Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24]OS(C)(=O)=O)=[N:22][CH:23]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[O:31]1[CH:35]=[C:34]([CH2:36][NH2:37])[CH:33]=[N:32]1>CN(C=O)C>[F:30][C:14]1[CH:13]=[C:12]([N:8]2[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]2=[O:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[N:22][C:21]([CH2:24][NH:37][CH2:36][C:34]2[CH:33]=[N:32][O:31][CH:35]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)nc3)c(F)c2)C(=O)O1
Reactant: NCc1cnoc1
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4cnoc4)nc3)c(F)c2)C(=O)O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
A solution of the methanesulfonic acid 5-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridin-2-ylmethyl ester 106 (220 mg, 0.5 mmol) in DMF (4.0 mL) was treated with C-isoxazol-4-yl-methylamine (68 mg, 0.5 mmol, 1.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 60° C. and stirred for 6 hours. When TLC and MS showed the reaction to be complete, the reaction mixture was concentrated in vacuo, and the residue was directly purified by column chromatography (0-5% MeOH/CH2Cl2 gradient elution) to afford the desired N-{3-[3-Fluoro-4-(6-{[(isoxazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4252 (22 mg, 10%) as off-white solids. LCMS (EI): 440 (M++H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1.CN(C=O)C>[CH2:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CN
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Isobutylamine (247 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (102 mg, 71%). NMR 1H (ppm, CDCl3): 7.97 (t, J4=1.71 Hz, 1H), 7.70 (dd, J3=7.65 Hz, J4=1.77 Hz, 2H), 7.62-7.58 (m, 2H), 7.51-7.34 (m, 4H), 6.18 (br. s., 1H), 3.33-3.29 (m, 2H), 1.91 (n, J3=6.71 Hz, 1H), 0.98 (d, J3=6.68 Hz, 6H).
Reaction SMILES: ClCCN(CCCl)C(Cl)=O.[Cl:11][CH2:12][CH2:13][N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:16][Cl:17].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1)[NH2:27].C1(C)C=CC=CC=1>C(O)C>[Cl:17][CH2:16][CH2:15][N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:13][CH2:12][Cl:11].[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:21]([NH:20][C:18]([N:14]([CH2:13][CH2:12][Cl:11])[CH2:15][CH2:16][Cl:17])=[O:19])=[S:22])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N(CCCl)CCCl
Agent: O=C(N=C=S)N(CCCl)CCCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(CCCl)CCCl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
[Di(2-chloroethyl)amino]methanoyl isothiocyanate was prepared using commercially available N,N-di(2-chloroethyl)carbamic chloride (80 mg) as a starting compound according to the description of the literature. [Di(2-chloroethyl)amino]methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:30])[C:18]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:30][C:17]1[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:19][C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a mixture of 1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.92 g, 4.13 mmol), THF (16 mL), and water (5 mL) was added LiOH.H2O (0.693 g, 16.5 mmol). The mixture was stirred for 18 h at 23° C. The solvent was evaporated, water (10 mL) was added and the mixture acidified with 1M HCl. The resulting precipitate was filtered and dried to yield the titled compound (1.73 g, 94%). MS (ESI/CI): mass calcd. for C17H10Cl2N4O4S, 436.0; m/z found, 437.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.89 (s, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.93-7.90 (m, 2H), 7.69-7.66 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([NH2:18])=[O:17])=[C:14]([OH:19])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:20].N[C:23]1[S:24][CH:25]=[CH:26][N:27]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:18][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:17])=[C:14]([OH:19])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:20]
Reactant: CN1C(C(N)=O)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Reactant: Nc1nccs1
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 46 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino-[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 36 from 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide and 2-amino-thiazole with a yield of 46% of theory; M.p.: 260°-261° C. (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10]([O:12]CC)=O)[CH:2]=1.[NH2:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1>CCO>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][N:19]1[CH2:18][CH:17]([OH:29])[CH2:16][NH:15][C:10](=[O:12])[CH2:9][O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COCc1cccnc1
Solvent: CCO
Product: O=C(COCc1cccnc1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 16.5 %

