Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:28]2[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=2)=[O:33])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: Cn1ccnc1C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 22.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), 1-methyl-1H-imidazole-2-carbonyl chloride (0.026 g, 0.283 mmol), dry THF (5 mL), DIPEA (2 mL). The obtained crude was purified by column chromatography using 2% ammonia in 20% MeOH:DCM as mobile phase to afford 0.020 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 3.50 (s, 3H), 4.41 (d, J=18.0 Hz, 1H), 6.99 (s, 1H), 7.43 (br, 2H), 7.67 (d, 1H), 7.78 (s, 1H), 8.28 (d, J=4.5 Hz, 2H), 8.30 (s, 1H), 9.08 (t, 1H); MS (m/z): 477.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:29]1[N:33]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:32]=[N:31][C:30]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][C:29]3[N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)[N:32]=[N:31][C:30]=3[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Cl
Reactant: Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of 1-[4-(4-chlorobenzyl)piperazin-1-yl]-3-(3-hydroxyphenoxy)propane (7.00 g, 0.019 mole), in dry dimethyl formamide, (200 ml) was treated portionwise with 60% sodium hydride in oil, (0.776 g, 0.019 mole), under a slow stream of nitrogen. The mixture was stirred at room temperature for 0.5 h, then Ethyl 5-chloro-1-(4-methoxybenzyl)-1,2,3-triazole 4-carboxylate (5.74 g, 0.019 mole) was added. The reaction was stirred at 100° C. for 24 hours, then cooled and the solvent removed in vacuo. The brown residue was partitioned between ethyl acetate and water and the organic phase separated, washed with water (twice), and dried, (MgSO4). Evaporation in vacuo gave the crude product as a pale brown oil which was purified by column chromatography to yield 8.52 g (72%) of the title compound as a pale yellow oil. νmax (film) 1510, 1560, 1590, 1615, 1730, 2810, 2940 cm-1 δ(CDCl3 ) 1.11 (3H, t, J 7 Hz, ester CH3), 1.91 (2H, m, CH2), 2.51 (10H, piperazinyl+CH2), 3.46 (2H, s, --NCH2), 3.73 (3H, s, OCH3), 3.87 (2H, t, J 6 Hz, OCH2), 4.18 (2H, q, J 7 Hz, ester CH2), 5.33 (2H, s, --NCH2), 6.33 (2H, m, aromatics), 6.80 (1H, m, aromatics), 7.00 (4H, ABq, Δν=39 Hz, J 9 Hz, --C6H4OCH3), 7.16 (1H, m, aromatics), 7.28 (4H, s, C6H4 --Cl). Mass Spec. Observed mass 619.2572, theoretical mass 619.2561 (C33H38ClN5O5).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC1CC1)c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Sodium triacetoxyborohydride (0.51 g) was added to a solution of 3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazine-2-carbaldehyde (0.37 g), N-benzylethanolamine (0.29 g) and acetic acid (0.28 mL) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20-*40% ethyl acetate/hexane) to give the title compound (0.5 g, 86%) as a pale-yellow oil.
