Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClC/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (E)-(3-chloro-1-propenyl)benzene (0.763 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from diethyl etherhexane to provide 0.8 g of (E)-alpha-oxo-4-[(3-phenyl-2-propenyl)oxy]benzeneacetic acid methyl ester 0.1 molar hydrate, mp 80°-82° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[OH:15])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:24][CH:25]([F:27])Cl>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH:25]([F:27])[F:24])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)Cl
Reactant: O=Cc1ccc(O)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1

Procedure:
A solution of 3-cyclopentyloxy-4-hydroxybenzaldehyde (5.1 g) in dimethylformamide (50 mL) is treated with potassium carbonate (4.83 g) and potassium iodide (1.2 g) and the solution is heated at 70°-75° C. whilst difluorochloromethane is bubbled though it at a slow rate, during 5 hours. Water (100 mL) is added and the mixture is extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and concentrated to give a brown oil. The oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give 3-cyclopentyloxy-4-difluoromethoxybenzaldehyde, in the form of a pale yellow oil (4.7 g). [NMR (CDCl3): 9.92(s,1H);7.5-7.24(m,3H); 6.34°-5.96(t, 1H); 4.9(m, 1H);2.0-1.6(m,8H)].
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15](I)[C:16]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)C.O>O.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>[CH2:1]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:16]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2c1C1CC2CN(Cc2ccccc2)C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc(CN2CC3CC(C2)c2c(-c4ccccc4)cccc23)cc1
Temperature: 90 °C
Yield: 55.3 %

Procedure:
(For a discussion, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.) 10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (375.3 mg, 1.0 mmol), potassium acetate (785 mg, 8.0 mmol) and phenyl boronic acid (183 mg, 1.5 mmol) were combined in 10/1 ethanol/H2O (5 mL). The mixture was degassed (3 vacuum/N2 cycles), treated with tetrakis(triphenylphosphine)palladium(0) (57.5 mg, 0.05 mmol) and warmed to 90° C. for 18 h. The reaction was cooled, diluted with H2O and extracted with Et2O (3×50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and concentrated to provide an oil (180 mg, 55%). (TLC 4% ethyl acetate/hexanes Rf 0.18). GCMS m/e 325 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N[CH2:33][CH2:34][SH:35].C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]4[S:35][CH2:34][CH2:33][N:28]=4)[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCS
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C2=NCCS2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile (100 mg, 0.24 mmol) in methanol (20 mL) was added 2-aminoethanethiol hydrochloride (41 mg, 0.36 mmol) and triethylamine (0.1 mL, excess). The reaction mixture was heated to reflux for 14 h and cooled to room temperature. After concentration, the residue was purified by prep. HPLC to yield the title compound (76 mg, 66%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.10 (1H, s), 7.71 (1H, s), 7.66 (1H, s), 7.25–7.53 (4H, m), 6.33 (1H, d, J=7.6 Hz), 5.01 (1H, dd, J=4.2, 7.0 Hz), 4.58 (2H, t, J=8.6 Hz), 3.91 (2H, t, J=8.6 Hz), 3.73 (1H, dd, J=4.2, 13.7 Hz), 3.63 (1H, dd, J=7.0, 13.7 Hz), 2.64 (3H, s). LCMS (M+H)+ m/z 480 (t=1.70 min.).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[O:16][C:17]([C:21]2[CH2:25][C:24]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=3)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=2)=[CH:18][C:19]=1[CH3:20])=O>C(OCC)C.C(OCC)(=O)C>[CH3:20][C:19]1[CH:18]=[C:17]([C:21]2[CH2:25][C:24]([C:30]3[CH:31]=[C:32]([Cl:38])[C:33]([Cl:37])=[C:34]([Cl:36])[CH:35]=3)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=2)[O:16][C:15]=1[CH2:13][OH:12]
Reactant: COC(=O)c1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1CO
Reaction time: 0.33 h
Yield: 103.1 %