Procedure:
To a solution of Ethyl 2-(pyridin-3-ylmethoxy)acetate (100 mg, 0.51 mmol) in EtOH (0.5 ml) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (105 mg, 0.51 mmol) at 28° C. The mixture was stirred at 120° C. under microwave heating for 1 hour until the reaction was completed by TLC. After evaporation of the solvent, the residue was purified by HPLC separation to give the title compound (30 mg, yield: 16.5%) as a white solid. LCMS: 356.2 [M+H]+. 1H NMR (MeOD, 400 MHz) δ 8.53 (s, 1H), 8.50 (d, J=4.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.462 (dd, J1=4.8 Hz, J2=8.0 Hz, 1H), 7.19-7.03 (m, 4H), 4.58 (s, 2H), 4.02 (br. s, 3H), 3.72 (s, 2H), 3.42-3.36 (m, 2H), 2.93-2.83 (m, 4H), 2.62-2.61 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].CC(OC)(C)C.[OH-].[Na+].CC(CC(C)=O)C>P(=O)(O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C@@H:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9]
Reactant: COC(=O)C(C)CCCC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](C)CCCC(C)=O
Temperature: 10 °C
Reaction time: 48 h
Yield: 40.3 %

Procedure:
10.6 g (content 94.3%, 5.75 mmol) of a racemate of 2-methyl-6-oxoheptanoic acid methyl ester and 20.0 g of MTBE were suspended in 50.0 g of 0.1 M phosphoric acid buffered solution (pH 7.0). The suspension was cooled to 10° C., then, 2.0 g (moisture percentage 56%, enzymatic activity 4028 KU/Kg, reduced by dry product) of immobilized Aspergillus flavus ATCC11492 strain-derived esterase (prepared by a method described in JP-A No. 2003-70471) was added, and the mixture was stirred at 10° C. for 48 hours while maintaining pH at 7.5 to 8.0 by appropriately adding 4% NaOH aqueous solution. Thereafter, the reaction solution was filtrated using Radiolite (filtration aid, trade name: manufactured by Showa Chemical Industry Co., Ltd.), to remove the esterase. The resultant filtrate was extracted twice with 25 g and 12.5 g of MIBK, then, the resultant organic layers were combined and washed with 15% saline, to obtain a MIBK solution of optically active (S)-2-methyl-6-oxoheptanoic acid methyl ester (optical purity 98.8% ee, yield 40.3%). The optical purity was analyzed by HPLC [Chiralpak AS-H, 4.6 mm×25 cm (manufactured by Daicel Chemical Industries, Ltd.)] like in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Al+3].[Cl-].[Cl-].[Cl-].Br[CH2:16][C:17](Br)=O.[NH2:20][C:21]([NH2:23])=[S:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16]3[N:20]=[C:21]([NH2:23])[S:22][CH:17]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: NC(N)=S
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Product: Nc1nc(-c2c[nH]c3ncc(Br)cc23)cs1

Procedure:
The title compound was synthesized in 2 steps in a manner similar to that described above using 5-bromo-7-azaindole (1.0 g, 5.07 mmol), AlCl3 (1.35 g, 10.15 mmol), bromoacetylbromide (0.41 mL, 6.34 mmol) and thiourea (0.36 g, 4.72 mmol) (0.21 g, 48%, 2 steps) as a brown solid. Mass Spec.; MS 297 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 8.63(d, 1H), 8.28(d,1H), 7.82(s,1H),6.98(s,2H), 6.82(s,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[NH:8][C:7]2=[O:22].[N:23]1[CH:28]=[CH:27]N=[CH:25][C:24]=1[C:29]([OH:31])=O.[CH3:32]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O.O>[O:22]=[C:7]1[C:6]2[C:11](=[C:2]([NH:1][C:29](=[O:31])[C:24]3[CH:25]=[CH:32][CH:27]=[CH:28][N:23]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[NH:8]1
Reactant: Nc1cccc2c(=O)[nH]c(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=C(O)c1cnccn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2c(=O)[nH]c(-c3cccc(C(F)(F)F)c3)nc12)c1ccccn1
Temperature: 70 °C
Yield: 85.6 %

