N:46]=[C:45]2[C:41]([N:42]=[CH:43][NH:44]2)=[C:40]([NH:47][CH:48]([C:50]2[N:59]([C:60]3[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=3)C#N)[C:58](=[O:68])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][C:56]=3[CH3:69])[N:51]=2)[CH3:49])[N:39]=1>>[NH2:37][C:38]1[N:46]=[C:45]2[C:41]([N:42]=[CH:43][NH:44]2)=[C:40]([NH:47][CH:48]([C:50]2[N:59]([C:60]3[CH:67]=[CH:66][CH:65]=[C:62]([N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:36]4)[CH:61]=3)[C:58](=[O:68])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][C:56]=3[CH3:69])[N:51]=2)[CH3:49])[N:39]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(OCCN(C)C)c3)c(=O)c12
Reactant: Cc1cccc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)n(-c3cccc(C#N)c3)c(=O)c12
Product: Cc1cccc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)n(-c3cccc(N4CCOCC4)c3)c(=O)c12

Procedure:
Compound 158 was prepared in accordance with the procedure described for compound 129, but compound 133 was used in place of compound 126. m/z=498 (M+H). The structure of compound 153 is shown below.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2].S(Cl)([Cl:18])=O>C(Cl)CCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([C:12]([Cl:18])=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1nsc2ccc([N+](=O)[O-])cc12
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1nsc2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 5-nitro-1,2-benzisothiazole-3-carboxylic acid (5.5 g, 0.0246 mole) and ethylene dichloride (55 ml) is added thionyl chloride (2.92 g, 1.63 ml, 1.0 eq.), and the reaction mixture heated to 70° C. An additional portion of thionyl chloride (1.46 g, 0.82 ml, 0.5 eq) is added and heating at 70° C. continued for 2.5 hours. The cooled solution is concentrated in vacuo to afford the title compound which is identified by NMR and IR analysis, and used without further purification.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([C:21]1[C:30]([C:31]#[N:32])=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26](/[CH:40]=[CH:41]/[CH:42]=O)[CH:27]=2)[N:22]=1)[CH:18]([CH3:20])[CH3:19]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[C:21]([CH2:17][CH:18]([CH3:20])[CH3:19])=[N:22][C:23]2[C:28]([C:29]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[CH:27][C:26](/[CH:40]=[CH:41]/[CH:42]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:25][CH:24]=2)#[N:32]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(/C=C/C=O)cc23)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C=C/c1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.90 g, 10.2 mmol) in tetrahydrofuran (50 ml) was added sodium hydride (60% in oil, 408 mg, 10.2 mmol) at 0° C. and the mixture was stirred for 10 min. To the reaction mixture was added 2-isobutyl-4-(4-methylphenyl)-6-[(1E)-3-oxoprop-1-en-1-yl]quinoline-3-carbonitrile (3.00 g, 8.47 mmol). The temperature of the mixture was raised to room temperature and the mixture was stirred for 10 min. The reaction mixture was diluted with a mixture of tetrahydrofuran and ethyl acetate, washed successively with 2N aqueous sodium hydroxide solution, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give yellow crystals. The crystals were washed with diisopropyl ether to give ethyl (2E,4E)-5-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]penta-2,4-dienoate (2.71 g, yield 75%) as yellow crystals. The solvent of the mother liquor was removed under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl (2E,4E)-5-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]penta-2,4-dienoate (320 mg, yield 9%) as yellow crystals.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:29])([F:28])[C:11](=[O:27])[CH2:12][C:13]([CH3:26])([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)[CH3:14].O>CS(C)=O>[CH3:26][C:13]([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)([CH3:14])[CH2:12][C:11]1([C:10]([F:9])([F:28])[F:29])[CH2:2][O:27]1
Reactant: C[S+](C)(C)=O
Reactant: CSc1cc2c(c(C(C)(C)CC(=O)C(F)(F)F)c1)OCC2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc2c(c(C(C)(C)CC3(C(F)(F)F)CO3)c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of trimethylsulfoxonium iodide (1.36 g, 6.1 mmol) in 7.7 mL of anhydrous DMSO was added sodium hydride (60% dispersion in mineral oil, 246 mg). The resulting solution was stirred at room temperature for 30 minutes and was then added dropwise to a solution of 1,1,1-trifluoro-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)pentan-2-one (1.63 g, 6.2 mmol) in 6.5 mL of anhydrous DMSO. After 2 hours, 100 mL of water was added and the resulting mixture was extracted with three 100 mL portions of diethyl ether. The combined organic phases were washed twice with water, aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, 1.64 g (95% yield) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:18][NH:19][CH3:20]>O1CCCC1>[CH3:18][N:19]([CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:20]
Reactant: CNC
Reactant: COC(=O)c1sc(-c2ccccn2)nc1CBr
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccn2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound prepared in Example 152 (500 mg) and dimethylamine (1.8 mL) in tetrahydrofuran (3 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1 then ethyl acetate=1) to obtain the title compound (191 mg) having the following physical data. 1H NMR (CDCl3): δ 8.63-8.59 (m, 1H), 8.34-8.25 (m, 1H), 7.84-7.76 (m, 1H), 7.40-7.33 (m, 1H), 4.01 (s, 2H), 3.91 (m, 3H), 2.41 (s, 6H);
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24][CH2:25][CH3:26])=[CH2:23])CCC>O1CCOCC1.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]>[CH2:25]([O:24][C:22]([C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([C:22]([O:24][CH2:25][CH3:26])=[CH2:23])=[CH:8][CH:7]=3)[CH:3]=1)=[CH2:23])[CH3:26]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nc3cc(Br)ccc3nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nc3cc(C(=C)OCC)ccc3nc2c1
Yield: 88.1 %