Reaction SMILES: [Na].CO.[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[N+:14]([CH:17]([CH3:19])[CH3:18])([O-:16])=[O:15]>C(O)(=O)C>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[C:17]([CH3:19])([N+:14]([O-:16])=[O:15])[CH3:18])=[CH:8][CH:7]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])cc1
Temperature: 13 °C
Reaction time: 0.42 h
Yield: 13.1 %

Procedure:
11.5 g of sodium are added to 300 ml of anhydrous methanol, and 67 g of 4-methoxybenzaldehyde and 105 g of 2-nitropropane are added thereto at 13° C. for 25 minutes under stirring. The mixture is stirred at 23° C. for 70 hours. 32 g of acetic acid are added to the mixture under ice-cooling, and said mixture is evaporated under reduced pressure to remove solvent. About 200 ml of water are added to the residue, and the aqueous mixture is extracted with benzene. The extract is washed with a saturated sodium chloride solution, a saturated sodium bisulfite solution, water and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. The residue (yellow oil, 65 g) is distilled at 75° C. under reduced pressure (1-2 mm Hg) to recover 47 g of the starting compound (i.e., 4-methoxybenzaldehyde). On the other hand, 14.5 g of 1-(4 -methoxyphenyl)-2-methyl-2-nitropropanol (crude product) are obtained as the residue.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C[Al](C)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH:19]1[C:24](O)=[O:25].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][C:24]([CH:19]2[CH2:20][O:21][CH2:22][CH2:23][NH:18]2)=[O:25])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1cc(NC(=O)C2COCCN2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a stirring solution of 4-chloro-2-fluoro-5-(1-methylethoxy)aniline (15.52 g, 76.26 mmol) in CH2Cl2 (100 mL), under nitrogen at 0° C. (ice-bath) was added dropwise trimethylaluminum (114.4 mL, 228.78 mmol). The mixture was then stirred overnight at room temperature. 3-Morpholinecarboxylic acid (10.0 g, 76.20 mmol) was added portionwise at room temperature. The resultant reaction mixture was stirred at room temperature for 2 days. 6N HCl was added dropwise to the reaction mixture at 0° C. (ice-bath). The solid formed was filtered off and suspended in water (100 mL). The suspension was basicified with 50% aqueous NaOH to pH 13. 400 mL of CH2Cl2 was added. The organic layer was separated, dried over MgSO4 and the solvent was removed under vacuum to give the title compound of Step B as a white solid (10.5 g), m.p. 99°-101° C. 1H NMR: δ9.30 (br s,1H), 8.17 (d,1H), 7.14 (d,1H), 4.53 (q,1H), 3.96-3.61 (m,5H), 3.00-3.01 (m,2H), 1.37 (d,6H).
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1.[CH:25](O)([CH3:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1C=CC=CC=1>[CH:25]([O:1][CH:2]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1)([CH3:27])[CH3:26]
Reactant: CC(C)O
Reactant: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(CN2CC=C(C3=NNC(=O)CS3)CC2)OC(C)C)cc1
Temperature: 25 °C

Procedure:
2-[1-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1,2,5,6-tetrahydropyrid-4-yl]-4H,6H-1,3,4-thiadiazin-5-one (300 mg, 0.86 mmol) was suspended in mixed solution of isopropanol(15 ml) and benzene (25 ml), added with p-toluenesulfonic acid monohydrate (4.5 g, 0.02 mol) and refluxed for 5 hours while being dehydrated by a Dean-Stark's dehydrator. After allowing to cool to room temperature, the reaction mixture was added dropwise to 1Naqueous sodium hydroxide (30 ml). The benzen layer was separated and the water layer was further extracted three times with benzen. The benzen layer was combined with the above-mentioned benzen layer and dried over anhydrous magnesium sulfate. Benzene was removed under reduced pressure and the residue was crystallized from a little amount of ether. The solid obtained was further crystallized from ether to obtain the titled compound(145 mg) as white power.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22](C)=O)[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
800 mg of the product obtained in Stage 5 above is introduced into 16 ml of methylene chloride and 0.54 ml of trifluoroacetic anhydride is added. Agitation is carried out for 30 minutes, followed by evaporating to dryness and the residue is taken up in 10 ml of methanol and 4 ml of triethylamine. Agitation is carried out for 30 minutes, followed by extraction with chloroform, washing with a saturated solution of ammonium chloride, drying and evaporating to dryness. In this way 720 mg of expected product is obtained.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=1.[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:52][CH:53]=[CH:54][N:55]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:46]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:55][CH:54]=[CH:53][N:52]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59][C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=2)[N:46]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