Procedure:
A mixture of 8-amino-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 9 (125 mg, 0.41 mmol), pyrazine-2-carboxylic acid 10 (102 mg, 0.82 mmol), HATU (342 mg, 0.90 mmo) and DIPEA (214 μl, 1.2 mmol) in DMAC (5 mL) were heated at 70° C. for 12 h then poured into H2O. The precipitate was collected by filtration, rinsed with H2O then recrystallized from EtOH to give Compound 231 (144 mg, 86% yield) as a white solid. MS (ESI) calc. for C20H12F3N5O2: 411.09. found: 412 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][CH3:17]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCBr
Product: CCCCOc1ccc2cc(Br)ccc2c1

Procedure:
2-Bromo-6-butoxynaphthalene was prepared according to the method of Example 1, part a, except using 6-bromo-2-naphthol instead of 4-hydroxyacetophenone and using 1-bromobutane instead of benzylbromide.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[OH:24])[C:9]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[O:24][CH2:32]3)[C:9]2=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C(c2cc(F)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (56%) as a colorless solid: mp 182-184° C.; 1H NMR (300 MHz, CDCl3) δ7.43-7.25 (m, 10H), 7.17-7.10 (m, 1H), 7.07-6.84 (m, 5H), 6.56-6.49 (m, 1H), 6.39-6.32 (m, 1H), 5.01 (t, J=9.0 Hz, 2H), 4.74 (t, J=9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.0, 159.3, 156.8, 156.1, 141.7, 137.5, 137.2, 131.9, 130.3, 130.2, 128.8, 128.7, 128.6, 128.4, 128.3, 128.1, 127.9, 123.8, 123.3, 116.5, 116.1, 112.4, 110.9, 110.8, 110.6, 110.2, 80.3, 58.8, 58.0; MS (ES+) m/z 444.0 (M+23).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([NH:25][CH2:26][P:27](=[O:34])([O:31]CC)[O:28]CC)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[K+].[Br-]>O>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]([NH:25][CH2:26][P:27](=[O:28])([OH:34])[OH:31])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOP(=O)(CNC(CCc1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1cc(C(CCc2ccccc2)NCP(=O)(O)O)cc(C(C)(C)C)c1O

Procedure:
Diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(3-phenylpropyl)aminomethylphosphonate (compound 22, 3.0 g, 6.1 mmol) was heated at reflux in 30 ml NHCl for 24 h. The compound was extracted with chloroform, 2.5 g were obtained. Yield =94%, mp=162°-169° C. IR (KBr) 3640 cm-1 : OH, 3400 (broad): NH, 2800 and 1600: PO-H, 1430: tert-Bu, 1200: P=O, 1000 and 940: P--OH Elemental analysis: C24H36NO4P. % Calc. C 66.49 H 8.37 N 3.23 P 7.14 % Found C 66.69 H 8.52 N 2.95 P 6.91 0.2 % H2O
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15](=[O:17])[NH2:16])[CH2:12][CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])=O)(C)(C)C.Cl.[CH3:32][N:33]1[CH2:38][CH2:37][C:36]2[N:39]=[C:40](C([O-])=O)[S:41][C:35]=2[CH2:34]1.[Li+]>O1CCOCC1>[C:15]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=3)=[O:20])[C@@H:9]([NH:8][C:6]([C:40]2[S:41][C:35]3[CH2:34][N:33]([CH3:32])[CH2:38][CH2:37][C:36]=3[N:39]=2)=[O:5])[CH2:14]1)(=[O:17])[NH2:16]
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(N)=O)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(N)=O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1

Procedure:
(1R*,2S*,4R*)-N2-(tert-Butoxycarbonyl)-4-carbamoyl-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:12][CH3:13])([O:10][CH3:11])[CH2:4][SiH:5]([O:8][CH3:9])[O:6][CH3:7].C(Cl)(Cl)(Cl)[Cl:15]>[Pd](Cl)Cl>[Cl:15][Si:5]([O:8][CH3:9])([O:6][CH3:7])[CH2:4][Si:3]([O:12][CH3:13])([O:10][CH3:11])[O:2][CH3:1]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CO[SiH](C[Si](OC)(OC)OC)OC
Agent: Cl[Pd]Cl
Product: CO[Si](Cl)(C[Si](OC)(OC)OC)OC
Reaction time: 4 h