Procedure:
To a solution of 2,7-dibromophenazine (13-2) (1.52 g, 4.50 mmol) in dry dioxane (75 mL) under N2 was added tributyl(1-ethoxyvinyl)stannane (3.34 ml, 9.89 mmol) and Pd(dppf)Cl2 (0.316 g, 0.450 mmol). The resultant mixture was heated at 100° C. for 4 hrs in a sealed tube. The crude reaction mixture was filtered through CELITE™ 545, and the volatiles were removed in vacuo. The crude brown solid was triturated with isohexanes and filtered to give 2,7-bis(1-ethoxyvinyl)phenazine as a brown solid (1.27 g, 88% yield). 1H NMR (CDCl3): δ 8.55-8.53 (2H, m), 8.19-8.15 (2H, m), 8.11-8.07 (2H, m), 4.98 (2H, d, J=3 Hz), 4.49 (2H, d, J=3 Hz), 4.03 (4H, q, J=7 Hz), 1.50 (6H, t, J=7 Hz) ppm. LC-MS (ESI): m/z 322.1 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Si:13]([O:20][CH2:21][CH:22]1[CH2:24][N:23]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNCC12CC3CC(CC(C3)C1)C2)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
To a solution of (1-adamantylmethyl)amine (15 g, 52 mmol) in anhydrous CH2Cl2 (50 mL) was added tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)aziridine-1-carboxylate (13 g, 78.3 mmol). The mixture was stirred for 10 min, the solvent was removed in vacuo and the residue was stirred at 40° C. for 5 h. The mixture was diluted with EtOAc (500 mL) and washed with water (100 mL),1N aq HCl (50 mL), satd aq NaHCO3 (50 ml) and brine (50 mL), and dried over MgSO4. The solution was concentrated to give a residue, which was purified by chromatography on silica gel to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-((1-adamantylmethyl)amino)propan-2-ylcarbamate (10 g, 24%). 1H NMR: (CDCl3, 400 MHz): δ=0.041 (s, 6H), 0.882 (s, 9H), 1.44 (s, 9H), 1.49 (s, 6H), 1.65 (m, 6H), 1.94 (s, 3H), 2.23 (s, 2H), 2.62-2.81 (m, 2H), 3.67 (m, 3H), 5.30 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:23]([N+:24]([O-])=O)=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=2)=[O:7])=[C:4]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH:3]=1>[Pd].C1COCC1.C(O)C>[NH2:1][C:2]1[C:23]([NH2:24])=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=2)=[O:7])=[C:4]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CN(C)c1cc(C(F)(F)F)cc(NC(=O)c2cc([N+](=O)[O-])c(N)cc2OCC(F)(F)F)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1cc(C(F)(F)F)cc(NC(=O)c2cc(N)c(N)cc2OCC(F)(F)F)n1