Procedure:
Diisobutylaluminium hydride (DIBAL-H, 12.1 ml, 1M in Toluene) is added to a solution of 3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-carboxylic acid methyl ester (1.84 g) in diethyl ether (30 ml) under nitrogen at −5° C. After 20 minutes at −5° C., the reaction mixture is diluted with ethyl acetate and is quenched with a saturated solution of NaHCO3. The resulted fine white precipitate is filtered and the aqueous phase is separated. The organic phase is washed with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield {3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-yl}-methanol (1.78 g) as a light yellow foam.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH:21]([NH2:23])[CH3:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:23][CH:21]([CH3:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(CC(C)N)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cccc(CC(C)NS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of p-toluenesulfonyl chloride (28.0 gm., 0.15 M) in benzene (100 ml.) was added dropwise to a solution of 2-(3-methoxyphenyl)-1-methylethylamine (23 gm., 0.139 M) and triethylamine (13 gm., 0.15 M) in benzene (200 ml.) during 30 minutes. The reaction was stirred at room temperature for 4 hours. The precipitated triethylamine hydrochloride was filtered off and the benzene solution was washed with hydrochloric acid (3N), water and saturated brine. The benzene solution was dried over magnesium sulfate. Evaporation of the solvent afforded N-toluene-p-sulfonyl-2-(3-methoxyphenyl)-1-methylethylamine as an oil Wt=42 gm.
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([O:50][CH2:51][CH2:52][CH2:53][CH2:54]O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.CCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:54][CH2:53][CH2:52][CH2:51][O:50][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:18][CH:17]=1
Reactant: OCCCCOCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(OCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of 14.36 g (82.5 mmol) of diethyl-azo-dicarboxylate in 50 ml of tetrahydrofuran was added within 30 minutes to a solution of 11.4 g (75.0 mmol) 4-hydroxy-benzoic acid methyl ester, 20.65 g (78.8 mmol) of triphenylphosphin and 13.5 g (75.0 mmol) of 4-benzyloxy-1-butanol dissolved in 100 ml of tetrahydrofuran. The reaction mixture was then stirred for 1 hour at room temperature, 1 g of triphenylphosphin was added and stirring continued for 1 hour at room temperature and for 30 minutes at reflux. The reaction mixture was then diluted with 200 ml of hexane and filtered. The filtrate was poured into 200 ml of a saturated potassium carbonate solution and extracted 3 times with 200 ml of ethylacetate. The combined ethylacetate phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 98:2 v/v mixture of dichloromethane and ether as the eluent giving 21.8 g (92.4%) 4-(4-benzyloxy-butoxy)-benzoic acid methyl ester as colorless viscous oil, MS: 314 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>C(O)(C)C>[N:13]1([C:4]2[N:3]=[C:2]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1NCc1ccc(F)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (607 mg, 2.0 mmol) in isopropanol (5 mL) were added sodium carbonate (424 mg, 4 mmol) and 4-fluorobenzylamine (313 mg, 4 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature and water was added. The precipitated crystals were collected by filtration, washed several times with cold water and cold ether and dried to give the title compound (637 mg, 81%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([NH:25][C:26](=[O:35])[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[C:15]([CH3:37])([CH3:36])[C:14]2=[O:38])=O)=CC=1)([O-])=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([NH:46][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[C:15]([CH3:36])([CH3:37])[C:14]1=[O:38])=[O:10])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C3(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)NCc2ccccc2)C(=O)C3(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-(4-methoxy-benzoylamino)-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-nitro-phenyl ester (54 mg) in CH2Cl2 (10 ml) is added benzyl amine (44 μl) at RT. The reaction mixture is stirred at RT for 20 h. After an aqueous work-up and concentration in vacuo, the residue is dissolved in acetic acid (3 ml) and iron (60 mg; powder) is added. The mixture is stirred in a microwave apparatus at 150° C. for 900 s. After filtration and evaporation of the solvent the crude material is purified by preparative RP-HPLC.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8](=[N:16][OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:16][O:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.45 g., 80% w/w suspension in mineral oil) was added gradually to a stirred solution of 4,4'-dichlorobenzophenone oxime (4.0 g.) in dry dimethylformamide (20 ml.) keeping the temperature below 30° C. After 30 minutes, ethyl bromoacetate (1.7 ml.) was added to the stirred solution and the temperature was allowed to rise to 30° C. After 16 hours stirring at ambient temperature the mixture was poured into water (100 ml.) and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl di-(4-chlorophenyl)methyleneamino-oxyacetate, as an oil (3.8 g.), essentially pure and having a characteristic ester absorption at 1740-1760 cm-1 in the infra-red spectrum.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CO.[BH4-].[Na+]>O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C(C)O)cc(Cl)c(F)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone (3.8 g, 14 mmol) in methanol (30 mL, 800 mmol) was added sodium tetrahydroborate (0.83 g, 22 mmol) at 0° C. The mix was stirred at 0° C. for 1 hour. Water (10 mL) was added to the mixture. The mixture was concentrated to about 30 mL. The residue was diluted with EtOAc, washed with water and brine, dried over magnesium sulfate and evaporated to yield the desired compound (3.9 g, 100%). LCMS calculated for C9H8BrClFO (M−OH)+: m/z=264.9, 266.9. found: 265.0, 267.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2Cl)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:22]>O1CCCC1>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:21]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:19]([Cl:18])[CH:20]=1)=[O:6]
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: COCNC(=O)c1ccc2ncnc(Cl)c2c1
Solvent: C1CCOC1
Product: COCNC(=O)c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
4-Chloroquinazoline-6-carboxylic acid methoxymethylamide (XIV-1, 5.78 g) was dissolved in tetrahydrofuran (100 ml), and 5.39 g of 3-chloro-4-(pyridin-2-ylmethoxy)aniline was added, followed by stirring at 60° C. for 1 hour. A precipitate was filtered, and washed with tetrahydrofuran to obtain 4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-quinazoline-6-carboxylic acid methoxymethylamide (XI-2, 7.87 g) as a white solid. The filtrate was allowed to stand at room temperature, and the resulting precipitate was collected by filtration, to newly obtain 2.21 g of XI-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)c(Cl)c1
Yield: 58 %