N-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)-amino]-3-nitro-2-pyridyl}acetamide was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and N-(6-chloro-3-nitro-2-pyridyl)acetamide in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]-ethyl}amine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([O:13][CH2:14][CH3:15])(=O)C.O>O1CCCC1>[CH2:14]([O:13][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[C:15]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(OCc2ccccc2)c1
Yield: 62 %

Procedure:
A solution of 2-chloro-4-cyanopyridine (0.40 g, 2.9 mmol) in tetrahydrofuran (1 ml) was added to the mixture and the mixture was refluxed for 6 hrs. The reaction mixture was combined with ethyl acetate and water and stirred. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel (30 g) column chromatography, eluted with hexane-ethyl acetate (4:1, v/v) to give the titled compound (0.37 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:25]=[C:24]([Cl:23])[CH:29]=[CH:28][C:27]=4[CH3:33])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1ccc(Cl)cc1B(O)O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4C)c3O2)cc1
Yield: 80.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (5-chloro-2-methylphenyl)boronic acid (0.334 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.451 g (81%) of (±)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]1.[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)[C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: CCN1CCN(c2cccc(Cl)c2CBr)CC1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2cccc(Cl)c2CSc2nc(C)cc(O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A mixture of 1-[2-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine (24.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (2.35 g, 16.5 mmol), and triethylamine (17 mL, 124 mmol) in absolute ethanol (300 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated. The solid residue was treated with water (500 mL). The mixture was extracted with DCM (3×200 mL) and EtOAc (1×200 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% MeOH/DCM and 0-15% MeOH/DCM), affording 2-({[2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (505 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, 3H, J=7.2 Hz), 2.24 (s, 3H), 2.85 (m, 2H), 2.50 (m, 4H), 2.87 (m, 4H), 4.67 (s, 2H), 6.02 (s, 1H), 7.22 (m, 2H), 7.32 (t, 1H, J=8.0 Hz); M+379.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([Si:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C1COCC1>[CH2:30]([Si:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH:40]([CH:2]=[O:4])[CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC[Si]1(c2ccccc2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
12 g of potassium t-butoxide was added to a mixture of 35 g of methoxymethyltriphenylphosphonium chloride and 200 ml of THF to prepare an orange ylide solution. A solution of 28 g of 4-n-heptyl-4-phenyl-4-silacyclohexanone in 50 ml of THF was added to the solution. After agitation for 2 hours at room temperature, the mixture was poured into iced water and extracted with methylene chloride. The extract was washed, dried and concentrated by a usual manner. n-Hexane was added to the resultant concentrate, followed by removal of the resultant triphenylphosphine oxide crystals by filtration. The resultant filtrate was concentrated. The concentrate was hydrolyzed with 100 ml of 20% hydrochloric acid, followed by washing, drying and concentration by a usual manner to obtain 4-n-heptyl-4-phenyl-4-silacyclohexane carbaldehyde.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.Cl[CH2:14][C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[O:21]=[C:15]([CH2:14][S:12][C:9]1[N:10]=[CH:11][NH:7][N:8]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: Sc1nc[nH]n1
Reactant: COC(=O)CC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1nc[nH]n1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
Add dropwise potassium tert-butoxide (11.4 g, 101.8 mmol) in 30 ml N,N-dimethylformamide (30 ml) to a solution of [1,2,4]triazole-3-thiol (10.3 gm, 101.8 mmol) in N,N-dimethylformamide (50 ml). Add dropwise methyl 4-chloroacetoacetate (15.3 gm, 101.8 mmol) in N,N-dimethylformamide (15 ml) and stir for 3 hours. Concentrate under reduced pressure, dilute with ethyl acetate (500 ml), filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography to provide the desired compound (18.3 gm, 83%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[CH:26]([N:29](CC)C(C)C)(C)C.CN>C(#N)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:29][CH3:26])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC)n(C)c(=O)c1OCc1ccccc1
Reaction time: 0.5 h
Yield: 303.5 %

Procedure:
A solution of 2-methanesulfonyl-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.180 g, 3.22 mmol) in acetonitrile (20 ml) was treated at 25° C. with N,N-diisopropylethylamine (1.5 ml, 0.87 mmol) followed by 4.8 ml (9.6 mmol) of a 2M solution of methylamine in tetrahydrofuran. After 30 min, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate, 25:75) to give 0.838 g (82% yield) of the title ester as a clear syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.30 (3H, t, J=7.1 Hz, CH3), 3.04 (3H, d, J=5.1 Hz, NCH3), 3.42 (3H, s, NCH3), 4.32 (2H, q, J=7.1 Hz, OCH2), 4.58 (1H, broad q, NH), 5.07 (2H, s, OCH2), 7.3–7.37 (3H, m, aromatics), 7.47 (2H, m, aromatics). HRMS (FAB POS) calculated for C16H20N3O4 [M+H+]: 318.145381. found: 318.144860.