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained in 656c with palladium on charcoal in THF and ethanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH3:25])[NH2:21]>C(O)(C)C>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][N:4]=[C:3]2[NH:21][C:20]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:18]([OH:17])[CH:19]=1
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(C)c(O)c3)c2cc1OC
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (130 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), and 3-hydroxy-4-methylaniline (62 mg, 0.5 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol and ether and dried to give 6,7-dimethoxy-4-(3-hydroxy-4-methylanilino)quinazoline hydrochloride (98 mg, 56%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:34]CCCCC.C([Li])CCC.CI>C1COCC1>[C:16]1([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH3:34])[N:11]=[CH:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of diethyl(1-triphenylmethylimidazol-4-yl)methylphosphonate (690 mg, 1.5 mmol) in THF (20 ml) was added 1.6M hexane solution of n-butyllithium (0.94 ml, 1.5 mmol) dropwise over 10 minutes at −72° C. under argon flow, followed by adding a solution of methyl iodide (213 mg, 1.5 mmol) in THF (5 ml) dropwise over 10 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was heated to room temperature, and then stirred at room temperature for 2 hours. The reaction was quenched with water (1 ml), and then the THF was removed under reduced pressure. Saturated brine (40 ml) was added to the residue, and the mixture was extracted 3 times with ethyl acetate (40 ml). The resultant organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a light yellow solid. It was purified through chromatography on silica gel column using methanol-ethyl acetate (1:9) to provide the titled compound (690 mg, 97%) as a white powder (m.p. 124-126° C.). This powder was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as a small needle crystal (m.p. 125-128° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](O)=[O:31])=[O:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH3:24][O:25][C:26](=[O:27])[NH:28][C@H:29]([C:30](=[O:31])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:22][OH:23])[CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (VII-deprotected) (step D) and (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (step E) using the coupling procedure with HOBt and EDAC described in example 3 (step D). The final product was obtained in 67% yield (121 mg).
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]([CH3:18])[C:9]=1[CH:19]([C:21]1[C:26]([Br:27])=[CH:25][N:24]=[CH:23][C:22]=1Br)[OH:20].C([Li])CCC.CI>O>[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]([CH3:18])[C:9]=1[CH:19]([C:21]1[C:22]([CH3:2])=[CH:23][N:24]=[CH:25][C:26]=1[Br:27])[OH:20]
Reactant: C1CCOC1
Reactant: COc1cc(C)c(C(O)c2c(Br)cncc2Br)c(OC)c1OC
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Product: COc1cc(C)c(C(O)c2c(C)cncc2Br)c(OC)c1OC
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A tetrahydrofuran (15 ml) solution of 2.0 g (4.6 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(3,5-dibromo-4-pyridyl)methanol obtained in step (a) was cooled to −78° C., 6.0 ml (9.4 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added thereto, followed by stirring for 5 minutes, and 0.5 ml (8.0 mmol) of methyl iodide was added thereto, followed by stirring for 2.5 hours. 20 ml of water was added, and tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 0.44 g (yield 25%) of (2,3,4-trimethoxy-6-methylphenyl)(3-bromo-5-methyl-4-pyridyl)methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (5.7 g, 16.34 mmol) and commercially available 3-nitrophenylboronic acid (3.274 g, 19.61 mmol) according to the general procedure VI. Obtained as a white solid (6.6 g, 92%). MS (ISP) 436.2 [(M+H)+]; mp 164° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]2=[N:20][CH:19]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ccncc4)c3F)cnc2n1

Procedure:
2-Fluoro-3-(pyridin-4-yl)benzeneboronic acid was coupled with 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 70% yield by a similar procedure to that described in Example 3, step f, to afford the title compound as a yellow solid: mp 221-223° C. (CH2Cl2-EtOAc-MeOH); 1H NMR (400 MHz, DMSO-d6) δ 1.57 (6H, s), 5.79 (1H, s), 7.55 (1H, t, J 7.8 Hz), 7.66 (2H, m), 7.73 (1H, m), 8.15 (1H, m), 8.29 (1H, d, J 2.3 Hz), 8.71 (2H, m), 9.02 (1H, s); MS (ES+) m/z 350 [M+H]+. Anal. Found: C, 65.06; H, 4.62; N, 19.91%. Required for C19H16FN5O: C, 65.32; H, 4.62; N, 20.05%.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][S:24][CH2:25][CH2:26][NH2:27].Cl>>[ClH:1].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: NCCSCc1nccs1
Agent: Cl
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1ccc(Cl)cc1

Procedure:
An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.36 g) and 2-(2-thiazolylmethylthio)ethylamine (0.9 g) was heated at 130°-135° for 31/2 hours. After cooling the reaction mixture was treated with 2 N hydrochloric acid. Evaporation to dryness followed by recrystallisation from isopropanol/methanol gave 2-[2-(2-thiazolyl-methylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 172.5°-174.5°.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>[Zn].O>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=C(Cl)CCl
Reactant: O=C1CCCCC1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(Cl)CC1(O)CCCCC1

Procedure:
45.23 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 20.00 g of cyclohexanone, 60 g of toluene, 60 g of water and 26.65 g of zinc powder at 35° C., and after the addition, the resultant mixture was maintained at the same temperature for 5 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase thereof was washed with a 7% sodium carbonate aqueous solution, and dried over magnesium sulfate. The desiccant was filtered off, and the resultant toluene solution was concentrated under reduced pressure to give 32.75 g of 1-(2'-chloroallyl)-1-cyclohexanol; nD20 =1.495, EI-MS m/e 156 (M-H2O+), 158 (M-H2O+2+).