Procedure:
The title compound is prepared in 58% yield (940 mg, clear colorless oil) from 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].CS([C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])=O>>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:20]2[NH:21][CH:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Agent: Cl
Product: N=C(N)Nc1nc(CCCCNc2[nH]ccc2[N+](=O)[O-])cs1

Procedure:
The title compound is prepared from 4-(2-guanidino-4-thiazolyl)butylamine dihydrochloride and 2-methylsulphinyl-3-nitropyrrole by a process analogous to that described in Example 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([O:14][CH2:13][CH2:12][CH:10]2[CH2:9][CH:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:11]2)=[CH:37][CH:36]=1
Reactant: OCCC1CC(OC2CCCCO2)C1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCC2CC(OC3CCCCO3)C2)cc1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
2-[3-(Tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethanol (1.08 g, 5.39 mmol) was dissolved in tetrahydrofuran (20 mL) and was cooled in an ice bath. Triphenylphosphine (2.12 g, 8.09 mmol) and 4-bromo-phenol (1.12 g, 6.47 mmol) were added and the reaction was stirred until dissolved. Diethylazodicarboxylate (1.45 g, 8.09 mmol) was added dropwise to the reaction and the reaction was then warmed to room temperature and stirred for 48 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a clear oil. Purification on silica gel with heptane-ethyl acetate (15% ethyl acetate) gave 2-({3-[2-(4-bromophenoxy)ethyl]cyclobutyl}oxy)tetrahydro-2H-pyran (622 mg, 32.4%) as a clear oil. Partial 1H NMR indicated a −4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.08 (m, 0.80H), 4.38 (m, 0.20H), 6.74 (d, J=8.98, 2H), 7.34 (d, J=9.18, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].[CH2:12](O)CCO.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)C>[O:10]1[CH2:11][CH2:12][CH2:1][O:2][CH:3]1[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: COC(CNC(=O)CCl)OC
Reactant: OCCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Product: O=C(CCl)NCC1OCCCO1
Temperature: 120 °C

Procedure:
N-(2,2-Dimethoxyethyl)-2-chloroacetamide (18.2 grams; 0.1 mole), 1,3-propanediol (7.61 grams; 0.1 mole) and 10 drops of a solution of 1 gram of toluenesulfonic acid in 100 ml of diethyl ether were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distillation head and condenser. The mixture was stirred and heated at about 120° C. for a period of about 1 hour while byproduct methanol was distilled off. The mixture was cooled to room temperature, sodium carbonate (2 grams) was added, and the slurry stirred for a period of about 1 hour. The slurry was filtered and the filtrate was stripped of solvent by mild warming under reduced pressure to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2-chloracetamide as a residue.
Reaction SMILES: [NH3:1].CO.[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([O:25]CC)=O)=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1>C1COCC1>[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([NH2:1])=[O:25])=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1ccc2ncccc2c1
Solvent: C1CCOC1
Solvent: CO
Product: CSc1nnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A 2 M ammonia-methanol solution (3 ml) was added to a solution of ethyl 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (150 mg) in THF (0.5 ml), and then the reaction solution was stirred in a microwave reactor at 130° C. for 30 minutes. The precipitate was filtrated to obtain 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxamide as a crude white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:8]=1.[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[F:29][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:37]([C:36]2[CH:40]=[CH:41][CH:42]=[C:34]([C:32]([O:31][CH3:30])=[O:33])[CH:35]=2)=[O:38])=[CH:8][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH:10]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.200 g, 0.5 mmol) in CH2Cl2 (5 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.0901 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol), and Et3N (0.0703 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 h and then quenched with H2O. The organic layer was separated, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.26 g (93%). LC-MS m/z 562 (M+H)+.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4]2[CH:12]=[N:13][NH:14][C:3]1=2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12
Reactant: O=c1c2c([nH]c3cn[nH]c13)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3cn[nH]c13)CCCC2
Yield: 88 %

Procedure:
4,5,6,7,8,9-Hexahydro-9-oxo-1H-pyrazolo[4,3-b]quinoline (5.0 g, 0.026 mole) was treated with phosphoryl chloride (40 ml) and the mixture heated under reflux for 30 minutes. The excess reagent was evaporated off and the residue treated with water (30 ml) and then made basic by the addition of sodium carbonate solution. The solid was filtered off, washed with water, dried and recrystallised from ethyl acetate to give the title compound as a yellow solid (4.85 g, 88%), m.p. 190°-193° C. Found: C, 57.85; H, 4.95; N, 20.00; Cl, 16.95% C10H10ClN3 requires C, 57.85; H, 4.85; N, 20.25; Cl, 17.20%