Procedure:
A solution of 7.27 mmol (1.29 g) of palladium (II) dichloride [PdCl2 (II)] in 30 ml of carbon tetrachloride is placed in a flask, and then 0.106 moles (24 g) of 1,1,1,3,3-pentamethoxy-1,3-disilapropane (98%, Korea Institute of Science and Technology (KIST)) is slowly added thereto at 0° C. The reaction is allowed to proceed at this temperature for 4 hours. The reaction mixture is filtered through celite to obtain 3-chloro-1,1,1,3,3-pentamethoxy-1,3-disilapropane.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:14](OCC)(=[O:16])[CH3:15].C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[C:6]([NH:7][C:14](=[O:16])[CH3:15])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A 100 mL three-neck round bottom flask was charged with 3-chloro-1(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). sodium bicarbonate (1.08 g, 12.9 mmol) was added, followed by dropwise addition of acetic anhydride (0.629 g, 6.17 mmol) at <20° C. The reaction was stirred at 20° C. for 2 hours to afford a suspension, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the resulting suspension was filtered. The solid was rinsed with water (10 mL) followed by methanol (5 mL). The solid was further dried under vacuum at 20° C. to afford the desired product as a white solid (0.804 g, 66%): mp 169-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.05 (dd, J=2.8, 0.8 Hz, 1H), 8.82 (s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.20 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.54, (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 168.12, 147.46, 139.42, 135.46, 133.60, 125.47, 124.21, 122.21, 120.16, 22.62; EIMS m/z 236 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:21]([O:30][CH3:31])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=S.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:21]([O:30][CH3:31])=[CH:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: COc1cnc(-c2ccc(NC(=S)Nc3ccccc3N)cc2)nc1N1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccc(Nc3nc4ccccc4[nH]3)cc2)nc1N1CCOCC1
Yield: 65.1 %

Procedure:
A mixture of 1-(2-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea (0.3 g, 1.0 eq.) and DCC (0.18 g, 1.3 eq.) in THF (10 ml) for 9 hrs at 80-90° C. The mixture was dried in vacuo, crystallized in a EA solution, and then filtered to give a white solid (0.18 g, 68.36%), which was then dried in vacuo to give of a product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)=[CH:30][CH:29]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(-c4cccnc4)cc3)nn12

Procedure:
[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (35 mg, 29%). LCMS (m/e) 394 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.84 (s, 1H), 8.72 (s, 1H), 8.59-8.51 (m, 1H), 7.97 (d, 1H, J=7.6 Hz), 7.86 (d, 1H, J=7.6 Hz), 7.71 (d, 1H, J=7.4 Hz), 7.48 (d, 2H, J=7.7 Hz), 7.44 (d, 1H, J=7.9 Hz), 7.39-7.31 (m, 1H), 7.19-7.11 (m, 1H), 7.11-7.02 (m, 2H), 6.96-6.85 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:14]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Ic1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1cc(I)cn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a stirred solution of 4-iodopyrazole (10.30 g, 53.1 mmol) in toluene (50 mL) at r.t. was added triethylamine (8.10 mL, 58.1 mmol), followed by benzoyl chloride (8.20 g, 58.3 mmol). The reaction mixture was then heated to 100° C. and stirred for 4 h. The solid was filtered and washed with toluene (50 mL). The organic filtrate was diluted with EtOAc (100 mL), washed with water (3×50 ml), then brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Recrystallisation from hexanes gave the title compound (13.80 g, 87%) as a white solid. δH (DMSO-d6) 8.77 (1H, s), 8.05 (1H, s), 8.02-7.95 (2H, m), 7.74-7.67 (1H, m), 7.61-7.53 (2H, m).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][O:9][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>CO>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 62.9 %

Procedure:
To a solution of [(R)-1,2-bis-(tert-butyl-dimethyl-silanyloxy)-ethyl]-benzene (625 mg, 1.7 mmol) in methanol (3 mL) was slowly added ferric chloride III) (276 mg, 1.7 mmol) with stirring at room temperature. When the reaction was monitored to be completed about 25 min after the addition, an aqueous saturated sodium bicarbonate solution was added. The solution was extracted with ethyl ether and the organic layer thus formed was separated. To the organic layer was added sodium sulfate, followed by stirring for 5 min and filtering. The filtrate was concentrated and dried in a vacuum, and the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 16/1) and dried in a vacuum to afford 270 mg of the compound as a colorless oil (yield 63%).