Reaction SMILES: Cl.[N+]([O-])(OCCC(C)C)=O.[CH3:11][O:12][C:13]1[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:29]([N:31]=[N+]=[N-])=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:20])=[CH:15][CH:14]=1.[N-]=[N+]=[N-].[CH:39]([O:42][C:43](=[O:55])[CH:44]([OH:54])[C@@H:45](N)[CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:41])[CH3:40]>CN(C)C=O.C(N(CC)CC)C>[CH:39]([O:42][C:43](=[O:55])[CH:44]([OH:54])[C@@H:45]([NH:31][C:29](=[O:30])[C@H:22]([CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)[NH:21][C:19]([O:18][CH2:17][C:16]1[CH:34]=[CH:35][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:20])[CH2:46][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1)([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)C(O)[C@@H](N)CC1CCCCC1
Reactant: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N=[N+]=[N-])cc1
Agent: CC(C)CCO[N+](=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CC2CCCCC2)C(O)C(=O)OC(C)C)cc1

Procedure:
In 15 ml of N,N-dimethylformamide was suspended 1.37 g of the hydrazide compound, and to the suspension were successively added a solution of a 5.95N-dry hydrogen chloride in 2.29 ml of N,N-dimethylformamide and 0.66 ml of isoamyl nitrate with stirring at -20° C. After disappearance of the hydrazide compound, the reaction mixture was cooled to -30° C., and then neutralized by an addition of 1.89 ml of triethylamine to prepare a cold solution of N-(4-methoxybenzyloxycarbonyl)-L-histidine azide. The cold azide solution was added to a solution of 1.00 g of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester in 40 ml of N,N-dimethylformamide with stirring under ice-cooling. The mixture was still stirred for 16 hours, and then the reaction mixture was evaporated under reduced pressure. To the residue was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1) to obtain 1.70 g of (2RS, 3S)-3-[N-(4-methoxybenzyloxycarbonyl)-L-histidyl]amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester as a white powder. In 50 ml of methanol was 1.70 g of the butyric acid isopropyl ester compound, and to the solution were added 10 ml of a 2N hydrochloric acid and 200 mg of a 10% palladium charcoal. The mixture was hydrogenated under an atmospheric pressure. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 1.36 g of (2RS, 3S)-3-(L-histidyl)amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester dihydrochloride as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[C:13]([Br:24])[N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Yield: 82.1 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.216 mmol) and N-bromosuccinimide (42 mg, 0.238 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH) to give 69 mg of the title compound as a yellow solid. MS: (−) m/z 387.13, 389.15 (M-1, 79/81Br).
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1CCC[CH2:7]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:17]=1>>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:17]=[C:12]([CH:7]=[O:6])[CH:13]=[N:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C#Cc2cncc(Br)c2)c1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Product: COc1cccc(C#Cc2cncc(C=O)c2)c1
Yield: 82 %

Procedure:
Prepare essentially as described in EXAMPLE 90 using a 1 M solution of isopropylmagnesium chloride in tetrahydrofuran (2.98 mL, 2.98 mmol), 3-bromo-5-(3-methoxyphenylethynyl)-pyridine, (prepared as described in PREPARATION 20), (430 mg, 1.49 mmol) to give the title compound (290 mg, 82%).